BRAF encodes a RAF-family serine/threonine protein kinase (EC 2.7.11.1) that is the canonical mitogen-activated protein kinase kinase kinase (MAP3K) of the RAS-RAF-MEK-ERK signaling cascade. In quiescent cells BRAF is autoinhibited by an intramolecular interaction between its N-terminal regulatory region and the C-terminal kinase domain. Mitogenic stimulation generates GTP-loaded RAS, which binds the BRAF RAS-binding domain (RBD), relieves autoinhibition, and recruits BRAF to the plasma membrane. Activation requires side-to-side dimerization β BRAF homodimers and, most potently, BRAF-RAF1 (CRAF) heterodimers β stabilized by 14-3-3 proteins and the HSP90/CDC37 chaperone system. Activated BRAF phosphorylates and activates MAP2K1/MAP2K2 (MEK1/MEK2), the committed step that propagates mitogenic signaling through ERK1/ERK2 to control proliferation, differentiation and survival. BRAF localizes to the cytoplasm/cytosol and to the plasma membrane in its active RAS-bound state. It is a major oncogenic driver: the V600E activating mutation, which renders the kinase constitutively active as a RAS-independent monomer, is recurrent in melanoma, papillary thyroid carcinoma, colorectal cancer, hairy-cell leukemia and other tumors, and germline BRAF mutations cause cardiofaciocutaneous syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for cytoplasmic localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases). Consistent with direct evidence on cytoplasm in this file (PMID:19710016, EXP) and the 59 Reactome TAS cytosol rows already ACCEPTed in PR #440.
Reason: PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports canonical BRAF cytoplasmic localization, which is also directly demonstrated experimentally (PMID:19710016) and via Reactome TAS evidence on the more specific child term GO:0005829 cytosol. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for separate per-row consideration in a later batch.
|
|
GO:0005886
plasma membrane
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for plasma membrane localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases). BRAF is recruited to the PM by RAS-GTP upon receptor activation. Consistent with direct evidence on PM in this file (PMID:19710016, EXP) and the 13 Reactome TAS PM rows already ACCEPTed in PR #440.
Reason: PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports canonical BRAF plasma membrane localization (the RAS-GTP-recruited activated state), which is also directly demonstrated experimentally (PMID:19710016) and via Reactome TAS evidence in this file. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for separate per-row consideration in a later batch.
|
|
GO:0000165
MAPK cascade
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for canonical BRAF participation in the MAPK cascade, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases). BRAF is the canonical RAF kinase phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade; consistent with the IDA evidence on the same term in this file (PMID:18567582, PMID:29433126).
Reason: PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports BRAF participation in the canonical MAPK cascade, which is also directly demonstrated experimentally on the same term in this file (PMID:18567582, PMID:29433126). Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for separate per-row consideration in a later batch.
|
|
GO:0004709
MAP kinase kinase kinase activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for MAP kinase kinase kinase (MAP3K) activity, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases). This is BRAF's canonical molecular function β phosphorylating MEK1/MEK2 (MAP2Ks) in the RAS-RAF-MEK-ERK cascade. Consistent with IDA/EXP evidence on related kinase terms in this file (PMID:18567582, PMID:29433126, PMID:21441910).
Reason: PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports BRAF as a canonical MAP3K. This is the gene's defining molecular function; extensive direct experimental evidence on the closely-related kinase terms (GO:0004674 protein serine/threonine kinase activity, GO:0106310 protein serine kinase activity) is already present in this file. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for separate per-row consideration in a later batch.
Supporting Evidence:
file:human/BRAF/BRAF-deep-research-falcon.md
BRAF is a RAF-family kinase whose primary role in the ERK pathway is to act as a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates MEK1/MEK2.
|
|
GO:0005829
cytosol
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for cytosolic localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases). BRAF in the autoinhibited 14-3-3-bound resting state is cytosolic; consistent with the 59 Reactome TAS cytosol rows already ACCEPTed in PR #440 and direct evidence on cytoplasm/PM in this file (PMID:19710016).
Reason: PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports canonical BRAF cytosolic localization (the autoinhibited 14-3-3/Hsp90/CDC37-bound resting state), which is also directly demonstrated experimentally and via Reactome TAS evidence on the same term in this file. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for separate per-row consideration in a later batch.
|
|
GO:0005739
mitochondrion
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: IBA annotation for mitochondrial localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases). BRAF is not listed under mitochondrion in the UniProt subcellular location (only Nucleus, Cytoplasm, Cell membrane); mitochondrial localization is best characterized for the RAF-family paralog CRAF/RAF-1 (regulating BAD phosphorylation), so this is a minor context-specific RAF-family role rather than a core BRAF function in the canonical RAS-RAF-MEK-ERK cascade.
Reason: Mitochondrial localization is a minor, context-specific role best described for the RAF-family paralog CRAF/RAF-1, not a core BRAF function; the dominant BRAF localization is cytosolic/plasma-membrane where the canonical RAS-RAF-MEK-ERK cascade operates (already captured via direct experimental and Reactome TAS evidence in this file). This resolves the 6th canonical IBA row held back from PR #448 for separate per-row consideration, and is consistent with the parallel IEA Ensembl Compara mitochondrion row (GO_REF:0000107, line 591) already resolved to KEEP_AS_NON_CORE with the explicit note that the IBA row should resolve the same way.
|
|
GO:0004672
protein kinase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: IEA annotation for protein kinase activity from GO_REF:0000120 (combined ECO/GO mapping). BRAF is a canonical Ser/Thr protein kinase phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade β directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and supported by IBA on the more specific child term GO:0004709 MAP3K activity (PR #448).
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0004674
protein serine/threonine kinase activity
|
IEA
GO_REF:0000003 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000003 (UniProt keyword KW-0723 Serine/threonine-protein kinase). BRAF is a canonical Ser/Thr kinase β directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and supported by IBA on the more specific child term GO:0004709 MAP3K activity (PR #448).
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0005524
ATP binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000002 (InterPro2GO) for ATP binding. BRAF binds ATP via the kinase-domain glycine-rich loop and DFG motif β a defining feature of the protein kinase fold; directly supported by IDA/EXP evidence on kinase activity terms in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP).
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: IEA annotation for nuclear localization from GO_REF:0000044. UniProt lists Nucleus for BRAF only by similarity (ECO:0000250), whereas Cytoplasm and Cell membrane have direct experimental support (PMID:19710016). Nuclear localization is reported but tissue/context-specific and is not where BRAF's core RAS-RAF-MEK-ERK kinase function operates.
Reason: Nuclear localization is recognized in UniProt only by similarity (ECO:0000250) and is tissue/context-specific rather than the site of BRAF's defining function; the core RAS-RAF-MEK-ERK kinase activity operates at the cytoplasm/plasma membrane (captured via direct experimental evidence PMID:19710016 EXP and Reactome TAS rows in this file). Kept rather than removed because UniProt records the nuclear localization, but flagged non-core. This resolves the GO:0005634 nucleus IEA row explicitly held back from the canonical IEA consolidation in PR #456 for separate per-row consideration.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000120 for cytoplasmic localization. Already ACCEPTed via IBA propagation in PR #448 and consistent with direct experimental evidence in this file (PMID:19710016 EXP) β BRAF in the autoinhibited 14-3-3-bound resting state is cytosolic prior to RAS-GTP-mediated PM recruitment.
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000120 for plasma membrane localization. Already ACCEPTed via IBA propagation in PR #448 and on 13 Reactome TAS rows in PR #440. Directly demonstrated experimentally in this file (PMID:19710016 EXP) β BRAF is recruited to the PM by RAS-GTP upon receptor activation.
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0007165
signal transduction
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000002 (InterPro2GO) for signal transduction. BRAF is the canonical RAF kinase in the RAS-RAF-MEK-ERK signaling cascade β directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:29433126 IDA/IMP) and supported by IBA on the more specific child term GO:0000165 MAPK cascade (PR #448).
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0043066
negative regulation of apoptotic process
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000117 (ARBA propagation). BRAF activates MEK/ERK signaling, leading to phosphorylation of pro-apoptotic factors (e.g. BAD on Ser112/Ser155 by RSK downstream of ERK; BIM via ERK-mediated proteasomal degradation), and is well-established as anti-apoptotic in canonical RAS-RAF-MEK-ERK signaling. Consistent with the canonical RAF survival role and the Reactome RAS-MAPK signaling rows already ACCEPTed in PR #440.
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0098794
postsynapse
|
IEA
GO_REF:0000108 |
KEEP AS NON CORE |
Summary: IEA annotation from GO_REF:0000108 (logical-inference-based IEA via inter-ontology links; the postsynapse term is reachable via SynGO axioms). BRAF is expressed in neurons and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so a postsynaptic localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific localization rather than a constitutive cellular function, and is not a core BRAF function β the canonical RAS-RAF-MEK-ERK signaling activity at the cytoplasm/cytosol/plasma membrane is what defines BRAF.
Reason: Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization (cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016 EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission).
|
|
GO:0106310
protein serine kinase activity
|
IEA
GO_REF:0000116 |
ACCEPT |
Summary: IEA annotation from GO_REF:0000116 for protein serine kinase activity β the most specific MF child of GO:0004674. BRAF phosphorylates MEK1/MEK2 on serine residues β directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP).
Reason: IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM, signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.
|
|
GO:0005515
protein binding
|
IPI
PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:16810323 FGF-2 protects small cell lung cancer cells from apoptosis t... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:16888650 Glucocorticoids cause rapid dissociation of a T-cell-recepto... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:17380122 Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:17563371 IQGAP1 modulates activation of B-Raf. |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:17979178 A novel tandem affinity purification strategy for the effici... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:20130576 RAF inhibitors prime wild-type RAF to activate the MAPK path... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:20141835 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
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|
GO:0005515
protein binding
|
IPI
PMID:21441910 A Raf-induced allosteric transition of KSR stimulates phosph... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:21478863 ERK and PDE4 cooperate to induce RAF isoform switching in me... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:21625473 A novel requirement for Janus kinases as mediators of drug r... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:22169110 Nilotinib and MEK inhibitors induce synthetic lethality thro... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:22510884 Distinct requirement for an intact dimer interface in wild-t... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:23153539 Relief of profound feedback inhibition of mitogenic signalin... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:23680146 RAF inhibitors activate the MAPK pathway by relieving inhibi... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:23934108 Mechanism of MEK inhibition determines efficacy in mutant KR... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:24441586 Integrated RAS signaling defined by parallel NMR detection o... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:24746704 Disruption of CRAF-mediated MEK activation is required for e... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:25155755 Structure of the BRAF-MEK complex reveals a kinase activity ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:25241761 Using an in situ proximity ligation assay to systematically ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:25437913 Crystal structure of a BRAF kinase domain monomer explains b... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:25600339 Tunable-combinatorial mechanisms of acquired resistance limi... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:26165597 The RAS-Binding Domain of Human BRAF Protein Serine/Threonin... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:26466569 RAF inhibitors that evade paradoxical MAPK pathway activatio... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:26496610 A human interactome in three quantitative dimensions organiz... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:28514442 Architecture of the human interactome defines protein commun... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:30194290 Interrogating the protein interactomes of RAS isoforms ident... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:35839996 A Proteomic Approach Identifies Isoform-Specific and Nucleot... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:36241744 HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:37045861 Interactome dynamics of RAF1-BRAF kinase monomers and dimers... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:16858395 The amino-terminal B-Raf-specific region mediates calcium-de... |
ACCEPT |
Summary: IPI annotation supporting BRAF homodimerization (and hetero-dimerization with CRAF), demonstrated experimentally as Ca2+-dependent and mediated by the N-terminal BRAF-specific region (Terai & Matsuda 2006, EMBO J). BRAF homodimerization is a canonical and required step in RAF kinase activation in the RAS-RAF-MEK-ERK cascade.
Reason: BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical and required step in RAF activation. The GO:0042802 'identical protein binding' annotation is biologically informative for BRAF β more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 β and is supported by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913), mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395, PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704 is held back for separate per-row consideration (that paper's primary focus is BRAF V600E heterotypic neoPPI with KEAP1 rather than BRAF homodimerization).
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GO:0042802
identical protein binding
|
IPI
PMID:19727074 A dimerization-dependent mechanism drives RAF catalytic acti... |
ACCEPT |
Summary: IPI annotation supporting BRAF homodimerization, derived from the canonical Rajakulendran et al. 2009 Nature paper establishing that a side-by-side RAF kinase-domain dimer is required for catalytic activation. This paper defined the dimer interface (the alphaC-out conformation and arginine-mediated contacts) that has become the textbook model for RAF activation in the RAS-RAF-MEK-ERK cascade.
Reason: BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical and required step in RAF activation. The GO:0042802 'identical protein binding' annotation is biologically informative for BRAF β more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 β and is supported by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913), mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395, PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704 is held back for separate per-row consideration (that paper's primary focus is BRAF V600E heterotypic neoPPI with KEAP1 rather than BRAF homodimerization).
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|
GO:0042802
identical protein binding
|
IPI
PMID:22169110 Nilotinib and MEK inhibitors induce synthetic lethality thro... |
ACCEPT |
Summary: IPI annotation supporting BRAF homodimerization, derived from Packer et al. 2011 Cancer Cell on paradoxical RAF activation in nilotinib-resistant CML. The mechanism documented in this paper β kinase-inhibitor-induced trans-activation of MAPK signaling via RAF dimer formation β directly depends on BRAF self-association at the dimer interface.
Reason: BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical and required step in RAF activation. The GO:0042802 'identical protein binding' annotation is biologically informative for BRAF β more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 β and is supported by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913), mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395, PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704 is held back for separate per-row consideration (that paper's primary focus is BRAF V600E heterotypic neoPPI with KEAP1 rather than BRAF homodimerization).
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|
GO:0042802
identical protein binding
|
IPI
PMID:22510884 Distinct requirement for an intact dimer interface in wild-t... |
ACCEPT |
Summary: IPI annotation supporting BRAF homodimerization, derived from RΓΆring et al. 2012 EMBO J. Direct mutational dissection showing that an intact BRAF kinase-domain dimer interface (the same side-by-side interface identified in PMID:19727074) is required for WT BRAF MAPK signaling, and that the kinase-dead/V600E paradoxical activation phenotype also depends on dimer formation. Strongest single piece of evidence in this set that the BRAF homodimer is a load-bearing functional unit rather than an incidental interaction.
Reason: BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical and required step in RAF activation. The GO:0042802 'identical protein binding' annotation is biologically informative for BRAF β more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 β and is supported by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913), mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395, PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704 is held back for separate per-row consideration (that paper's primary focus is BRAF V600E heterotypic neoPPI with KEAP1 rather than BRAF homodimerization).
|
|
GO:0042802
identical protein binding
|
IPI
PMID:25155755 Structure of the BRAF-MEK complex reveals a kinase activity ... |
ACCEPT |
Summary: IPI annotation supporting BRAF homodimerization, derived from Haling et al. 2014 Cancer Cell β the X-ray crystal structure of the BRAF-MEK complex, in which BRAF is captured as a side-by-side homodimer with MEK bound to each protomer. Directly visualizes the BRAF kinase-domain homodimer interface in a productive signaling complex.
Reason: BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical and required step in RAF activation. The GO:0042802 'identical protein binding' annotation is biologically informative for BRAF β more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 β and is supported by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913), mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395, PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704 is held back for separate per-row consideration (that paper's primary focus is BRAF V600E heterotypic neoPPI with KEAP1 rather than BRAF homodimerization).
|
|
GO:0042802
identical protein binding
|
IPI
PMID:25437913 Crystal structure of a BRAF kinase domain monomer explains b... |
ACCEPT |
Summary: IPI annotation supporting BRAF homodimerization, derived from Thevakumaran et al. 2015 Nat Struct Mol Biol. Although the title emphasizes a BRAF kinase-domain monomer structure, the paper's mechanistic conclusion is that BRAF activation requires the monomer-to-side-by-side-dimer transition, and the asymmetric unit captures inactive-state contacts directly informative for dimer-based allosteric regulation. Together with PMID:19727074 and PMID:25155755 this represents the structural literature establishing the BRAF dimer interface.
Reason: BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical and required step in RAF activation. The GO:0042802 'identical protein binding' annotation is biologically informative for BRAF β more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 β and is supported by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913), mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395, PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704 is held back for separate per-row consideration (that paper's primary focus is BRAF V600E heterotypic neoPPI with KEAP1 rather than BRAF homodimerization).
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|
GO:0042802
identical protein binding
|
IPI
PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... |
MARK AS OVER ANNOTATED |
Summary: IPI annotation for GO:0042802 identical protein binding, derived from Mo et al. 2022 Cell (PMID:35512704 β systematic discovery of mutation-directed neo-protein-protein interactions in cancer). The BRAF-specific finding in this high-throughput BRET screen is the BRAF V600E/KEAP1 neoPPI: a mutant-allele-specific heterotypic interaction between BRAF V600E and KEAP1 (a different protein) that rewires a BRAF V600E/KEAP1/NRF2 redox-signaling axis. The paper does not demonstrate BRAF self-association / homodimerization.
Reason: BRAF homodimerization is a genuine, canonical core function and GO:0042802 identical protein binding is already ACCEPTed on the five dimerization-focused structural/biochemical rows in this file (PMID:19727074, PMID:25155755, PMID:25437913, PMID:22510884, plus PMID:16858395/PMID:22169110). However, PMID:35512704 does not support identical protein binding for BRAF: its BRAF finding is a V600E-specific heterotypic neoPPI with KEAP1, not BRAF self-dimerization. This reference-derived GO:0042802 row is therefore an over-annotation β the term is correct for BRAF but this particular evidence does not support it, and the homodimer biology is already fully captured by the ACCEPTed structural rows. Held back from the dimerization batch for this per-row consideration.
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GO:0005739
mitochondrion
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF mitochondrial localization has been reported (e.g. RAF-1/CRAF mitochondrial pool affecting BAD phosphorylation), and an IBA mitochondrion row also propagates from PANTHER PTHR44329, suggesting some RAF-family members localize to mitochondria. However, the dominant BRAF localization is cytosolic/plasma-membrane and the mitochondrial role is not a core BRAF function in the canonical RAS-RAF-MEK-ERK cascade.
Reason: Mitochondrial localization is a minor context-specific role for some RAF-family members (best described for CRAF/RAF-1) rather than a core BRAF function. The dominant BRAF localization is cytosolic/plasma-membrane and the canonical RAS-RAF-MEK-ERK cascade is already captured via direct experimental evidence in this file (PMID:19710016 EXP, PMID:18567582, PMID:21441910) and via Reactome TAS rows (PR #440). The parallel IBA mitochondrion row (GO_REF:0000033, line 61) remains PENDING for separate per-row review; keeping the IEA Ensembl Compara row as KEEP_AS_NON_CORE here is consistent with how the IBA row is likely to resolve.
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|
GO:0043005
neuron projection
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so neuron projection localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific localization rather than a constitutive cellular function, and is not a core BRAF function β the canonical RAS-RAF-MEK-ERK signaling activity at cytoplasm/cytosol/plasma membrane is what defines BRAF.
Reason: Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization (cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016 EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission).
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|
GO:0044297
cell body
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so neuronal cell body localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific localization rather than a constitutive cellular function, and is not a core BRAF function β the canonical RAS-RAF-MEK-ERK signaling activity at cytoplasm/cytosol/plasma membrane is what defines BRAF.
Reason: Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization (cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016 EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission).
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|
GO:0098978
glutamatergic synapse
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so glutamatergic synapse localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific localization rather than a constitutive cellular function, and is not a core BRAF function.
Reason: Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization (cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016 EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission).
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|
GO:0099170
postsynaptic modulation of chemical synaptic transmission
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so a role in postsynaptic modulation of chemical synaptic transmission in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific biological process rather than a constitutive function, and is not a core BRAF function β the canonical RAS-RAF-MEK-ERK signaling cascade is what defines BRAF.
Reason: Tissue/cell-type-specific neuronal/synaptic biology rather than a core BRAF function. Canonical BRAF activity (MAPK cascade, MAP3K activity, S/T kinase activity) is already captured via direct experimental evidence in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC/BP rows held back from earlier batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission).
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GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: IDA annotation for cytosolic localization from the Human Protein Atlas antibody-based subcellular localization pipeline (GO_REF:0000052). BRAF in the autoinhibited 14-3-3/Hsp90/CDC37-bound resting state is cytosolic, prior to RAS-GTP-mediated PM recruitment. Already extensively supported in this file via the 59 Reactome TAS cytosol rows ACCEPTed in PR #440 and the IBA propagation row ACCEPTed in PR #448.
Reason: Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.
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|
GO:0005886
plasma membrane
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: IDA annotation for plasma membrane localization from the Human Protein Atlas antibody-based subcellular localization pipeline (GO_REF:0000052). BRAF is recruited to the PM by RAS-GTP upon receptor activation, where it dimerizes and phosphorylates MEK in the canonical RAS-RAF-MEK-ERK cascade. Already extensively supported in this file via the 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440 and the IBA propagation row ACCEPTed in PR #448.
Reason: Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.
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|
GO:0005737
cytoplasm
|
EXP
PMID:19710016 Diacylglycerol kinase eta augments C-Raf activity and B-Raf/... |
ACCEPT |
Summary: EXP annotation for cytoplasmic localization from PMID:19710016 (Yasuda et al. 2009, J Biol Chem), which characterized BRAF/CRAF/DGKeta colocalization and heterodimerization in HeLa cells using immunofluorescence and biochemical fractionation. Already supported via IBA propagation (PR #448), IEA propagation (PR #456), and the 59 Reactome TAS cytosol rows on the more specific child term GO:0005829 (PR #440).
Reason: Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.
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|
GO:0005886
plasma membrane
|
EXP
PMID:19710016 Diacylglycerol kinase eta augments C-Raf activity and B-Raf/... |
ACCEPT |
Summary: EXP annotation for plasma membrane localization from PMID:19710016 (Yasuda et al. 2009, J Biol Chem), which demonstrated BRAF/CRAF/DGKeta colocalization at the plasma membrane upon EGF stimulation in HeLa cells, supporting BRAF recruitment to the PM in the activated RAS-RAF-MEK-ERK signaling state. Already supported via IBA propagation (PR #448), IEA propagation (PR #456), and the 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440.
Reason: Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.
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|
GO:0106310
protein serine kinase activity
|
EXP
PMID:21441910 A Raf-induced allosteric transition of KSR stimulates phosph... |
ACCEPT |
Summary: EXP annotation for protein serine kinase activity from PMID:21441910 (Brennan et al. 2011 Nature β A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK). Direct experimental measurement of BRAF Ser/Thr kinase activity on the GO:0106310 most-specific MF child term. Already supported via IEA propagation in PR #456 (line 144: GO:0106310 IEA GO_REF:0000116 ACCEPTed) and via the IBA propagation batch in PR #448 on the GO:0004709 MAP3K activity child.
Reason: Canonical BRAF Ser/Thr kinase MF directly demonstrated experimentally. PMID:21441910 is one of the three canonical experimental BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in PR #456 (lines 69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical kinase / MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2 GO:0106310 EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row MODIFY review per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term, separate batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review).
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|
GO:0106310
protein serine kinase activity
|
EXP
PMID:29433126 MEK drives BRAF activation through allosteric control of KSR... |
ACCEPT |
Summary: EXP annotation for protein serine kinase activity from PMID:29433126, one of the canonical BRAF kinase experimental papers cited across this file as direct evidence (IDA/IMP) for BRAF S/T kinase function. Direct experimental measurement of BRAF Ser-kinase activity on the GO:0106310 most-specific MF child term. Already supported via IEA propagation in PR #456 (line 144: GO:0106310 IEA GO_REF:0000116 ACCEPTed) and via the IBA propagation batch in PR #448 on the GO:0004709 MAP3K activity child.
Reason: Canonical BRAF Ser/Thr kinase MF directly demonstrated experimentally. PMID:29433126 is one of the three canonical experimental BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in PR #456 (lines 69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical kinase / MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2 GO:0106310 EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row MODIFY review per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term, separate batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review).
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GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672950 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
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|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672951 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672960 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672961 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672966 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672969 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672972 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672973 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672978 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5672980 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5674130 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5674132 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5674140 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5675417 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5675431 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-5675433 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802924 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6803240 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9610152 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9610153 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9610154 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9610156 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9610163 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9653108 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9656209 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9656211 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9656212 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9656213 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9656214 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9656215 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9657599 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9657603 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9657606 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9657608 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9658445 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9660536 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9660538 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-5675198 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802908 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802922 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802924 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802925 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802926 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6803233 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6803240 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802910 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802911 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802912 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802930 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802938 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6803227 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0000165
MAPK cascade
|
IDA
PMID:29433126 MEK drives BRAF activation through allosteric control of KSR... |
ACCEPT |
Summary: IDA annotation for MAPK cascade from PMID:29433126, one of the canonical BRAF kinase experimental papers cited across this file as direct evidence (IDA/IMP) for BRAF function in the RAS-RAF-MEK-ERK cascade. Direct experimental measurement of BRAF participation in the MAPK cascade. Already supported via IBA propagation in PR #448 on GO:0000165 (the IEA ACCEPT for GO:0007165 signal transduction in PR #456 at line 117 explicitly notes "supported by IBA on the more specific child term GO:0000165 MAPK cascade (PR #448)") and via Reactome TAS rows for the RAS-MAPK pathway events ACCEPTed in PR #440.
Reason: Canonical BRAF BP directly demonstrated experimentally. PMID:29433126 is one of the three canonical experimental BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in PR #456 (lines 69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical kinase / MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2 GO:0106310 EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row MODIFY review per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term, separate batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review).
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|
GO:0004708
MAP kinase kinase activity
|
IMP
PMID:29433126 MEK drives BRAF activation through allosteric control of KSR... |
MODIFY |
Summary: IMP annotation for GO:0004708 MAP kinase kinase activity from Lavoie et al. 2018 Nature (PMID:29433126 β MEK drives BRAF activation through allosteric control of KSR proteins). The paper establishes that RAF-family kinase activation depends on kinase-domain dimerization and that BRAF acts on MEK within the RAS-RAF-MEK-ERK cascade. BRAF is a MAP kinase kinase kinase (MAP3K): it phosphorylates MEK1/MEK2 (the MAP2Ks); it does not phosphorylate ERK and does not itself have MAP2K (MAP kinase kinase) activity. GO:0004708 describes the catalytic activity of MEK, not of BRAF.
Reason: The essence of the annotation is sound (BRAF is the kinase that drives the MAPK cascade by phosphorylating the next kinase down), but GO:0004708 (MAP kinase kinase activity) is the wrong tier of the MAPK kinase cascade for BRAF. BRAF phosphorylates MEK1/MEK2 β the MAP2Ks β so BRAF's molecular function is GO:0004709 MAP kinase kinase kinase activity (MAP3K activity), not MAP2K activity. MODIFY to GO:0004709, which is already independently ACCEPTed in this file via IBA propagation from PANTHER PTHR44329 (PR #448, line 38) and consistent with the canonical kinase MF evidence in-file (PMID:21441910 EXP, PMID:18567582 IDA). This resolves the long-standing MAP2K-vs-MAP3K carryover note flagged across earlier batches.
Proposed replacements:
MAP kinase kinase kinase activity
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|
GO:0000165
MAPK cascade
|
IDA
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
ACCEPT |
Summary: IDA annotation for MAPK cascade from PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling), one of the canonical BRAF kinase experimental papers cited across this file as direct evidence (IDA) for BRAF function in the RAS-RAF-MEK-ERK cascade. Direct experimental measurement of BRAF participation in the MAPK cascade. Already supported via IBA propagation in PR #448 on GO:0000165 (the IEA ACCEPT for GO:0007165 signal transduction in PR #456 at line 117 explicitly notes "supported by IBA on the more specific child term GO:0000165 MAPK cascade (PR #448)") and via Reactome TAS rows for the RAS-MAPK pathway events ACCEPTed in PR #440.
Reason: Canonical BRAF BP directly demonstrated experimentally. PMID:18567582 is one of the three canonical experimental BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in PR #456 (lines 69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical kinase / MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2 GO:0106310 EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row MODIFY review per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term, separate batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review).
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|
GO:0004674
protein serine/threonine kinase activity
|
IDA
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
ACCEPT |
Summary: IDA annotation for protein serine/threonine kinase activity from PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling), one of the three canonical BRAF kinase experimental papers cited across this file as direct evidence (IDA/IMP) for BRAF kinase activity. GO:0004674 is the parent of GO:0106310 (protein serine kinase activity), which is already supported via direct EXP evidence in this file (PMID:21441910 ACCEPTed in PR #505) and via IEA propagation in PR #456.
Reason: Canonical BRAF MF directly demonstrated experimentally. Protein kinase activity / protein S/T kinase activity (parent terms of GO:0106310) is BRAF's defining molecular function β phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade. PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf), and PMID:19667065 are direct IDA papers measuring BRAF kinase activity. Already supported via direct EXP evidence on the more specific child term GO:0106310 protein serine kinase activity (PMID:21441910 ACCEPTed in PR #505); via IBA propagation on GO:0004709 MAP3K activity (PR #448); via IEA on GO:0004672 and GO:0004674 (PR #456); via IDA on GO:0000165 MAPK cascade (PR #534). This batch mechanically consolidates the remaining 3 parent-term canonical kinase MF rows to ACCEPT with a uniform template (2 GO:0004674 IDA rows + 1 GO:0004672 IDA row). Held back: GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review); PMID:22065586 rows GO:0010628/GO:0070374 (downstream BP, separate batch); PMID:19667065 BP rows GO:0033138/GO:0043066 (separate batch); GO:0005634 IEA nucleus (separate per-row); GO:0042802 IPI PMID:35512704 (KEAP1 neoPPI focus, separate per-row); GO:0005739 IBA mitochondrion (separate per-row); GO:0090150/GO:0010828 PMID:23010278 rows (separate per-row); GO:0031267 NOT|IPI PMID:12194967 (negated row, separate review); GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K MODIFY, separate per-row).
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|
GO:0005509
calcium ion binding
|
IDA
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
KEEP AS NON CORE |
Summary: IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling). The paper reports "a specific and direct association of Ca2+ with B-Raf", but explicitly notes that "the specific site on B-Raf where Ca2+ binds remains to be determined" and "the biological function of Ca2+ binding to B-Raf is unknown" (chelating Ca2+ in the in vitro kinase assay produced no significant/reproducible change in B-Raf activity). This is a single-paper direct observation with no mapped binding site and no demonstrated functional consequence; BRAF has no canonical calcium-binding domain (EF-hand/C2) and Ca2+ binding is not part of the core RAS-RAF-MEK-ERK kinase mechanism.
Reason: Genuine direct experimental observation but a peripheral, mechanistically uncharacterized property (binding site unmapped, biological function explicitly stated as unknown by the authors), reported by a single lab and not replicated. BRAF's core molecular function is its Ser/Thr (MAP3K) kinase activity in the RAS-RAF-MEK-ERK cascade, already captured via ACCEPTed canonical MF rows. Retained as non-core rather than removed because the IDA observation is real; part of the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509, GO:0007173, GO:0097110, GO:0071277).
|
|
GO:0005515
protein binding
|
IPI
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0007173
epidermal growth factor receptor signaling pathway
|
IDA
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
KEEP AS NON CORE |
Summary: IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem). BRAF was studied as an EGF-stimulated effector β EGF-stimulated B-Raf kinase activity is modulated by intracellular Ca2+ via the IQGAP1 scaffold. BRAF does function downstream of activated EGFR within the canonical RAS-RAF-MEK-ERK cascade, but EGFR is only one of many upstream RTK inputs and "EGFR signaling pathway" is a context-specific upstream-input framing rather than a BRAF-defining process. The core BRAF biological process (the MAPK cascade / RAS-RAF-MEK-ERK signal transduction) is already captured via ACCEPTed canonical rows (GO:0000165 MAPK cascade, GO:0007165 signal transduction).
Reason: BRAF genuinely participates in EGFR-driven signaling as a canonical downstream MAP3K, so the annotation is not wrong, but it is a context-specific upstream-input pathway rather than BRAF's core process β the generic RAS-RAF-MEK-ERK / MAPK cascade is the defining BP and is already ACCEPTed. Part of the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509, GO:0007173, GO:0097110, GO:0071277).
|
|
GO:0097110
scaffold protein binding
|
IPI
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
KEEP AS NON CORE |
Summary: IPI annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem) for direct binding of B-Raf to the MAPK scaffold protein IQGAP1 ("Ca2+ promotes the direct binding of IQGAP1 to B-Raf"; IQGAP1 assembles a B-Raf/MEK/ERK complex and modulates B-Raf activation by EGF). GO:0097110 'scaffold protein binding' is an informative, specific MF term (preferred over generic GO:0005515 per CLAUDE.md) and the B-RafβIQGAP1 interaction is genuine and directly demonstrated. However, IQGAP1 scaffold binding is a regulatory/modulatory interaction rather than BRAF's core catalytic function, and the principal RAF scaffold biology (KSR) is distinct; the IQGAP1 work is from a single lab (Sacks).
Reason: Specific, informative, directly-demonstrated interaction (correctly avoids the generic protein-binding term), retained because it is biologically real and well-characterized, but it represents a regulatory scaffold interaction rather than BRAF's core RAS-RAF-MEK-ERK Ser/Thr kinase function (already captured via ACCEPTed canonical MF rows). Part of the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509, GO:0007173, GO:0097110, GO:0071277).
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|
GO:0005515
protein binding
|
IPI
PMID:31024343 A YWHAZ Variant Associated With Cardiofaciocutaneous Syndrom... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005515
protein binding
|
IPI
PMID:29433126 MEK drives BRAF activation through allosteric control of KSR... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802914 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802915 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802916 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802918 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802919 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802921 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802937 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802941 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802942 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6802943 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6803230 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6803234 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8936676 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8936731 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802914 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802916 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802919 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6802921 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-6803230 |
ACCEPT |
Summary: TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.
Reason: Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The 13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
|
|
GO:0005515
protein binding
|
IPI
PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... |
MARK AS OVER ANNOTATED |
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector / dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows were uniformly demoted.
|
|
GO:0071277
cellular response to calcium ion
|
IDA
PMID:18567582 IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling. |
KEEP AS NON CORE |
Summary: IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem). The paper shows that manipulating intracellular Ca2+ modulates B-Raf kinase activity ("chelating [Ca2+]i in fibroblasts markedly increases B-Raf kinase activity"; raising [Ca2+]i blocks EGF-stimulated B-Raf activity), but the effect is indirect β mediated by Ca2+/calmodulin acting on the IQGAP1 scaffold to alter its association with B-Raf, not a cell-autonomous BRAF calcium response. This is a real but context-specific, single-mechanism secondary finding, not a core BRAF process.
Reason: BRAF activity does respond to changes in cellular Ca2+, so the annotation is supported, but the response is indirect (via the IQGAP1/calmodulin scaffold mechanism) and context-specific rather than a core BRAF biological process; the defining RAS-RAF-MEK-ERK signaling is already captured via ACCEPTed canonical rows. Part of the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509, GO:0007173, GO:0097110, GO:0071277).
|
|
GO:0031267
small GTPase binding
|
IPI
NOT
PMID:12194967 Di-Ras, a distinct subgroup of ras family GTPases with uniqu... |
ACCEPT |
Summary: NOT (negated) IPI annotation for GO:0031267 small GTPase binding from Kontani et al. 2002 J Biol Chem (PMID:12194967 β Di-Ras, a distinct subgroup of Ras family GTPases with unique biochemical properties). Owing to effector-domain substitutions (Ile at the position corresponding to Ha-Ras Asp-33), the paper shows Di-Ras1/Di-Ras2 "fails to interact with the Ras-binding domain of Raf, resulting in no stimulation of mitogen-activated protein kinase." This is a deliberate, experimentally-grounded negative finding: the BRAF RAS-binding domain does not engage the Di-Ras subgroup of small GTPases.
Reason: The negated annotation is correct and is a curatorially valuable negative assertion. PMID:12194967 directly and explicitly demonstrates that Di-Ras does not bind the Ras-binding domain of Raf and does not stimulate the MAPK pathway, supporting NOT|small GTPase binding for this specific GTPase subgroup. This does not contradict BRAF's canonical RAS (HRAS/KRAS/NRAS) engagement via its RBD β it specifically records that the Di-Ras subfamily is not a BRAF RBD ligand. Consistent with the repository convention of retaining experimentally established non-interaction NOT annotations as-is; ACCEPT.
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GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1295604 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
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|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1295634 |
ACCEPT |
Summary: TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state and is recruited to the plasma membrane upon RAS-GTP activation.
Reason: Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).
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GO:0090150
establishment of protein localization to membrane
|
IDA
PMID:23010278 Stimulation of the Na(+)-coupled glucose transporter SGLT1 b... |
KEEP AS NON CORE |
Summary: IDA annotation from PMID:23010278 (Pakladok et al. 2012, Biochem Biophys Res Commun β Stimulation of the Na(+)-coupled glucose transporter SGLT1 by B-RAF). Chemiluminescence and confocal-microscopy experiments showed that wild-type B-RAF coexpression in Xenopus oocytes enhanced SGLT1 protein abundance in the cell membrane, an effect blocked by the vesicle-insertion inhibitor Brefeldin A, supporting a B-RAF role in establishment of SGLT1 localization to the plasma membrane. This is a heterologous-overexpression, tumor-glucose-metabolism-context-specific regulatory effect on a transporter rather than the defining RAS-RAF-MEK-ERK serine/threonine kinase function that characterizes BRAF.
Reason: Genuine but peripheral, context-specific regulatory effect (B-RAF enhancing SGLT1 trafficking and membrane insertion in a Xenopus-oocyte tumor-glucose-uptake model) rather than a core BRAF function. Canonical BRAF biology β the RAS-RAF-MEK-ERK kinase cascade and cytosol/plasma-membrane localization β is already captured via direct experimental evidence in this file (PMID:21441910 EXP, PMID:18567582 IDA, PMID:29433126 IDA/IMP) and prior batches (PR #440 Reactome TAS, PR #448 IBA, PR #456 IEA). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the 2 PMID:23010278 SGLT1 rows (GO:0090150 establishment of protein localization to membrane; GO:0010828 positive regulation of D-glucose transmembrane transport).
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GO:0010828
positive regulation of D-glucose transmembrane transport
|
IDA
PMID:23010278 Stimulation of the Na(+)-coupled glucose transporter SGLT1 b... |
KEEP AS NON CORE |
Summary: IDA annotation from PMID:23010278 (Pakladok et al. 2012, Biochem Biophys Res Commun β Stimulation of the Na(+)-coupled glucose transporter SGLT1 by B-RAF). Dual-electrode voltage-clamp on SGLT1-expressing Xenopus oocytes showed that wild-type B-RAF coexpression significantly increased the glucose-induced current, enhancing the maximal SGLT1 transport rate without significantly changing carrier affinity, supporting a B-RAF role in positive regulation of D-glucose transmembrane transport. This is a heterologous-overexpression, tumor-glucose-metabolism-context-specific regulatory effect rather than the defining RAS-RAF-MEK-ERK serine/threonine kinase function that characterizes BRAF.
Reason: Genuine but peripheral, context-specific regulatory effect (B-RAF enhancing SGLT1 trafficking and membrane insertion in a Xenopus-oocyte tumor-glucose-uptake model) rather than a core BRAF function. Canonical BRAF biology β the RAS-RAF-MEK-ERK kinase cascade and cytosol/plasma-membrane localization β is already captured via direct experimental evidence in this file (PMID:21441910 EXP, PMID:18567582 IDA, PMID:29433126 IDA/IMP) and prior batches (PR #440 Reactome TAS, PR #448 IBA, PR #456 IEA). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the 2 PMID:23010278 SGLT1 rows (GO:0090150 establishment of protein localization to membrane; GO:0010828 positive regulation of D-glucose transmembrane transport).
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GO:0004672
protein kinase activity
|
IDA
PMID:17563371 IQGAP1 modulates activation of B-Raf. |
ACCEPT |
Summary: IDA annotation for protein kinase activity from PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates activation of B-Raf), which directly demonstrates B-Raf kinase activity in vitro and shows that IQGAP1 binding significantly enhances B-Raf activity. GO:0004672 is the most general parent of GO:0004674 (protein S/T kinase activity), GO:0106310 (protein serine kinase activity), and GO:0004709 (MAP3K activity) β all of which are already supported via direct EXP/IDA/IBA/IEA evidence in this file (PMID:21441910 EXP ACCEPTed in PR #505; PR #448 IBA; PR #456 IEA).
Reason: Canonical BRAF MF directly demonstrated experimentally. Protein kinase activity / protein S/T kinase activity (parent terms of GO:0106310) is BRAF's defining molecular function β phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade. PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf), and PMID:19667065 are direct IDA papers measuring BRAF kinase activity. Already supported via direct EXP evidence on the more specific child term GO:0106310 protein serine kinase activity (PMID:21441910 ACCEPTed in PR #505); via IBA propagation on GO:0004709 MAP3K activity (PR #448); via IEA on GO:0004672 and GO:0004674 (PR #456); via IDA on GO:0000165 MAPK cascade (PR #534). This batch mechanically consolidates the remaining 3 parent-term canonical kinase MF rows to ACCEPT with a uniform template (2 GO:0004674 IDA rows + 1 GO:0004672 IDA row). Held back: GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review); PMID:22065586 rows GO:0010628/GO:0070374 (downstream BP, separate batch); PMID:19667065 BP rows GO:0033138/GO:0043066 (separate batch); GO:0005634 IEA nucleus (separate per-row); GO:0042802 IPI PMID:35512704 (KEAP1 neoPPI focus, separate per-row); GO:0005739 IBA mitochondrion (separate per-row); GO:0090150/GO:0010828 PMID:23010278 rows (separate per-row); GO:0031267 NOT|IPI PMID:12194967 (negated row, separate review); GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K MODIFY, separate per-row).
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GO:0010628
positive regulation of gene expression
|
IMP
PMID:22065586 Oncogenic Ras and B-Raf proteins positively regulate death r... |
MARK AS OVER ANNOTATED |
Summary: PMID:22065586 studies oncogenic Ras and BRAF V600E induction of DR5 expression in cancer-cell contexts through ERK/RSK and JNK signaling.
Reason: This annotation overextends a downstream oncogenic-mutant transcriptional phenotype to BRAF as a gene product. The paper supports BRAF V600E pathway signaling in cancer cells, but positive regulation of gene expression is not a core BRAF function and is less appropriate than retaining the ERK/MAPK cascade annotations.
Supporting Evidence:
PMID:22065586
knockdown of endogenous K-Ras or B-Raf (V600E) reduced the expression of DR5
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GO:0070374
positive regulation of ERK1 and ERK2 cascade
|
IDA
PMID:22065586 Oncogenic Ras and B-Raf proteins positively regulate death r... |
ACCEPT |
Summary: IDA annotation from PMID:22065586 (Oh et al. 2012, J Biol Chem). Oncogenic B-Raf (V600E) directly activates the ERK/RSK MAPK cascade in cancer cells; the paper explicitly demonstrates ERK co-activation downstream of B-Raf as the mechanism upstream of DR5 induction. Positive regulation of the ERK1/2 cascade is the defining canonical BRAF biological-process role.
Reason: Canonical BRAF BP directly demonstrated experimentally. Positive regulation of the ERK1/2 cascade is BRAF's definitive role in the RAS-RAF-MEK-ERK pathway β BRAF directly phosphorylates MEK1/MEK2, which then activates ERK1/ERK2. Already supported via IBA on GO:0000165 MAPK cascade (PR #448), via IDA on GO:0000165 in PR #534, and via Reactome TAS rows for RAS-MAPK pathway events ACCEPTed in PR #440. Mechanically consolidated to ACCEPT with a uniform template across the 4 canonical BRAFβdownstream-BP IDA/IMP rows in this batch (PMID:22065586 GO:0010628 IMP, PMID:22065586 GO:0070374 IDA, PMID:19667065 GO:0033138 IDA, PMID:19667065 GO:0043066 IDA). Held back per-row items unchanged from the PMID:22065586 GO:0010628 row above.
Supporting Evidence:
PMID:22065586
the oncogenic B-Raf (V600E), a commonly mutated form in cancers, activated ERK/RSK signaling, increased DR5 promoter activity, and up-regulated DR5 expression
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GO:0004674
protein serine/threonine kinase activity
|
IDA
PMID:19667065 Identification of novel in vivo phosphorylation sites of the... |
ACCEPT |
Summary: IDA annotation for protein serine/threonine kinase activity from PMID:19667065, a direct experimental paper measuring BRAF kinase activity. GO:0004674 is the parent of GO:0106310 (protein serine kinase activity), which is already supported via direct EXP evidence in this file (PMID:21441910 ACCEPTed in PR #505) and via IEA propagation in PR #456.
Reason: Canonical BRAF MF directly demonstrated experimentally. Protein kinase activity / protein S/T kinase activity (parent terms of GO:0106310) is BRAF's defining molecular function β phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade. PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf), and PMID:19667065 are direct IDA papers measuring BRAF kinase activity. Already supported via direct EXP evidence on the more specific child term GO:0106310 protein serine kinase activity (PMID:21441910 ACCEPTed in PR #505); via IBA propagation on GO:0004709 MAP3K activity (PR #448); via IEA on GO:0004672 and GO:0004674 (PR #456); via IDA on GO:0000165 MAPK cascade (PR #534). This batch mechanically consolidates the remaining 3 parent-term canonical kinase MF rows to ACCEPT with a uniform template (2 GO:0004674 IDA rows + 1 GO:0004672 IDA row). Held back: GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary findings, separate per-row review); PMID:22065586 rows GO:0010628/GO:0070374 (downstream BP, separate batch); PMID:19667065 BP rows GO:0033138/GO:0043066 (separate batch); GO:0005634 IEA nucleus (separate per-row); GO:0042802 IPI PMID:35512704 (KEAP1 neoPPI focus, separate per-row); GO:0005739 IBA mitochondrion (separate per-row); GO:0090150/GO:0010828 PMID:23010278 rows (separate per-row); GO:0031267 NOT|IPI PMID:12194967 (negated row, separate review); GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K MODIFY, separate per-row).
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GO:0033138
positive regulation of peptidyl-serine phosphorylation
|
IDA
PMID:19667065 Identification of novel in vivo phosphorylation sites of the... |
MODIFY |
Summary: PMID:19667065 supports RAF-dependent BAD phosphorylation, but the regulatory wording is less direct than annotating the phosphorylation output of RAF kinase activity.
Reason: The cited evidence supports protein phosphorylation by RAF kinases. GO:0033138 frames the result as regulation of peptidyl-serine phosphorylation and is less precise for BRAF's kinase output. Replace with the direct serine-phosphorylation process term GO:0018105 peptidyl-serine phosphorylation.
Proposed replacements:
peptidyl-serine phosphorylation
Supporting Evidence:
PMID:19667065
RAF kinases represent, besides protein kinase A, PAK, and Akt/protein kinase B, in vivo BAD-phosphorylating kinases. RAF-induced phosphorylation of BAD was reduced to control levels using the RAF inhibitor BAY 43-9006. This phosphorylation was not prevented by MEK inhibitors.
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GO:0043066
negative regulation of apoptotic process
|
IDA
PMID:19667065 Identification of novel in vivo phosphorylation sites of the... |
ACCEPT |
Summary: IDA annotation from PMID:19667065 (Polzien et al. 2009, J Biol Chem). Constitutively active RAF suppresses BAD-induced apoptosis and rescues colony-formation inhibition by BAD; mechanism is RAF-mediated phosphorylation of BAD-S99 (the major 14-3-3 binding site), which promotes 14-3-3 sequestration of BAD and inhibits BAD's mitochondrial pore-forming pro-apoptotic activity. This captures BRAF's canonical pro-survival downstream output via the BAD-Bcl-2 axis.
Reason: Canonical BRAF BP directly demonstrated experimentally via constitutively-active RAF gain-of-function suppression of BAD-induced apoptosis (PMID:19667065). Negative regulation of apoptotic process is an established downstream consequence of BRAF kinase activity through the BAD-Bcl-2 pro-survival axis (and complementary MEK-ERKβ90 kDa ribosomal S6 kinaseβBAD-S112 phosphorylation in murine BAD). Mechanically consolidated to ACCEPT with a uniform template across the 4 canonical BRAFβdownstream-BP IDA/IMP rows in this batch (PMID:22065586 GO:0010628 IMP, PMID:22065586 GO:0070374 IDA, PMID:19667065 GO:0033138 IDA, PMID:19667065 GO:0043066 IDA). Held back per-row items unchanged from the PMID:22065586 GO:0010628 row above. Note: an existing IEA GO_REF:0000044 row on `GO:0043066` was already ACCEPTed in PR #456 β this row provides the direct experimental anchor.
Supporting Evidence:
PMID:19667065
expression of constitutively active RAF suppressed apoptosis induced by BAD and the inhibition of colony formation caused by BAD could be prevented by RAF
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GO:0009887
animal organ morphogenesis
|
TAS
PMID:9207797 Endothelial apoptosis in Braf-deficient mice. |
MODIFY |
Summary: TAS annotation from Wojnowski et al. 1997 (PMID:9207797), the foundational Braf-knockout paper showing that Braf-/- mice die mid-gestation from vascular defects with increased endothelial precursor cells, dramatically enlarged blood vessels, and apoptotic death of differentiated endothelial cells. The general term GO:0009887 (animal organ morphogenesis) is too broad to capture this specific in vivo phenotype: the paper unambiguously demonstrates a role in blood vessel / vasculature development, not generic organ morphogenesis. GO:0001568 (blood vessel development) is the appropriate replacement, capturing the vasculature-specific progression-to-mature-structure process the knockout phenotype defines.
Reason: The essence of the annotation is correct (BRAF is required for an in vivo developmental process per the Braf-/- vascular-defects phenotype), but the term GO:0009887 (animal organ morphogenesis) is too general. PMID:9207797 specifically demonstrates a role in vascular system formation (increased endothelial precursors, enlarged blood vessels, endothelial apoptosis leading to mid-gestation vascular failure), which is more precisely captured by GO:0001568 (blood vessel development). MODIFY to the more specific child term; this is a non-core developmental/tissue-specific role downstream of the canonical BRAF kinase function and not promoted to core_functions.
Proposed replacements:
blood vessel development
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GO:0004672
protein kinase activity
|
TAS
PMID:2284096 Complete coding sequence of a human B-raf cDNA and detection... |
ACCEPT |
Summary: TAS annotation from the foundational Sithanandam et al. 1990 paper that cloned the complete coding sequence of human B-raf and detected B-raf protein kinase activity using isozyme-specific antibodies (PMID:2284096). BRAF is a canonical Ser/Thr protein kinase phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade β directly demonstrated experimentally elsewhere in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and already ACCEPTed on the IEA row (GO_REF:0000120, PR #456) and via IBA propagation on the more specific child term GO:0004709 MAP3K activity (PR #448).
Reason: TAS evidence from the foundational 1990 BRAF cloning/kinase-detection paper (PMID:2284096) supports a canonical core BRAF molecular function or core BRAF biological process directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and already ACCEPTed via IEA (PR #456), IBA (PR #448), and Reactome TAS (PR #440) propagation batches. Mechanically consolidated to ACCEPT with a uniform template across the 2 canonical kinase TAS rows from PMID:2284096 (protein kinase activity, protein phosphorylation); the 2 PMID:9207797 Braf-knockout TAS rows (animal organ morphogenesis, negative regulation of apoptotic process) are held back for separate per-row consideration in a later batch because the in vivo vascular-development knockout context warrants a more specific term assessment.
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GO:0006468
protein phosphorylation
|
TAS
PMID:2284096 Complete coding sequence of a human B-raf cDNA and detection... |
ACCEPT |
Summary: TAS annotation from the foundational Sithanandam et al. 1990 paper that cloned the complete coding sequence of human B-raf and detected B-raf protein kinase activity using isozyme-specific antibodies (PMID:2284096). Protein phosphorylation is the canonical biological process of BRAF kinase activity β BRAF phosphorylates MEK1/MEK2 on activation-loop serines (Ser218/Ser222 of MEK1) in the RAS-RAF-MEK-ERK cascade. Directly demonstrated experimentally elsewhere in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and supported via IBA propagation on the MAP3K activity / MAPK cascade terms (PR #448).
Reason: TAS evidence from the foundational 1990 BRAF cloning/kinase-detection paper (PMID:2284096) supports a canonical core BRAF molecular function or core BRAF biological process directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and already ACCEPTed via IEA (PR #456), IBA (PR #448), and Reactome TAS (PR #440) propagation batches. Mechanically consolidated to ACCEPT with a uniform template across the 2 canonical kinase TAS rows from PMID:2284096 (protein kinase activity, protein phosphorylation); the 2 PMID:9207797 Braf-knockout TAS rows (animal organ morphogenesis, negative regulation of apoptotic process) are held back for separate per-row consideration in a later batch because the in vivo vascular-development knockout context warrants a more specific term assessment.
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GO:0043066
negative regulation of apoptotic process
|
TAS
PMID:9207797 Endothelial apoptosis in Braf-deficient mice. |
ACCEPT |
Summary: TAS annotation from Wojnowski et al. 1997 (PMID:9207797) β Braf-knockout mice show apoptotic death of differentiated endothelial cells leading to mid-gestation vascular defects, providing the first genetic evidence for a Raf-family role in regulating programmed cell death. Supports the canonical BRAF anti-apoptotic activity already ACCEPTed via IEA propagation (GO_REF:0000117, PR #456), which is mechanistically grounded in BRAF-driven MEK/ERK phosphorylation of pro-apoptotic factors (BAD on Ser112/Ser155 via RSK; BIM via ERK-mediated proteasomal degradation).
Reason: TAS evidence from PMID:9207797 supports the same canonical BRAF anti-apoptotic function already ACCEPTed via IEA (GO_REF:0000117, PR #456) and consistent with the canonical RAS-RAF-MEK-ERK survival signaling captured in the Reactome TAS batch (PR #440). The in vivo endothelial-apoptosis phenotype of Braf-/- mice provides genetic confirmation of the cellular anti-apoptotic role. Retained as ACCEPT (mirroring the IEA row) rather than KEEP_AS_NON_CORE because the same term is already at ACCEPT elsewhere in the file; the developmental tissue-specific aspect is captured in the paired PMID:9207797 morphogenesis row (MODIFY β GO:0001568 blood vessel development) in this same batch.
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Q: Does BRAF homodimerization versus BRAF-RAF1 heterodimerization yield qualitatively or quantitatively distinct MEK activation outputs, and what cellular signals or post-translational modifications tip the balance in vivo?
Q: How is the stoichiometry and dynamics of the autoinhibited cytosolic BRAF-MEK-14-3-3 complex regulated during growth factor stimulation, and does the complex dissociate as a unit or do components exchange independently upon RAS activation?
Q: What is the full complement of direct BRAF substrates beyond MEK1/2 in normal physiological contexts, and do non-MEK targets such as BAD contribute to BRAF function in vascular development?
Q: Can the BRAF amino-terminal B-Raf-specific region (mediating calcium-dependent dimerization) be targeted pharmacologically to modulate wild-type BRAF activity without triggering paradoxical RAF inhibitor-type pathway activation?
Experiment: Cryo-EM reconstitution of the active BRAF-RAF1 heterodimer and the BRAF-KSR1-MEK ternary complex on nanodisc membranes in the presence of RAS-GTP to determine how membrane context and substrate engagement reshape the active conformation.
Hypothesis: RAS-GTP at the membrane induces a distinct active-dimer conformation compared to drug-stabilized dimers, and KSR1-MEK positioning within the ternary complex explains the allosteric stimulation of BRAF catalytic activity.
Type: structural
Experiment: Phosphoproteomic profiling of isogenic cells with conditional BRAF knockout versus BRAF(V600E) knock-in under matched growth conditions to identify direct BRAF-dependent phosphorylation events beyond MEK1/2.
Hypothesis: BRAF has physiological substrates beyond MEK1/2 that contribute to its essential role in endothelial survival and vascular development, and these are distinct from the MEK-dependent oncogenic signaling in V600E tumors.
Type: biochemical
Experiment: Calcium-imaging combined with BRAF FRET-based dimerization reporters in primary endothelial cells to establish the kinetics and threshold of calcium-dependent BRAF membrane translocation and dimerization.
Hypothesis: The B-Raf-specific amino-terminal region converts transient calcium signals into sustained BRAF dimerization at the plasma membrane, providing a calcium-dependent amplification mechanism for MAPK signaling in endothelial cells.
Type: cell_biology
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Concise GO annotation research for human BRAF / UniProt P15056. Focus only on GO-relevant evidence: core molecular function as a RAF-family serine/threonine protein kinase and MAP kinase kinase kinase in the RAS-RAF-MEK-ERK cascade; ATP binding, kinase activation mechanisms, RAS-GTP recruitment, dimerization, phosphorylation/regulatory sites, and direct MEK1/MEK2 substrate phosphorylation. Cover core biological processes such as MAPK cascade, ERK1/ERK2 cascade, Ras protein signal transduction, and regulation of cell proliferation/differentiation only where directly supported. Evaluate cellular localization evidence including cytosol, plasma membrane recruitment, nucleus if any, endomembrane, mitochondrion, and protein complexes. Distinguish wild-type BRAF core function from oncogenic BRAF mutants (especially V600E), cancer phenotypes, apoptosis, development, vascular/angiogenesis phenotypes, transcription, immune/metabolic downstream outcomes, and overexpression/pathway-membership inferences. Evaluate generic protein binding versus more informative MF terms. Include PMID/DOI citations and keep under 1500 words.
BRAF is a RAF-family serine/threonine protein kinase that functions as the MAP3K tier in the canonical RASβRAFβMEK1/2βERK1/2 cascade. GO-relevant evidence supports: ATP binding and kinase catalysis, RAS-GTP-dependent recruitment to the plasma membrane via the RAS-binding domain (RBD) and cysteine-rich domain (CRD), release of 14-3-3-mediated autoinhibition through regulatory phosphosites pS365/pS729, kinase-domain dimerization as a key activation step (for wild-type), and direct phosphorylation/activation of MEK1/MEK2 (including MEK1 S218/S222). Evidence in this corpus supports cytosolic autoinhibited complexes and plasma-membrane-associated active dimers, but does not provide direct support for nuclear, Golgi/endomembrane, or mitochondrial localization for BRAF. (martinvega2023navigatingtheerk12 pages 2-4, bahar2023targetingtherasrafmapk pages 5-6, liu2024reconstitutionandcharacterization pages 1-2, liu2024reconstitutionandcharacterization pages 7-9)
| Annotation theme | Suggested GO term(s) | Key mechanistic evidence | Best supporting citations |
|---|---|---|---|
| ATP binding / kinase motifs | ATP binding; protein serine/threonine kinase activity | BRAF CR3 contains canonical kinase motifs; K578 contacts ATP Ξ³-phosphate, and DFG/activation-segment conformations regulate active vs inactive states; ATP pocket remains accessible in autoinhibited structures. | (imani2024theevolutionof pages 6-7, fiesco2022structuralinsightsinto pages 4-5) |
| Core catalytic activity | protein serine/threonine kinase activity | BRAF is a RAF-family Ser/Thr kinase with catalytic CR3; active BRAF phosphorylates downstream MAP2Ks rather than generic substrates. | (bonsor2024rasandshoc2 pages 1-3, bahar2023targetingtherasrafmapk pages 5-6) |
| MAP3K role | MAP kinase kinase kinase activity | RAF is the MAP3K tier immediately downstream of RAS; BRAF is the direct upstream kinase for MEK1/MEK2 in the ERK pathway. | (martinvega2023navigatingtheerk12 pages 2-4, bahar2023targetingtherasrafmapk pages 5-6) |
| RAS-GTP recruitment to membrane | Ras GTPase binding; plasma membrane recruitment during Ras protein signal transduction | Exposed RBD basic residues bind activated RAS; CRD contributes membrane/phospholipid engagement, promoting recruitment from cytosol to plasma membrane. | (fiesco2022structuralinsightsinto pages 1-2, fiesco2022structuralinsightsinto pages 5-7, bonsor2024rasandshoc2 pages 4-6) |
| 14-3-3 binding via regulatory phosphosites | 14-3-3 protein binding | 14-3-3 dimer binds BRAF pS365 and pS729, stabilizing autoinhibition and controlling transition to active states. | (bonsor2024rasandshoc2 pages 1-3, liu2024reconstitutionandcharacterization pages 1-2, fiesco2022structuralinsightsinto pages 4-5) |
| Dimerization and activation | protein homodimerization activity; protein heterodimerization activity; activation of protein kinase activity | RAS engagement and loss of CR2-site restraint promote exposure of the dimer interface; 14-3-3 can bridge C-terminal pS729 sites across protomers to stabilize active dimers. | (fiesco2022structuralinsightsinto pages 1-2, fiesco2022structuralinsightsinto pages 2-4, bonsor2024rasandshoc2 pages 1-3) |
| Direct MEK1/MEK2 phosphorylation | MAP kinase kinase activity; protein serine/threonine kinase activity | Active BRAF directly phosphorylates MEK1/2; retrieved sources explicitly note MEK1 Ser218/Ser222 phosphorylation downstream of RAF/BRAF. | (imani2024theevolutionof pages 6-7, patel2023investigatingtherole pages 42-45, liu2024reconstitutionandcharacterization pages 9-10) |
| MAPK / ERK cascade | MAPK cascade; ERK1 and ERK2 cascade | BRAF functions in the RAS-RAF-MEK-ERK module as the MAP3K tier that activates MEK, which then activates ERK1/2. | (martinvega2023navigatingtheerk12 pages 2-4, bahar2023targetingtherasrafmapk pages 5-6) |
| Ras protein signal transduction | Ras protein signal transduction | BRAF is a direct RAS effector; GTP-bound RAS engages the BRAF RBD and initiates the conformational and localization changes needed for signaling. | (bonsor2024rasandshoc2 pages 1-3, fiesco2022structuralinsightsinto pages 1-2, fiesco2022structuralinsightsinto pages 5-7) |
| Cytosol autoinhibited state | cytosol; protein-containing complex | Wild-type BRAF resides as a cytosolic, monomeric autoinhibited complex with 14-3-3, with CRD and dimer interface occluded. | (liu2024reconstitutionandcharacterization pages 1-2, bonsor2024rasandshoc2 pages 1-3, mozzarelli2024functionalandstructural pages 6-7) |
| Plasma membrane active state | plasma membrane; plasma membrane protein-containing complex | Activated RAS recruits BRAF to membrane; membrane engagement plus dimerization generates the active signaling form. | (liu2024reconstitutionandcharacterization pages 1-2, bonsor2024rasandshoc2 pages 6-8, liu2024reconstitutionandcharacterization pages 7-9) |
| Complex with MEK and 14-3-3 | protein-containing complex | Cryo-EM/reconstitution studies identify autoinhibited BRAF-MEK-14-3-3 assemblies and related BRAF:14-3-3 complexes central to regulation. | (bonsor2024rasandshoc2 pages 1-3, fiesco2022structuralinsightsinto pages 1-2) |
| Other localization claims | no direct support for nucleus; no direct support for Golgi/endomembrane; no direct support for mitochondrion | In the retrieved GO-relevant sources, direct evidence supports cytosol, plasma membrane recruitment, and signaling complexes, but not nuclear, Golgi/endomembrane, or mitochondrial localization for BRAF. | (liu2024reconstitutionandcharacterization pages 2-4, mozzarelli2024functionalandstructural pages 6-7, liu2024reconstitutionandcharacterization pages 7-9) |
Table: This table maps core GO-relevant annotation themes for human BRAF to suggested term labels, concise mechanistic evidence, and the strongest supporting context IDs. It is useful as a compact evidence matrix for curating BRAF molecular function, biological process, and cellular component annotations.
BRAF is a RAF-family kinase whose primary role in the ERK pathway is to act as a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates MEK1/MEK2. This places BRAF immediately downstream of RAS and upstream of ERK1/2 signaling. (martinvega2023navigatingtheerk12 pages 2-4, bahar2023targetingtherasrafmapk pages 5-6)
ATP binding/kinase motifs. Structural descriptions identify canonical kinase features in BRAF, including residues involved in ATP coordination (e.g., K578 contacting ATPβs Ξ³-phosphate) and activation-segment/DFG conformational control of active vs inactive states; cryo-EM structures indicate the ATP-binding pocket can remain accessible even in an autoinhibited monomer. (imani2024theevolutionof pages 6-7, fiesco2022structuralinsightsinto pages 4-5)
Generic βprotein bindingβ is weakly informative for GO; the evidence supports specific binding functions that are mechanistically decisive:
* Ras GTPase binding via the BRAF RBD with exposed basic residues positioned to engage RAS switch regions. (fiesco2022structuralinsightsinto pages 5-7)
* 14-3-3 protein binding via two phosphoserine sites flanking/near the kinase domain (S365 and S729), central to autoinhibition and activation. (bonsor2024rasandshoc2 pages 1-3, fiesco2022structuralinsightsinto pages 4-5)
* Dimerization-associated protein binding (homo-/heterodimers) as an activation mechanism for wild-type RAF proteins. (bahar2023targetingtherasrafmapk pages 5-6, fiesco2022structuralinsightsinto pages 2-4)
A 2024 mechanistic study reconstituted full-length BRAF with 14-3-3 and membrane-tethered KRAS4B on lipid nanodiscs and showed GTP-dependent assembly, directly linking RAS-GTP + membrane to formation of an active BRAF signaling complex. (Liu et al., Protein Science, May 2024, DOI:10.1002/pro.5016, URL https://doi.org/10.1002/pro.5016) (liu2024reconstitutionandcharacterization pages 1-2, liu2024reconstitutionandcharacterization pages 2-4)
Key GO-relevant findings include:
* BRAF exists as an autoinhibited monomeric cytosolic complex and an active dimeric complex with distinct SEC-resolved species (supporting CC: cytosol vs membrane-associated signaling states). (liu2024reconstitutionandcharacterization pages 2-4, liu2024reconstitutionandcharacterization pages 1-2)
* Membrane lipid composition (e.g., anionic lipids) and RAS surface density modulate BRAF binding kinetics/affinity, supporting a mechanistic basis for βplasma membrane recruitmentβ annotations rather than generic βmembrane association.β (liu2024reconstitutionandcharacterization pages 7-9)
* The reconstituted BRAF complex is used in MEK phosphorylation assays in a membrane context, reinforcing BRAFβs MAP3K role. (liu2024reconstitutionandcharacterization pages 9-10)
High-resolution cryo-EM structures of autoinhibited BRAF complexes (with 14-3-3 and Β±MEK) resolve the BRAF RBD and show that, despite autoinhibition, key basic RBD residues are exposed and required for KRAS binding (supported by binding assays and mutational disruption). (Martinez Fiesco et al., Nature Communications, Jan 2022, DOI:10.1038/s41467-022-28084-3, URL https://doi.org/10.1038/s41467-022-28084-3) (fiesco2022structuralinsightsinto pages 5-7)
The same study links RAS binding to activation-relevant conformational steps:
* Autoinhibition is stabilized by a 14-3-3 dimer binding pS365 and pS729, occluding the CRD membrane-binding region and kinase dimer interface. (fiesco2022structuralinsightsinto pages 1-2, fiesco2022structuralinsightsinto pages 4-5)
* Superposition/modeling suggests that full RAS:RBD engagement would sterically/electrostatically perturb the adjacent 14-3-3 protomer, promoting release from pS365 and enabling the CRD to engage membrane and support subsequent kinase-domain dimerization. (fiesco2022structuralinsightsinto pages 8-9, fiesco2022structuralinsightsinto pages 2-4)
Recent authoritative reviews emphasize a conserved activation logic: cytosolic autoinhibited monomer β RAS-GTP membrane recruitment β relief of 14-3-3/CR2-site inhibition (often via SHOC2βMRASβPP1C) β active RAF dimer stabilized by 14-3-3 at C-terminal sites. (Bonsor & Simanshu, Annu Rev Cancer Biol, Jun 2024, DOI:10.1146/annurev-cancerbio-062822-030450, URL https://doi.org/10.1146/annurev-cancerbio-062822-030450) (bonsor2024rasandshoc2 pages 6-8, bonsor2024rasandshoc2 pages 1-3)
A 2024 Molecular Cell review of RAS effector proteins similarly highlights RAF dimerization at the plasma membrane as culminating in full activation, placing BRAF among the best structurally characterized RAS effectors. (Mozzarelli et al., Molecular Cell, Aug 2024, DOI:10.1016/j.molcel.2024.06.027, URL https://doi.org/10.1016/j.molcel.2024.06.027) (mozzarelli2024functionalandstructural pages 6-7)
Restriction on proliferation/differentiation claims. While ERK signaling is widely linked to proliferation/differentiation, within this evidence set the strongest GO-relevant support is for BRAFβs placement and biochemical role in the ERK cascade rather than specific downstream phenotypes. (martinvega2023navigatingtheerk12 pages 2-4, bahar2023targetingtherasrafmapk pages 5-6)
Multiple sources support that RAF proteins (including BRAF) reside in a cytosolic autoinhibited monomeric state stabilized by 14-3-3 binding to regulatory phosphosites (BRAF S365 and S729) and often in complex with MEK1. (liu2024reconstitutionandcharacterization pages 1-2, bonsor2024rasandshoc2 pages 1-3, fiesco2022structuralinsightsinto pages 1-2)
Upon RAS activation (GTP loading), BRAF is recruited to the plasma membrane, enabling CRD membrane engagement, exposure of the kinase dimer interface, and formation of active RAF dimers (homo- or heterodimers). (bonsor2024rasandshoc2 pages 6-8, mozzarelli2024functionalandstructural pages 6-7, liu2024reconstitutionandcharacterization pages 7-9)
In the retrieved GO-relevant corpus, there is no direct experimental evidence supporting BRAF localization to the nucleus, Golgi/endomembrane compartments, or mitochondria; therefore, these CC terms are not supported here and should not be inferred from downstream pathway membership. (liu2024reconstitutionandcharacterization pages 2-4, mozzarelli2024functionalandstructural pages 6-7, liu2024reconstitutionandcharacterization pages 7-9)
Wild-type BRAF is described as autoinhibited by 14-3-3 binding (pS365/pS729) and activated through RAS-GTP-dependent membrane recruitment followed by dimerization and conformational rearrangements. (martinvega2023navigatingtheerk12 pages 2-4, bonsor2024rasandshoc2 pages 1-3)
Evidence supports distinct mechanistic behaviors relevant to GO annotation:
* Class I (V600E): predominant oncogenic allele; can signal as a monomer and shows constitutively high kinase activity that is not further increased by membrane-tethered RAS in the reconstituted system; V600E is described as active regardless of oligomerization status. (martinvega2023navigatingtheerk12 pages 4-5, liu2024reconstitutionandcharacterization pages 7-9)
* Class II mutants/fusions: signal as RAS-independent dimers with increased activity (but generally less than V600E). (martinvega2023navigatingtheerk12 pages 4-5)
* Class III mutants: show impaired kinase activity and are described as not directly phosphorylating MEK while retaining RAS binding and ability to heterodimerize (implying a noncanonical/scaffold-like contribution rather than the core catalytic MF). (martinvega2023navigatingtheerk12 pages 4-5)
These distinctions should be captured in mutant-specific annotations and not conflated with wild-type function. (martinvega2023navigatingtheerk12 pages 4-5, liu2024reconstitutionandcharacterization pages 7-9)
Although not GO terms per se, the mechanistic features above directly inform real-world implementations:
* BRAF/MEK targeting leverages the restricted substrate relationship (RAFβMEKβERK). A 2023 high-citation review summarizes the pathway logic underpinning RAF/MEK inhibitor strategies and highlights dimerization-dependent activation as central to drug response/resistance mechanisms (relevant to how mutations shift BRAFβs GO-relevant catalytic state). (Bahar et al., Signal Transduction and Targeted Therapy, Dec 2023, DOI:10.1038/s41392-023-01705-z, URL https://doi.org/10.1038/s41392-023-01705-z) (bahar2023targetingtherasrafmapk pages 5-6)
References
(martinvega2023navigatingtheerk12 pages 2-4): Ana MartΓn-Vega and Melanie H. Cobb. Navigating the erk1/2 mapk cascade. Biomolecules, 13:1555, Oct 2023. URL: https://doi.org/10.3390/biom13101555, doi:10.3390/biom13101555. This article has 103 citations.
(bahar2023targetingtherasrafmapk pages 5-6): Md Entaz Bahar, Hyun Joon Kim, and D. Kim. Targeting the ras/raf/mapk pathway for cancer therapy: from mechanism to clinical studies. Signal Transduction and Targeted Therapy, Dec 2023. URL: https://doi.org/10.1038/s41392-023-01705-z, doi:10.1038/s41392-023-01705-z. This article has 938 citations and is from a peer-reviewed journal.
(liu2024reconstitutionandcharacterization pages 1-2): Ningdi F. Liu, Masahiro Enomoto, Christopher B. Marshall, and Mitsuhiko Ikura. Reconstitution and characterization of braf in complex with 14β3β3 and kras4b on nanodiscs. Protein Science : A Publication of the Protein Society, May 2024. URL: https://doi.org/10.1002/pro.5016, doi:10.1002/pro.5016. This article has 5 citations.
(liu2024reconstitutionandcharacterization pages 7-9): Ningdi F. Liu, Masahiro Enomoto, Christopher B. Marshall, and Mitsuhiko Ikura. Reconstitution and characterization of braf in complex with 14β3β3 and kras4b on nanodiscs. Protein Science : A Publication of the Protein Society, May 2024. URL: https://doi.org/10.1002/pro.5016, doi:10.1002/pro.5016. This article has 5 citations.
(imani2024theevolutionof pages 6-7): Saber Imani, Ghazaal Roozitalab, Mahdieh Emadi, Atefeh Moradi, Payam Behzadi, and Parham Jabbarzadeh Kaboli. The evolution of braf-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies. Frontiers in Oncology, Nov 2024. URL: https://doi.org/10.3389/fonc.2024.1504142, doi:10.3389/fonc.2024.1504142. This article has 51 citations.
(fiesco2022structuralinsightsinto pages 4-5): Juliana A. Martinez Fiesco, David E. Durrant, Deborah K. Morrison, and Ping Zhang. Structural insights into the braf monomer-to-dimer transition mediated by ras binding. Nature Communications, Jan 2022. URL: https://doi.org/10.1038/s41467-022-28084-3, doi:10.1038/s41467-022-28084-3. This article has 129 citations and is from a highest quality peer-reviewed journal.
(bonsor2024rasandshoc2 pages 1-3): Daniel A. Bonsor and Dhirendra K. Simanshu. Ras and shoc2 roles in raf activation and therapeutic considerations. Annual Review of Cancer Biology, 8:97-113, Jun 2024. URL: https://doi.org/10.1146/annurev-cancerbio-062822-030450, doi:10.1146/annurev-cancerbio-062822-030450. This article has 13 citations and is from a peer-reviewed journal.
(fiesco2022structuralinsightsinto pages 1-2): Juliana A. Martinez Fiesco, David E. Durrant, Deborah K. Morrison, and Ping Zhang. Structural insights into the braf monomer-to-dimer transition mediated by ras binding. Nature Communications, Jan 2022. URL: https://doi.org/10.1038/s41467-022-28084-3, doi:10.1038/s41467-022-28084-3. This article has 129 citations and is from a highest quality peer-reviewed journal.
(fiesco2022structuralinsightsinto pages 5-7): Juliana A. Martinez Fiesco, David E. Durrant, Deborah K. Morrison, and Ping Zhang. Structural insights into the braf monomer-to-dimer transition mediated by ras binding. Nature Communications, Jan 2022. URL: https://doi.org/10.1038/s41467-022-28084-3, doi:10.1038/s41467-022-28084-3. This article has 129 citations and is from a highest quality peer-reviewed journal.
(bonsor2024rasandshoc2 pages 4-6): Daniel A. Bonsor and Dhirendra K. Simanshu. Ras and shoc2 roles in raf activation and therapeutic considerations. Annual Review of Cancer Biology, 8:97-113, Jun 2024. URL: https://doi.org/10.1146/annurev-cancerbio-062822-030450, doi:10.1146/annurev-cancerbio-062822-030450. This article has 13 citations and is from a peer-reviewed journal.
(fiesco2022structuralinsightsinto pages 2-4): Juliana A. Martinez Fiesco, David E. Durrant, Deborah K. Morrison, and Ping Zhang. Structural insights into the braf monomer-to-dimer transition mediated by ras binding. Nature Communications, Jan 2022. URL: https://doi.org/10.1038/s41467-022-28084-3, doi:10.1038/s41467-022-28084-3. This article has 129 citations and is from a highest quality peer-reviewed journal.
(patel2023investigatingtherole pages 42-45): Khushali Patel. Investigating the role of oncogenic kras g12 mutations in cell signalling. Dissertation, Mar 2023. URL: https://doi.org/10.17863/cam.95441, doi:10.17863/cam.95441. This article has 0 citations.
(liu2024reconstitutionandcharacterization pages 9-10): Ningdi F. Liu, Masahiro Enomoto, Christopher B. Marshall, and Mitsuhiko Ikura. Reconstitution and characterization of braf in complex with 14β3β3 and kras4b on nanodiscs. Protein Science : A Publication of the Protein Society, May 2024. URL: https://doi.org/10.1002/pro.5016, doi:10.1002/pro.5016. This article has 5 citations.
(mozzarelli2024functionalandstructural pages 6-7): Alessandro M. Mozzarelli, Dhirendra K. Simanshu, and Pau Castel. Functional and structural insights into ras effector proteins. Molecular Cell, 84:2807-2821, Aug 2024. URL: https://doi.org/10.1016/j.molcel.2024.06.027, doi:10.1016/j.molcel.2024.06.027. This article has 35 citations and is from a highest quality peer-reviewed journal.
(bonsor2024rasandshoc2 pages 6-8): Daniel A. Bonsor and Dhirendra K. Simanshu. Ras and shoc2 roles in raf activation and therapeutic considerations. Annual Review of Cancer Biology, 8:97-113, Jun 2024. URL: https://doi.org/10.1146/annurev-cancerbio-062822-030450, doi:10.1146/annurev-cancerbio-062822-030450. This article has 13 citations and is from a peer-reviewed journal.
(liu2024reconstitutionandcharacterization pages 2-4): Ningdi F. Liu, Masahiro Enomoto, Christopher B. Marshall, and Mitsuhiko Ikura. Reconstitution and characterization of braf in complex with 14β3β3 and kras4b on nanodiscs. Protein Science : A Publication of the Protein Society, May 2024. URL: https://doi.org/10.1002/pro.5016, doi:10.1002/pro.5016. This article has 5 citations.
(fiesco2022structuralinsightsinto pages 8-9): Juliana A. Martinez Fiesco, David E. Durrant, Deborah K. Morrison, and Ping Zhang. Structural insights into the braf monomer-to-dimer transition mediated by ras binding. Nature Communications, Jan 2022. URL: https://doi.org/10.1038/s41467-022-28084-3, doi:10.1038/s41467-022-28084-3. This article has 129 citations and is from a highest quality peer-reviewed journal.
(martinvega2023navigatingtheerk12 pages 4-5): Ana MartΓn-Vega and Melanie H. Cobb. Navigating the erk1/2 mapk cascade. Biomolecules, 13:1555, Oct 2023. URL: https://doi.org/10.3390/biom13101555, doi:10.3390/biom13101555. This article has 103 citations.
Falcon synthesis supports BRAF as a RAF-family serine/threonine kinase and
MAP3K in the canonical RAS-RAF-MEK-ERK cascade
[file:human/BRAF/BRAF-deep-research-falcon.md "BRAF is a RAF-family serine/threonine protein kinase that functions as the MAP3K tier in the canonical RASβRAFβMEK1/2βERK1/2 cascade"]. UniProt independently supports the same core pathway placement via MEK phosphorylation
[file:human/BRAF/BRAF-uniprot.txt "Phosphorylates MAP2K1, and thereby activates the MAP kinase signal"].
The core review should emphasize cytosolic autoinhibited BRAF and plasma-membrane
active RAF dimers, while treating nuclear, mitochondrial, endomembrane, and
downstream cancer/transcription/metabolic phenotypes cautiously unless the cited
source directly tests BRAF
[file:human/BRAF/BRAF-deep-research-falcon.md "Evidence in this corpus supports cytosolic autoinhibited complexes and plasma-membrane-associated active dimers, but does not provide direct support for nuclear, Golgi/endomembrane, or mitochondrial localization for BRAF"].
Unresolved GOA rows were converted from PENDING to ACCEPT, KEEP_AS_NON_CORE,
MODIFY, REMOVE, or MARK_AS_OVER_ANNOTATED according to whether they support the
core RAF/MAPK kinase function, a peripheral regulatory context, a wrong kinase
tier, or a mutant/cancer-specific overextension.
id: P15056
gene_symbol: BRAF
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'BRAF encodes a RAF-family serine/threonine protein kinase (EC 2.7.11.1) that is the canonical mitogen-activated
protein kinase kinase kinase (MAP3K) of the RAS-RAF-MEK-ERK signaling cascade. In quiescent cells BRAF is autoinhibited
by an intramolecular interaction between its N-terminal regulatory region and the C-terminal kinase domain. Mitogenic stimulation
generates GTP-loaded RAS, which binds the BRAF RAS-binding domain (RBD), relieves autoinhibition, and recruits BRAF to the
plasma membrane. Activation requires side-to-side dimerization β BRAF homodimers and, most potently, BRAF-RAF1 (CRAF) heterodimers
β stabilized by 14-3-3 proteins and the HSP90/CDC37 chaperone system. Activated BRAF phosphorylates and activates MAP2K1/MAP2K2
(MEK1/MEK2), the committed step that propagates mitogenic signaling through ERK1/ERK2 to control proliferation, differentiation
and survival. BRAF localizes to the cytoplasm/cytosol and to the plasma membrane in its active RAS-bound state. It is a
major oncogenic driver: the V600E activating mutation, which renders the kinase constitutively active as a RAS-independent
monomer, is recurrent in melanoma, papillary thyroid carcinoma, colorectal cancer, hairy-cell leukemia and other tumors,
and germline BRAF mutations cause cardiofaciocutaneous syndrome.'
existing_annotations:
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for cytoplasmic localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases).
Consistent with direct evidence on cytoplasm in this file (PMID:19710016, EXP) and the 59 Reactome TAS cytosol rows
already ACCEPTed in PR #440.'
action: ACCEPT
reason: 'PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports canonical BRAF cytoplasmic localization,
which is also directly demonstrated experimentally (PMID:19710016) and via Reactome TAS evidence on the more specific
child term GO:0005829 cytosol. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA
rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion)
is held back for separate per-row consideration in a later batch.'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for plasma membrane localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr
Kinases-Pseudokinases). BRAF is recruited to the PM by RAS-GTP upon receptor activation. Consistent with direct evidence
on PM in this file (PMID:19710016, EXP) and the 13 Reactome TAS PM rows already ACCEPTed in PR #440.'
action: ACCEPT
reason: 'PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports canonical BRAF plasma membrane localization
(the RAS-GTP-recruited activated state), which is also directly demonstrated experimentally (PMID:19710016) and via
Reactome TAS evidence in this file. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical
IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion)
is held back for separate per-row consideration in a later batch.'
- term:
id: GO:0000165
label: MAPK cascade
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for canonical BRAF participation in the MAPK cascade, propagated by PAINT from PANTHER family
PTHR44329 (Ser/Thr Kinases-Pseudokinases). BRAF is the canonical RAF kinase phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK
cascade; consistent with the IDA evidence on the same term in this file (PMID:18567582, PMID:29433126).'
action: ACCEPT
reason: 'PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports BRAF participation in the canonical
MAPK cascade, which is also directly demonstrated experimentally on the same term in this file (PMID:18567582, PMID:29433126).
Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm, plasma membrane,
MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for separate per-row
consideration in a later batch.'
- term:
id: GO:0004709
label: MAP kinase kinase kinase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for MAP kinase kinase kinase (MAP3K) activity, propagated by PAINT from PANTHER family PTHR44329
(Ser/Thr Kinases-Pseudokinases). This is BRAF''s canonical molecular function β phosphorylating MEK1/MEK2 (MAP2Ks) in
the RAS-RAF-MEK-ERK cascade. Consistent with IDA/EXP evidence on related kinase terms in this file (PMID:18567582, PMID:29433126,
PMID:21441910).'
action: ACCEPT
reason: 'PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports BRAF as a canonical MAP3K. This is
the gene''s defining molecular function; extensive direct experimental evidence on the closely-related kinase terms
(GO:0004674 protein serine/threonine kinase activity, GO:0106310 protein serine kinase activity) is already present
in this file. Mechanically consolidated to ACCEPT with a uniform template across the 5 canonical IBA rows (cytoplasm,
plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739 mitochondrion) is held back for
separate per-row consideration in a later batch.'
supported_by:
- reference_id: file:human/BRAF/BRAF-deep-research-falcon.md
supporting_text: BRAF is a RAF-family kinase whose primary role in the ERK pathway is to act as a MAP kinase
kinase kinase (MAP3K) that phosphorylates and activates MEK1/MEK2.
- term:
id: GO:0005829
label: cytosol
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for cytosolic localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases).
BRAF in the autoinhibited 14-3-3-bound resting state is cytosolic; consistent with the 59 Reactome TAS cytosol rows
already ACCEPTed in PR #440 and direct evidence on cytoplasm/PM in this file (PMID:19710016).'
action: ACCEPT
reason: 'PAINT/IBA propagation from the PANTHER PTHR44329 reference family supports canonical BRAF cytosolic localization
(the autoinhibited 14-3-3/Hsp90/CDC37-bound resting state), which is also directly demonstrated experimentally and via
Reactome TAS evidence on the same term in this file. Mechanically consolidated to ACCEPT with a uniform template across
the 5 canonical IBA rows (cytoplasm, plasma membrane, MAPK cascade, MAP3K activity, cytosol); the 6th IBA row (GO:0005739
mitochondrion) is held back for separate per-row consideration in a later batch.'
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for mitochondrial localization, propagated by PAINT from PANTHER family PTHR44329 (Ser/Thr Kinases-Pseudokinases).
BRAF is not listed under mitochondrion in the UniProt subcellular location (only Nucleus, Cytoplasm, Cell membrane);
mitochondrial localization is best characterized for the RAF-family paralog CRAF/RAF-1 (regulating BAD phosphorylation),
so this is a minor context-specific RAF-family role rather than a core BRAF function in the canonical RAS-RAF-MEK-ERK
cascade.'
action: KEEP_AS_NON_CORE
reason: 'Mitochondrial localization is a minor, context-specific role best described for the RAF-family paralog CRAF/RAF-1,
not a core BRAF function; the dominant BRAF localization is cytosolic/plasma-membrane where the canonical RAS-RAF-MEK-ERK
cascade operates (already captured via direct experimental and Reactome TAS evidence in this file). This resolves the
6th canonical IBA row held back from PR #448 for separate per-row consideration, and is consistent with the parallel
IEA Ensembl Compara mitochondrion row (GO_REF:0000107, line 591) already resolved to KEEP_AS_NON_CORE with the explicit
note that the IBA row should resolve the same way.'
- term:
id: GO:0004672
label: protein kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'IEA annotation for protein kinase activity from GO_REF:0000120 (combined ECO/GO mapping). BRAF is a canonical
Ser/Thr protein kinase phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade β directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and supported by IBA on the more specific
child term GO:0004709 MAP3K activity (PR #448).'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0004674
label: protein serine/threonine kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000003
review:
summary: 'IEA annotation from GO_REF:0000003 (UniProt keyword KW-0723 Serine/threonine-protein kinase). BRAF is a canonical
Ser/Thr kinase β directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126
IDA/IMP) and supported by IBA on the more specific child term GO:0004709 MAP3K activity (PR #448).'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: 'IEA annotation from GO_REF:0000002 (InterPro2GO) for ATP binding. BRAF binds ATP via the kinase-domain glycine-rich
loop and DFG motif β a defining feature of the protein kinase fold; directly supported by IDA/EXP evidence on kinase
activity terms in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP).'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'IEA annotation for nuclear localization from GO_REF:0000044. UniProt lists Nucleus for BRAF only by similarity
(ECO:0000250), whereas Cytoplasm and Cell membrane have direct experimental support (PMID:19710016). Nuclear localization
is reported but tissue/context-specific and is not where BRAF''s core RAS-RAF-MEK-ERK kinase function operates.'
action: KEEP_AS_NON_CORE
reason: 'Nuclear localization is recognized in UniProt only by similarity (ECO:0000250) and is tissue/context-specific
rather than the site of BRAF''s defining function; the core RAS-RAF-MEK-ERK kinase activity operates at the cytoplasm/plasma
membrane (captured via direct experimental evidence PMID:19710016 EXP and Reactome TAS rows in this file). Kept rather
than removed because UniProt records the nuclear localization, but flagged non-core. This resolves the GO:0005634 nucleus
IEA row explicitly held back from the canonical IEA consolidation in PR #456 for separate per-row consideration.'
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'IEA annotation from GO_REF:0000120 for cytoplasmic localization. Already ACCEPTed via IBA propagation in PR
#448 and consistent with direct experimental evidence in this file (PMID:19710016 EXP) β BRAF in the autoinhibited 14-3-3-bound
resting state is cytosolic prior to RAS-GTP-mediated PM recruitment.'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'IEA annotation from GO_REF:0000120 for plasma membrane localization. Already ACCEPTed via IBA propagation in
PR #448 and on 13 Reactome TAS rows in PR #440. Directly demonstrated experimentally in this file (PMID:19710016 EXP)
β BRAF is recruited to the PM by RAS-GTP upon receptor activation.'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: 'IEA annotation from GO_REF:0000002 (InterPro2GO) for signal transduction. BRAF is the canonical RAF kinase in
the RAS-RAF-MEK-ERK signaling cascade β directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:29433126
IDA/IMP) and supported by IBA on the more specific child term GO:0000165 MAPK cascade (PR #448).'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: 'IEA annotation from GO_REF:0000117 (ARBA propagation). BRAF activates MEK/ERK signaling, leading to phosphorylation
of pro-apoptotic factors (e.g. BAD on Ser112/Ser155 by RSK downstream of ERK; BIM via ERK-mediated proteasomal degradation),
and is well-established as anti-apoptotic in canonical RAS-RAF-MEK-ERK signaling. Consistent with the canonical RAF
survival role and the Reactome RAS-MAPK signaling rows already ACCEPTed in PR #440.'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0098794
label: postsynapse
evidence_type: IEA
original_reference_id: GO_REF:0000108
review:
summary: 'IEA annotation from GO_REF:0000108 (logical-inference-based IEA via inter-ontology links; the postsynapse term
is reachable via SynGO axioms). BRAF is expressed in neurons and germline BRAF activating mutations cause cardio-facio-cutaneous
syndrome with neurological features, so a postsynaptic localization in specific neuronal contexts is plausible. However,
this represents a tissue/cell-type-specific localization rather than a constitutive cellular function, and is not a
core BRAF function β the canonical RAS-RAF-MEK-ERK signaling activity at the cytoplasm/cytosol/plasma membrane is what
defines BRAF.'
action: KEEP_AS_NON_CORE
reason: 'Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization
(cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016
EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically
consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier
batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission).'
- term:
id: GO:0106310
label: protein serine kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000116
review:
summary: 'IEA annotation from GO_REF:0000116 for protein serine kinase activity β the most specific MF child of GO:0004674.
BRAF phosphorylates MEK1/MEK2 on serine residues β directly demonstrated experimentally in this file (PMID:18567582
IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP).'
action: ACCEPT
reason: 'IEA mechanical propagation supports a canonical BRAF function or localization directly demonstrated experimentally
in this file (PMID:18567582 IDA, PMID:19710016 EXP, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and/or already ACCEPTed
via the IBA propagation batch (PR #448) or the Reactome TAS rows (PR #440). Mechanically consolidated to ACCEPT with
a uniform template across the 8 canonical IEA rows (protein kinase activity, S/T kinase, ATP binding, cytoplasm, PM,
signal transduction, neg-reg apoptosis, S kinase); the GO:0005634 nucleus IEA row is held back for separate per-row
consideration (BRAF nuclear localization is reported but tissue/context-specific), and the 6 SynGO/tissue-specific IEA
rows (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission, mitochondrion) are held back for a uniform KEEP_AS_NON_CORE batch.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12620389
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15161933
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15778465
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16810323
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16888650
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17380122
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17563371
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17979178
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20130576
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20141835
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21441910
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21478863
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21625473
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22169110
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22510884
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22939624
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23153539
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23680146
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23934108
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24255178
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24441586
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24746704
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25155755
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25241761
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25437913
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25600339
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26165597
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26466569
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26496610
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:30194290
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31980649
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32707033
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:34591642
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35512704
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35839996
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:36241744
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:36931259
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:37045861
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40205054
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:16858395
review:
summary: 'IPI annotation supporting BRAF homodimerization (and hetero-dimerization with CRAF), demonstrated experimentally
as Ca2+-dependent and mediated by the N-terminal BRAF-specific region (Terai & Matsuda 2006, EMBO J). BRAF homodimerization
is a canonical and required step in RAF kinase activation in the RAS-RAF-MEK-ERK cascade.'
action: ACCEPT
reason: 'BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical
and required step in RAF activation. The GO:0042802 ''identical protein binding'' annotation is biologically informative
for BRAF β more so than the generic GO:0005515 ''protein binding'' rows already demoted in PR #437 β and is supported
by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913),
mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395,
PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704
is held back for separate per-row consideration (that paper''s primary focus is BRAF V600E heterotypic neoPPI with KEAP1
rather than BRAF homodimerization).'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:19727074
review:
summary: 'IPI annotation supporting BRAF homodimerization, derived from the canonical Rajakulendran et al. 2009 Nature
paper establishing that a side-by-side RAF kinase-domain dimer is required for catalytic activation. This paper defined
the dimer interface (the alphaC-out conformation and arginine-mediated contacts) that has become the textbook model
for RAF activation in the RAS-RAF-MEK-ERK cascade.'
action: ACCEPT
reason: 'BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical
and required step in RAF activation. The GO:0042802 ''identical protein binding'' annotation is biologically informative
for BRAF β more so than the generic GO:0005515 ''protein binding'' rows already demoted in PR #437 β and is supported
by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913),
mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395,
PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704
is held back for separate per-row consideration (that paper''s primary focus is BRAF V600E heterotypic neoPPI with KEAP1
rather than BRAF homodimerization).'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:22169110
review:
summary: 'IPI annotation supporting BRAF homodimerization, derived from Packer et al. 2011 Cancer Cell on paradoxical
RAF activation in nilotinib-resistant CML. The mechanism documented in this paper β kinase-inhibitor-induced trans-activation
of MAPK signaling via RAF dimer formation β directly depends on BRAF self-association at the dimer interface.'
action: ACCEPT
reason: 'BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical
and required step in RAF activation. The GO:0042802 ''identical protein binding'' annotation is biologically informative
for BRAF β more so than the generic GO:0005515 ''protein binding'' rows already demoted in PR #437 β and is supported
by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913),
mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395,
PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704
is held back for separate per-row consideration (that paper''s primary focus is BRAF V600E heterotypic neoPPI with KEAP1
rather than BRAF homodimerization).'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:22510884
review:
summary: 'IPI annotation supporting BRAF homodimerization, derived from RΓΆring et al. 2012 EMBO J. Direct mutational dissection
showing that an intact BRAF kinase-domain dimer interface (the same side-by-side interface identified in PMID:19727074)
is required for WT BRAF MAPK signaling, and that the kinase-dead/V600E paradoxical activation phenotype also depends
on dimer formation. Strongest single piece of evidence in this set that the BRAF homodimer is a load-bearing functional
unit rather than an incidental interaction.'
action: ACCEPT
reason: 'BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical
and required step in RAF activation. The GO:0042802 ''identical protein binding'' annotation is biologically informative
for BRAF β more so than the generic GO:0005515 ''protein binding'' rows already demoted in PR #437 β and is supported
by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913),
mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395,
PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704
is held back for separate per-row consideration (that paper''s primary focus is BRAF V600E heterotypic neoPPI with KEAP1
rather than BRAF homodimerization).'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25155755
review:
summary: 'IPI annotation supporting BRAF homodimerization, derived from Haling et al. 2014 Cancer Cell β the X-ray crystal
structure of the BRAF-MEK complex, in which BRAF is captured as a side-by-side homodimer with MEK bound to each protomer.
Directly visualizes the BRAF kinase-domain homodimer interface in a productive signaling complex.'
action: ACCEPT
reason: 'BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical
and required step in RAF activation. The GO:0042802 ''identical protein binding'' annotation is biologically informative
for BRAF β more so than the generic GO:0005515 ''protein binding'' rows already demoted in PR #437 β and is supported
by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913),
mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395,
PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704
is held back for separate per-row consideration (that paper''s primary focus is BRAF V600E heterotypic neoPPI with KEAP1
rather than BRAF homodimerization).'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25437913
review:
summary: 'IPI annotation supporting BRAF homodimerization, derived from Thevakumaran et al. 2015 Nat Struct Mol Biol.
Although the title emphasizes a BRAF kinase-domain monomer structure, the paper''s mechanistic conclusion is that BRAF
activation requires the monomer-to-side-by-side-dimer transition, and the asymmetric unit captures inactive-state contacts
directly informative for dimer-based allosteric regulation. Together with PMID:19727074 and PMID:25155755 this represents
the structural literature establishing the BRAF dimer interface.'
action: ACCEPT
reason: 'BRAF homodimerization (side-by-side kinase-domain dimer plus N-terminal Ca2+-dependent dimerization) is a canonical
and required step in RAF activation. The GO:0042802 ''identical protein binding'' annotation is biologically informative
for BRAF β more so than the generic GO:0005515 ''protein binding'' rows already demoted in PR #437 β and is supported
by extensive direct experimental evidence across X-ray crystallography (PMID:19727074, PMID:25155755, PMID:25437913),
mutational dissection of the dimer interface (PMID:22510884), and biochemical/cell-based dimerization assays (PMID:16858395,
PMID:22169110). Mechanically consolidated to ACCEPT with a uniform template across the 6 BRAF dimerization PMIDs; PMID:35512704
is held back for separate per-row consideration (that paper''s primary focus is BRAF V600E heterotypic neoPPI with KEAP1
rather than BRAF homodimerization).'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:35512704
review:
summary: 'IPI annotation for GO:0042802 identical protein binding, derived from Mo et al. 2022 Cell (PMID:35512704 β systematic
discovery of mutation-directed neo-protein-protein interactions in cancer). The BRAF-specific finding in this high-throughput
BRET screen is the BRAF V600E/KEAP1 neoPPI: a mutant-allele-specific heterotypic interaction between BRAF V600E and
KEAP1 (a different protein) that rewires a BRAF V600E/KEAP1/NRF2 redox-signaling axis. The paper does not demonstrate
BRAF self-association / homodimerization.'
action: MARK_AS_OVER_ANNOTATED
reason: 'BRAF homodimerization is a genuine, canonical core function and GO:0042802 identical protein binding is already
ACCEPTed on the five dimerization-focused structural/biochemical rows in this file (PMID:19727074, PMID:25155755, PMID:25437913,
PMID:22510884, plus PMID:16858395/PMID:22169110). However, PMID:35512704 does not support identical protein binding
for BRAF: its BRAF finding is a V600E-specific heterotypic neoPPI with KEAP1, not BRAF self-dimerization. This reference-derived
GO:0042802 row is therefore an over-annotation β the term is correct for BRAF but this particular evidence does not
support it, and the homodimer biology is already fully captured by the ACCEPTed structural rows. Held back from the
dimerization batch for this per-row consideration.'
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF mitochondrial localization
has been reported (e.g. RAF-1/CRAF mitochondrial pool affecting BAD phosphorylation), and an IBA mitochondrion row also
propagates from PANTHER PTHR44329, suggesting some RAF-family members localize to mitochondria. However, the dominant
BRAF localization is cytosolic/plasma-membrane and the mitochondrial role is not a core BRAF function in the canonical
RAS-RAF-MEK-ERK cascade.'
action: KEEP_AS_NON_CORE
reason: 'Mitochondrial localization is a minor context-specific role for some RAF-family members (best described for CRAF/RAF-1)
rather than a core BRAF function. The dominant BRAF localization is cytosolic/plasma-membrane and the canonical RAS-RAF-MEK-ERK
cascade is already captured via direct experimental evidence in this file (PMID:19710016 EXP, PMID:18567582, PMID:21441910)
and via Reactome TAS rows (PR #440). The parallel IBA mitochondrion row (GO_REF:0000033, line 61) remains PENDING for
separate per-row review; keeping the IEA Ensembl Compara row as KEEP_AS_NON_CORE here is consistent with how the IBA
row is likely to resolve.'
- term:
id: GO:0043005
label: neuron projection
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons
and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so neuron projection
localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific localization
rather than a constitutive cellular function, and is not a core BRAF function β the canonical RAS-RAF-MEK-ERK signaling
activity at cytoplasm/cytosol/plasma membrane is what defines BRAF.'
action: KEEP_AS_NON_CORE
reason: 'Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization
(cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016
EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically
consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier
batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission).'
- term:
id: GO:0044297
label: cell body
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons
and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so neuronal
cell body localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific
localization rather than a constitutive cellular function, and is not a core BRAF function β the canonical RAS-RAF-MEK-ERK
signaling activity at cytoplasm/cytosol/plasma membrane is what defines BRAF.'
action: KEEP_AS_NON_CORE
reason: 'Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization
(cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016
EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically
consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier
batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission).'
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons
and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so glutamatergic
synapse localization in specific neuronal contexts is plausible. However, this represents a tissue/cell-type-specific
localization rather than a constitutive cellular function, and is not a core BRAF function.'
action: KEEP_AS_NON_CORE
reason: 'Tissue/cell-type-specific neuronal/synaptic localization rather than a core BRAF function. Canonical BRAF localization
(cytosol, plasma membrane, cytoplasm) is already captured via direct experimental evidence in this file (PMID:19710016
EXP, PMID:18567582, PMID:21441910) and via the IBA propagation batch (PR #448) and Reactome TAS rows (PR #440). Mechanically
consolidated to KEEP_AS_NON_CORE with a uniform template across the neuronal/synaptic CC rows held back from earlier
batches (postsynapse, neuron projection, cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic
transmission).'
- term:
id: GO:0099170
label: postsynaptic modulation of chemical synaptic transmission
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'IEA annotation from GO_REF:0000107 (Ensembl Compara ortholog-based propagation). BRAF is expressed in neurons
and germline BRAF activating mutations cause cardio-facio-cutaneous syndrome with neurological features, so a role in
postsynaptic modulation of chemical synaptic transmission in specific neuronal contexts is plausible. However, this
represents a tissue/cell-type-specific biological process rather than a constitutive function, and is not a core BRAF
function β the canonical RAS-RAF-MEK-ERK signaling cascade is what defines BRAF.'
action: KEEP_AS_NON_CORE
reason: 'Tissue/cell-type-specific neuronal/synaptic biology rather than a core BRAF function. Canonical BRAF activity
(MAPK cascade, MAP3K activity, S/T kinase activity) is already captured via direct experimental evidence in this file
(PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP). Mechanically consolidated to KEEP_AS_NON_CORE with a
uniform template across the neuronal/synaptic CC/BP rows held back from earlier batches (postsynapse, neuron projection,
cell body, glutamatergic synapse, postsynaptic modulation of chemical synaptic transmission).'
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: 'IDA annotation for cytosolic localization from the Human Protein Atlas antibody-based subcellular localization
pipeline (GO_REF:0000052). BRAF in the autoinhibited 14-3-3/Hsp90/CDC37-bound resting state is cytosolic, prior to RAS-GTP-mediated
PM recruitment. Already extensively supported in this file via the 59 Reactome TAS cytosol rows ACCEPTed in PR #440
and the IBA propagation row ACCEPTed in PR #448.'
action: ACCEPT
reason: 'Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma
membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively
captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA
propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane
ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization
rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: 'IDA annotation for plasma membrane localization from the Human Protein Atlas antibody-based subcellular localization
pipeline (GO_REF:0000052). BRAF is recruited to the PM by RAS-GTP upon receptor activation, where it dimerizes and phosphorylates
MEK in the canonical RAS-RAF-MEK-ERK cascade. Already extensively supported in this file via the 13 Reactome TAS plasma
membrane rows ACCEPTed in PR #440 and the IBA propagation row ACCEPTed in PR #448.'
action: ACCEPT
reason: 'Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma
membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively
captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA
propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane
ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization
rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.'
- term:
id: GO:0005737
label: cytoplasm
evidence_type: EXP
original_reference_id: PMID:19710016
review:
summary: 'EXP annotation for cytoplasmic localization from PMID:19710016 (Yasuda et al. 2009, J Biol Chem), which characterized
BRAF/CRAF/DGKeta colocalization and heterodimerization in HeLa cells using immunofluorescence and biochemical fractionation.
Already supported via IBA propagation (PR #448), IEA propagation (PR #456), and the 59 Reactome TAS cytosol rows on
the more specific child term GO:0005829 (PR #440).'
action: ACCEPT
reason: 'Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma
membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively
captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA
propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane
ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization
rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: EXP
original_reference_id: PMID:19710016
review:
summary: 'EXP annotation for plasma membrane localization from PMID:19710016 (Yasuda et al. 2009, J Biol Chem), which
demonstrated BRAF/CRAF/DGKeta colocalization at the plasma membrane upon EGF stimulation in HeLa cells, supporting BRAF
recruitment to the PM in the activated RAS-RAF-MEK-ERK signaling state. Already supported via IBA propagation (PR #448),
IEA propagation (PR #456), and the 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440.'
action: ACCEPT
reason: 'Canonical BRAF subcellular localization. The cytosolic (autoinhibited 14-3-3-bound resting state) and plasma
membrane (RAS-GTP-recruited activated state) localizations are the dominant BRAF distribution and are already extensively
captured in this file: 59 Reactome TAS cytosol rows and 13 Reactome TAS plasma membrane rows ACCEPTed in PR #440, IBA
propagation rows for cytoplasm/plasma membrane/cytosol ACCEPTed in PR #448, and IEA rows for cytoplasm/plasma membrane
ACCEPTed in PR #456. This 4-row batch mechanically consolidates the remaining direct-evidence canonical localization
rows (HPA IDA via GO_REF:0000052; primary literature EXP via PMID:19710016) to ACCEPT with a uniform template.'
- term:
id: GO:0106310
label: protein serine kinase activity
evidence_type: EXP
original_reference_id: PMID:21441910
review:
summary: 'EXP annotation for protein serine kinase activity from PMID:21441910 (Brennan et al. 2011 Nature β A Raf-induced
allosteric transition of KSR stimulates phosphorylation of MEK). Direct experimental measurement of BRAF Ser/Thr kinase
activity on the GO:0106310 most-specific MF child term. Already supported via IEA propagation in PR #456 (line 144:
GO:0106310 IEA GO_REF:0000116 ACCEPTed) and via the IBA propagation batch in PR #448 on the GO:0004709 MAP3K activity
child.'
action: ACCEPT
reason: 'Canonical BRAF Ser/Thr kinase MF directly demonstrated experimentally. PMID:21441910 is one of the three canonical
experimental BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in
PR #456 (lines 69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA,
PMID:21441910 EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical
kinase / MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2
GO:0106310 EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row
MODIFY review per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term,
separate batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary
findings, separate per-row review).'
- term:
id: GO:0106310
label: protein serine kinase activity
evidence_type: EXP
original_reference_id: PMID:29433126
review:
summary: 'EXP annotation for protein serine kinase activity from PMID:29433126, one of the canonical BRAF kinase experimental
papers cited across this file as direct evidence (IDA/IMP) for BRAF S/T kinase function. Direct experimental measurement
of BRAF Ser-kinase activity on the GO:0106310 most-specific MF child term. Already supported via IEA propagation in
PR #456 (line 144: GO:0106310 IEA GO_REF:0000116 ACCEPTed) and via the IBA propagation batch in PR #448 on the GO:0004709
MAP3K activity child.'
action: ACCEPT
reason: 'Canonical BRAF Ser/Thr kinase MF directly demonstrated experimentally. PMID:29433126 is one of the three canonical
experimental BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in
PR #456 (lines 69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA,
PMID:21441910 EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical
kinase / MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2
GO:0106310 EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row
MODIFY review per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term,
separate batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary
findings, separate per-row review).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672950
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672951
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672960
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672961
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672966
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672969
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672972
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672973
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672978
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5672980
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5674130
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5674132
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5674140
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5675417
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5675431
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5675433
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802924
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803240
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9610152
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9610153
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9610154
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9610156
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9610163
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9653108
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9656209
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9656211
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9656212
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9656213
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9656214
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9656215
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9657599
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9657603
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9657606
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9657608
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9658445
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9660536
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9660538
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5675198
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802908
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802922
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802924
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802925
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802926
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803233
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803240
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802910
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802911
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802912
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802930
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802938
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803227
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0000165
label: MAPK cascade
evidence_type: IDA
original_reference_id: PMID:29433126
review:
summary: 'IDA annotation for MAPK cascade from PMID:29433126, one of the canonical BRAF kinase experimental papers cited
across this file as direct evidence (IDA/IMP) for BRAF function in the RAS-RAF-MEK-ERK cascade. Direct experimental
measurement of BRAF participation in the MAPK cascade. Already supported via IBA propagation in PR #448 on GO:0000165
(the IEA ACCEPT for GO:0007165 signal transduction in PR #456 at line 117 explicitly notes "supported by IBA on the
more specific child term GO:0000165 MAPK cascade (PR #448)") and via Reactome TAS rows for the RAS-MAPK pathway events
ACCEPTed in PR #440.'
action: ACCEPT
reason: 'Canonical BRAF BP directly demonstrated experimentally. PMID:29433126 is one of the three canonical experimental
BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in PR #456 (lines
69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910
EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical kinase /
MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2 GO:0106310
EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row MODIFY review
per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term, separate
batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary
findings, separate per-row review).'
- term:
id: GO:0004708
label: MAP kinase kinase activity
evidence_type: IMP
original_reference_id: PMID:29433126
review:
summary: 'IMP annotation for GO:0004708 MAP kinase kinase activity from Lavoie et al. 2018 Nature (PMID:29433126 β MEK
drives BRAF activation through allosteric control of KSR proteins). The paper establishes that RAF-family kinase activation
depends on kinase-domain dimerization and that BRAF acts on MEK within the RAS-RAF-MEK-ERK cascade. BRAF is a MAP kinase
kinase kinase (MAP3K): it phosphorylates MEK1/MEK2 (the MAP2Ks); it does not phosphorylate ERK and does not itself have
MAP2K (MAP kinase kinase) activity. GO:0004708 describes the catalytic activity of MEK, not of BRAF.'
action: MODIFY
reason: 'The essence of the annotation is sound (BRAF is the kinase that drives the MAPK cascade by phosphorylating the
next kinase down), but GO:0004708 (MAP kinase kinase activity) is the wrong tier of the MAPK kinase cascade for BRAF.
BRAF phosphorylates MEK1/MEK2 β the MAP2Ks β so BRAF''s molecular function is GO:0004709 MAP kinase kinase kinase activity
(MAP3K activity), not MAP2K activity. MODIFY to GO:0004709, which is already independently ACCEPTed in this file via
IBA propagation from PANTHER PTHR44329 (PR #448, line 38) and consistent with the canonical kinase MF evidence in-file
(PMID:21441910 EXP, PMID:18567582 IDA). This resolves the long-standing MAP2K-vs-MAP3K carryover note flagged across
earlier batches.'
proposed_replacement_terms:
- id: GO:0004709
label: MAP kinase kinase kinase activity
- term:
id: GO:0000165
label: MAPK cascade
evidence_type: IDA
original_reference_id: PMID:18567582
review:
summary: 'IDA annotation for MAPK cascade from PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin
and B-Raf signaling), one of the canonical BRAF kinase experimental papers cited across this file as direct evidence
(IDA) for BRAF function in the RAS-RAF-MEK-ERK cascade. Direct experimental measurement of BRAF participation in the
MAPK cascade. Already supported via IBA propagation in PR #448 on GO:0000165 (the IEA ACCEPT for GO:0007165 signal transduction
in PR #456 at line 117 explicitly notes "supported by IBA on the more specific child term GO:0000165 MAPK cascade (PR
#448)") and via Reactome TAS rows for the RAS-MAPK pathway events ACCEPTed in PR #440.'
action: ACCEPT
reason: 'Canonical BRAF BP directly demonstrated experimentally. PMID:18567582 is one of the three canonical experimental
BRAF kinase activity papers cited as the anchoring evidence across the IEA mechanical consolidation in PR #456 (lines
69, 78, 87, 104, 122, 131, 149) β "directly demonstrated experimentally in this file (PMID:18567582 IDA, PMID:21441910
EXP, PMID:29433126 IDA/IMP)". This batch mechanically consolidates the remaining direct-evidence canonical kinase /
MAPK cascade rows from the three canonical experimental papers to ACCEPT with a uniform template (4 rows: 2 GO:0106310
EXP rows + 2 GO:0000165 IDA rows). Held back: GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K β needs per-row MODIFY review
per PR #505 carryover note); GO:0004674 IDA rows on PMID:18567582/PMID:19667065 (more general parent term, separate
batch); GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582 rows (calcium-response and EGFR-pathway secondary
findings, separate per-row review).'
- term:
id: GO:0004674
label: protein serine/threonine kinase activity
evidence_type: IDA
original_reference_id: PMID:18567582
review:
summary: 'IDA annotation for protein serine/threonine kinase activity from PMID:18567582 (Ren et al. 2008 J Biol Chem
β IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling), one of the three canonical BRAF kinase experimental papers
cited across this file as direct evidence (IDA/IMP) for BRAF kinase activity. GO:0004674 is the parent of GO:0106310
(protein serine kinase activity), which is already supported via direct EXP evidence in this file (PMID:21441910 ACCEPTed
in PR #505) and via IEA propagation in PR #456.'
action: ACCEPT
reason: 'Canonical BRAF MF directly demonstrated experimentally. Protein kinase activity / protein S/T kinase activity
(parent terms of GO:0106310) is BRAF''s defining molecular function β phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK
cascade. PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity
in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf), and PMID:19667065
are direct IDA papers measuring BRAF kinase activity. Already supported via direct EXP evidence on the more specific
child term GO:0106310 protein serine kinase activity (PMID:21441910 ACCEPTed in PR #505); via IBA propagation on GO:0004709
MAP3K activity (PR #448); via IEA on GO:0004672 and GO:0004674 (PR #456); via IDA on GO:0000165 MAPK cascade (PR #534).
This batch mechanically consolidates the remaining 3 parent-term canonical kinase MF rows to ACCEPT with a uniform template
(2 GO:0004674 IDA rows + 1 GO:0004672 IDA row). Held back: GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582
rows (calcium-response and EGFR-pathway secondary findings, separate per-row review); PMID:22065586 rows GO:0010628/GO:0070374
(downstream BP, separate batch); PMID:19667065 BP rows GO:0033138/GO:0043066 (separate batch); GO:0005634 IEA nucleus
(separate per-row); GO:0042802 IPI PMID:35512704 (KEAP1 neoPPI focus, separate per-row); GO:0005739 IBA mitochondrion
(separate per-row); GO:0090150/GO:0010828 PMID:23010278 rows (separate per-row); GO:0031267 NOT|IPI PMID:12194967 (negated
row, separate review); GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K MODIFY, separate per-row).'
- term:
id: GO:0005509
label: calcium ion binding
evidence_type: IDA
original_reference_id: PMID:18567582
review:
summary: 'IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf
signaling). The paper reports "a specific and direct association of Ca2+ with B-Raf", but explicitly notes that "the
specific site on B-Raf where Ca2+ binds remains to be determined" and "the biological function of Ca2+ binding to B-Raf
is unknown" (chelating Ca2+ in the in vitro kinase assay produced no significant/reproducible change in B-Raf activity).
This is a single-paper direct observation with no mapped binding site and no demonstrated functional consequence; BRAF
has no canonical calcium-binding domain (EF-hand/C2) and Ca2+ binding is not part of the core RAS-RAF-MEK-ERK kinase
mechanism.'
action: KEEP_AS_NON_CORE
reason: 'Genuine direct experimental observation but a peripheral, mechanistically uncharacterized property (binding site
unmapped, biological function explicitly stated as unknown by the authors), reported by a single lab and not replicated.
BRAF''s core molecular function is its Ser/Thr (MAP3K) kinase activity in the RAS-RAF-MEK-ERK cascade, already captured
via ACCEPTed canonical MF rows. Retained as non-core rather than removed because the IDA observation is real; part of
the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509,
GO:0007173, GO:0097110, GO:0071277).'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18567582
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0007173
label: epidermal growth factor receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:18567582
review:
summary: 'IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem). BRAF was studied as an EGF-stimulated effector
β EGF-stimulated B-Raf kinase activity is modulated by intracellular Ca2+ via the IQGAP1 scaffold. BRAF does function
downstream of activated EGFR within the canonical RAS-RAF-MEK-ERK cascade, but EGFR is only one of many upstream RTK
inputs and "EGFR signaling pathway" is a context-specific upstream-input framing rather than a BRAF-defining process.
The core BRAF biological process (the MAPK cascade / RAS-RAF-MEK-ERK signal transduction) is already captured via ACCEPTed
canonical rows (GO:0000165 MAPK cascade, GO:0007165 signal transduction).'
action: KEEP_AS_NON_CORE
reason: 'BRAF genuinely participates in EGFR-driven signaling as a canonical downstream MAP3K, so the annotation is not
wrong, but it is a context-specific upstream-input pathway rather than BRAF''s core process β the generic RAS-RAF-MEK-ERK
/ MAPK cascade is the defining BP and is already ACCEPTed. Part of the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582
IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509, GO:0007173, GO:0097110, GO:0071277).'
- term:
id: GO:0097110
label: scaffold protein binding
evidence_type: IPI
original_reference_id: PMID:18567582
review:
summary: 'IPI annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem) for direct binding of B-Raf to the MAPK scaffold
protein IQGAP1 ("Ca2+ promotes the direct binding of IQGAP1 to B-Raf"; IQGAP1 assembles a B-Raf/MEK/ERK complex and
modulates B-Raf activation by EGF). GO:0097110 ''scaffold protein binding'' is an informative, specific MF term (preferred
over generic GO:0005515 per CLAUDE.md) and the B-RafβIQGAP1 interaction is genuine and directly demonstrated. However,
IQGAP1 scaffold binding is a regulatory/modulatory interaction rather than BRAF''s core catalytic function, and the
principal RAF scaffold biology (KSR) is distinct; the IQGAP1 work is from a single lab (Sacks).'
action: KEEP_AS_NON_CORE
reason: 'Specific, informative, directly-demonstrated interaction (correctly avoids the generic protein-binding term),
retained because it is biologically real and well-characterized, but it represents a regulatory scaffold interaction
rather than BRAF''s core RAS-RAF-MEK-ERK Ser/Thr kinase function (already captured via ACCEPTed canonical MF rows).
Part of the uniform KEEP_AS_NON_CORE treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster
(GO:0005509, GO:0007173, GO:0097110, GO:0071277).'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31024343
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29433126
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802914
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802915
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802916
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802918
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802919
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802921
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802937
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802941
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802942
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802943
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803230
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803234
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8936676
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8936731
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802914
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802916
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802919
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6802921
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6803230
review:
summary: 'TAS annotation for plasma membrane localization. BRAF is recruited to the plasma membrane via the RBD-RAS-GTP
interaction, where it dimerizes (homo- and with CRAF/ARAF) and phosphorylates MEK1/2 in the MAPK cascade.'
action: ACCEPT
reason: 'Plasma membrane recruitment is the canonical activated-state localization for BRAF. RAS-GTP at the inner leaflet
binds the BRAF RBD, releasing 14-3-3-mediated autoinhibition and enabling dimerization and MEK phosphorylation. The
13 Reactome events are separate annotations of the same activated-state localization, mechanically consolidated to ACCEPT
with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:27353360
review:
summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic
term GO:0005515. BRAF has dozens of well-characterized binding partners β RAS-GTP isoforms (HRAS/KRAS/NRAS) via
the RBD; CRAF/ARAF heterodimers and BRAF homodimers via the kinase domain; MEK1/MEK2 substrates; 14-3-3 proteins
on phospho-S365/S729; and Hsp90/CDC37 chaperones β and specific MF terms should be preferred per CLAUDE.md
curation guidelines.
action: MARK_AS_OVER_ANNOTATED
reason: Generic 'protein binding' is uninformative for BRAF's well-characterized RAF-kinase / RAS-effector /
dimerization biology. Same precedent as BAG3 (#313), KRAS (#349), and RB1 (#430) where all GO:0005515 IPI rows
were uniformly demoted.
- term:
id: GO:0071277
label: cellular response to calcium ion
evidence_type: IDA
original_reference_id: PMID:18567582
review:
summary: 'IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem). The paper shows that manipulating intracellular
Ca2+ modulates B-Raf kinase activity ("chelating [Ca2+]i in fibroblasts markedly increases B-Raf kinase activity"; raising
[Ca2+]i blocks EGF-stimulated B-Raf activity), but the effect is indirect β mediated by Ca2+/calmodulin acting on the
IQGAP1 scaffold to alter its association with B-Raf, not a cell-autonomous BRAF calcium response. This is a real but
context-specific, single-mechanism secondary finding, not a core BRAF process.'
action: KEEP_AS_NON_CORE
reason: 'BRAF activity does respond to changes in cellular Ca2+, so the annotation is supported, but the response is indirect
(via the IQGAP1/calmodulin scaffold mechanism) and context-specific rather than a core BRAF biological process; the
defining RAS-RAF-MEK-ERK signaling is already captured via ACCEPTed canonical rows. Part of the uniform KEEP_AS_NON_CORE
treatment of the PMID:18567582 IQGAP1/Ca2+-calmodulin secondary-finding cluster (GO:0005509, GO:0007173, GO:0097110,
GO:0071277).'
- term:
id: GO:0031267
label: small GTPase binding
evidence_type: IPI
original_reference_id: PMID:12194967
negated: true
review:
summary: 'NOT (negated) IPI annotation for GO:0031267 small GTPase binding from Kontani et al. 2002 J Biol Chem (PMID:12194967
β Di-Ras, a distinct subgroup of Ras family GTPases with unique biochemical properties). Owing to effector-domain substitutions
(Ile at the position corresponding to Ha-Ras Asp-33), the paper shows Di-Ras1/Di-Ras2 "fails to interact with the Ras-binding
domain of Raf, resulting in no stimulation of mitogen-activated protein kinase." This is a deliberate, experimentally-grounded
negative finding: the BRAF RAS-binding domain does not engage the Di-Ras subgroup of small GTPases.'
action: ACCEPT
reason: 'The negated annotation is correct and is a curatorially valuable negative assertion. PMID:12194967 directly and
explicitly demonstrates that Di-Ras does not bind the Ras-binding domain of Raf and does not stimulate the MAPK pathway,
supporting NOT|small GTPase binding for this specific GTPase subgroup. This does not contradict BRAF''s canonical RAS
(HRAS/KRAS/NRAS) engagement via its RBD β it specifically records that the Di-Ras subfamily is not a BRAF RBD ligand.
Consistent with the repository convention of retaining experimentally established non-interaction NOT annotations as-is;
ACCEPT.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1295604
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1295634
review:
summary: 'TAS annotation for cytosol localization. BRAF is cytosolic in the autoinhibited (14-3-3-bound) resting state
and is recruited to the plasma membrane upon RAS-GTP activation.'
action: ACCEPT
reason: 'Cytosolic localization is well supported: BRAF in the autoinhibited closed conformation is bound to 14-3-3 and
Hsp90/CDC37 in the cytoplasm, and only translocates to the plasma membrane upon receptor-driven RAS activation. Each
of the 59 Reactome events is a separate cytosol annotation describing the same localization context, so they are mechanically
consolidated to ACCEPT with a uniform template (KRAS PR #349 precedent).'
- term:
id: GO:0090150
label: establishment of protein localization to membrane
evidence_type: IDA
original_reference_id: PMID:23010278
review:
summary: 'IDA annotation from PMID:23010278 (Pakladok et al. 2012, Biochem Biophys Res Commun β Stimulation of the Na(+)-coupled
glucose transporter SGLT1 by B-RAF). Chemiluminescence and confocal-microscopy experiments showed that wild-type B-RAF
coexpression in Xenopus oocytes enhanced SGLT1 protein abundance in the cell membrane, an effect blocked by the vesicle-insertion
inhibitor Brefeldin A, supporting a B-RAF role in establishment of SGLT1 localization to the plasma membrane. This is
a heterologous-overexpression, tumor-glucose-metabolism-context-specific regulatory effect on a transporter rather than
the defining RAS-RAF-MEK-ERK serine/threonine kinase function that characterizes BRAF.'
action: KEEP_AS_NON_CORE
reason: 'Genuine but peripheral, context-specific regulatory effect (B-RAF enhancing SGLT1 trafficking and membrane insertion
in a Xenopus-oocyte tumor-glucose-uptake model) rather than a core BRAF function. Canonical BRAF biology β the RAS-RAF-MEK-ERK
kinase cascade and cytosol/plasma-membrane localization β is already captured via direct experimental evidence in this
file (PMID:21441910 EXP, PMID:18567582 IDA, PMID:29433126 IDA/IMP) and prior batches (PR #440 Reactome TAS, PR #448
IBA, PR #456 IEA). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the 2 PMID:23010278
SGLT1 rows (GO:0090150 establishment of protein localization to membrane; GO:0010828 positive regulation of D-glucose
transmembrane transport).'
- term:
id: GO:0010828
label: positive regulation of D-glucose transmembrane transport
evidence_type: IDA
original_reference_id: PMID:23010278
review:
summary: 'IDA annotation from PMID:23010278 (Pakladok et al. 2012, Biochem Biophys Res Commun β Stimulation of the Na(+)-coupled
glucose transporter SGLT1 by B-RAF). Dual-electrode voltage-clamp on SGLT1-expressing Xenopus oocytes showed that wild-type
B-RAF coexpression significantly increased the glucose-induced current, enhancing the maximal SGLT1 transport rate without
significantly changing carrier affinity, supporting a B-RAF role in positive regulation of D-glucose transmembrane transport.
This is a heterologous-overexpression, tumor-glucose-metabolism-context-specific regulatory effect rather than the defining
RAS-RAF-MEK-ERK serine/threonine kinase function that characterizes BRAF.'
action: KEEP_AS_NON_CORE
reason: 'Genuine but peripheral, context-specific regulatory effect (B-RAF enhancing SGLT1 trafficking and membrane insertion
in a Xenopus-oocyte tumor-glucose-uptake model) rather than a core BRAF function. Canonical BRAF biology β the RAS-RAF-MEK-ERK
kinase cascade and cytosol/plasma-membrane localization β is already captured via direct experimental evidence in this
file (PMID:21441910 EXP, PMID:18567582 IDA, PMID:29433126 IDA/IMP) and prior batches (PR #440 Reactome TAS, PR #448
IBA, PR #456 IEA). Mechanically consolidated to KEEP_AS_NON_CORE with a uniform template across the 2 PMID:23010278
SGLT1 rows (GO:0090150 establishment of protein localization to membrane; GO:0010828 positive regulation of D-glucose
transmembrane transport).'
- term:
id: GO:0004672
label: protein kinase activity
evidence_type: IDA
original_reference_id: PMID:17563371
review:
summary: 'IDA annotation for protein kinase activity from PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates activation
of B-Raf), which directly demonstrates B-Raf kinase activity in vitro and shows that IQGAP1 binding significantly enhances
B-Raf activity. GO:0004672 is the most general parent of GO:0004674 (protein S/T kinase activity), GO:0106310 (protein
serine kinase activity), and GO:0004709 (MAP3K activity) β all of which are already supported via direct EXP/IDA/IBA/IEA
evidence in this file (PMID:21441910 EXP ACCEPTed in PR #505; PR #448 IBA; PR #456 IEA).'
action: ACCEPT
reason: 'Canonical BRAF MF directly demonstrated experimentally. Protein kinase activity / protein S/T kinase activity
(parent terms of GO:0106310) is BRAF''s defining molecular function β phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK
cascade. PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity
in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf), and PMID:19667065
are direct IDA papers measuring BRAF kinase activity. Already supported via direct EXP evidence on the more specific
child term GO:0106310 protein serine kinase activity (PMID:21441910 ACCEPTed in PR #505); via IBA propagation on GO:0004709
MAP3K activity (PR #448); via IEA on GO:0004672 and GO:0004674 (PR #456); via IDA on GO:0000165 MAPK cascade (PR #534).
This batch mechanically consolidates the remaining 3 parent-term canonical kinase MF rows to ACCEPT with a uniform template
(2 GO:0004674 IDA rows + 1 GO:0004672 IDA row). Held back: GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582
rows (calcium-response and EGFR-pathway secondary findings, separate per-row review); PMID:22065586 rows GO:0010628/GO:0070374
(downstream BP, separate batch); PMID:19667065 BP rows GO:0033138/GO:0043066 (separate batch); GO:0005634 IEA nucleus
(separate per-row); GO:0042802 IPI PMID:35512704 (KEAP1 neoPPI focus, separate per-row); GO:0005739 IBA mitochondrion
(separate per-row); GO:0090150/GO:0010828 PMID:23010278 rows (separate per-row); GO:0031267 NOT|IPI PMID:12194967 (negated
row, separate review); GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K MODIFY, separate per-row).'
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IMP
original_reference_id: PMID:22065586
review:
summary: >-
PMID:22065586 studies oncogenic Ras and BRAF V600E induction of DR5 expression
in cancer-cell contexts through ERK/RSK and JNK signaling.
action: MARK_AS_OVER_ANNOTATED
reason: >-
This annotation overextends a downstream oncogenic-mutant transcriptional
phenotype to BRAF as a gene product. The paper supports BRAF V600E pathway
signaling in cancer cells, but positive regulation of gene expression is not
a core BRAF function and is less appropriate than retaining the ERK/MAPK
cascade annotations.
supported_by:
- reference_id: PMID:22065586
supporting_text: 'knockdown of endogenous K-Ras or B-Raf (V600E) reduced the expression of DR5'
- term:
id: GO:0070374
label: positive regulation of ERK1 and ERK2 cascade
evidence_type: IDA
original_reference_id: PMID:22065586
review:
summary: 'IDA annotation from PMID:22065586 (Oh et al. 2012, J Biol Chem). Oncogenic B-Raf (V600E) directly activates
the ERK/RSK MAPK cascade in cancer cells; the paper explicitly demonstrates ERK co-activation downstream of B-Raf as
the mechanism upstream of DR5 induction. Positive regulation of the ERK1/2 cascade is the defining canonical BRAF biological-process
role.'
action: ACCEPT
reason: 'Canonical BRAF BP directly demonstrated experimentally. Positive regulation of the ERK1/2 cascade is BRAF''s
definitive role in the RAS-RAF-MEK-ERK pathway β BRAF directly phosphorylates MEK1/MEK2, which then activates ERK1/ERK2.
Already supported via IBA on GO:0000165 MAPK cascade (PR #448), via IDA on GO:0000165 in PR #534, and via Reactome TAS
rows for RAS-MAPK pathway events ACCEPTed in PR #440. Mechanically consolidated to ACCEPT with a uniform template across
the 4 canonical BRAFβdownstream-BP IDA/IMP rows in this batch (PMID:22065586 GO:0010628 IMP, PMID:22065586 GO:0070374
IDA, PMID:19667065 GO:0033138 IDA, PMID:19667065 GO:0043066 IDA). Held back per-row items unchanged from the PMID:22065586
GO:0010628 row above.'
supported_by:
- reference_id: PMID:22065586
supporting_text: 'the oncogenic B-Raf (V600E), a commonly mutated form in cancers, activated ERK/RSK signaling, increased
DR5 promoter activity, and up-regulated DR5 expression'
- term:
id: GO:0004674
label: protein serine/threonine kinase activity
evidence_type: IDA
original_reference_id: PMID:19667065
review:
summary: 'IDA annotation for protein serine/threonine kinase activity from PMID:19667065, a direct experimental paper
measuring BRAF kinase activity. GO:0004674 is the parent of GO:0106310 (protein serine kinase activity), which is already
supported via direct EXP evidence in this file (PMID:21441910 ACCEPTed in PR #505) and via IEA propagation in PR #456.'
action: ACCEPT
reason: 'Canonical BRAF MF directly demonstrated experimentally. Protein kinase activity / protein S/T kinase activity
(parent terms of GO:0106310) is BRAF''s defining molecular function β phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK
cascade. PMID:17563371 (Ren et al. 2007 PNAS β IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity
in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem β IQGAP1 integrates Ca2+/calmodulin and B-Raf), and PMID:19667065
are direct IDA papers measuring BRAF kinase activity. Already supported via direct EXP evidence on the more specific
child term GO:0106310 protein serine kinase activity (PMID:21441910 ACCEPTed in PR #505); via IBA propagation on GO:0004709
MAP3K activity (PR #448); via IEA on GO:0004672 and GO:0004674 (PR #456); via IDA on GO:0000165 MAPK cascade (PR #534).
This batch mechanically consolidates the remaining 3 parent-term canonical kinase MF rows to ACCEPT with a uniform template
(2 GO:0004674 IDA rows + 1 GO:0004672 IDA row). Held back: GO:0005509/GO:0007173/GO:0097110/GO:0071277 PMID:18567582
rows (calcium-response and EGFR-pathway secondary findings, separate per-row review); PMID:22065586 rows GO:0010628/GO:0070374
(downstream BP, separate batch); PMID:19667065 BP rows GO:0033138/GO:0043066 (separate batch); GO:0005634 IEA nucleus
(separate per-row); GO:0042802 IPI PMID:35512704 (KEAP1 neoPPI focus, separate per-row); GO:0005739 IBA mitochondrion
(separate per-row); GO:0090150/GO:0010828 PMID:23010278 rows (separate per-row); GO:0031267 NOT|IPI PMID:12194967 (negated
row, separate review); GO:0004708 IMP PMID:29433126 (MAP2K vs MAP3K MODIFY, separate per-row).'
- term:
id: GO:0033138
label: positive regulation of peptidyl-serine phosphorylation
evidence_type: IDA
original_reference_id: PMID:19667065
review:
summary: >-
PMID:19667065 supports RAF-dependent BAD phosphorylation, but the regulatory
wording is less direct than annotating the phosphorylation output of RAF
kinase activity.
action: MODIFY
reason: >-
The cited evidence supports protein phosphorylation by RAF kinases. GO:0033138
frames the result as regulation of peptidyl-serine phosphorylation and is less
precise for BRAF's kinase output. Replace with the direct serine-phosphorylation
process term GO:0018105 peptidyl-serine phosphorylation.
supported_by:
- reference_id: PMID:19667065
supporting_text: 'RAF kinases represent, besides protein kinase A, PAK, and Akt/protein kinase B, in vivo BAD-phosphorylating
kinases. RAF-induced phosphorylation of BAD was reduced to control levels using the RAF inhibitor BAY 43-9006. This
phosphorylation was not prevented by MEK inhibitors.'
proposed_replacement_terms:
- id: GO:0018105
label: peptidyl-serine phosphorylation
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: IDA
original_reference_id: PMID:19667065
review:
summary: 'IDA annotation from PMID:19667065 (Polzien et al. 2009, J Biol Chem). Constitutively active RAF suppresses BAD-induced
apoptosis and rescues colony-formation inhibition by BAD; mechanism is RAF-mediated phosphorylation of BAD-S99 (the
major 14-3-3 binding site), which promotes 14-3-3 sequestration of BAD and inhibits BAD''s mitochondrial pore-forming
pro-apoptotic activity. This captures BRAF''s canonical pro-survival downstream output via the BAD-Bcl-2 axis.'
action: ACCEPT
reason: 'Canonical BRAF BP directly demonstrated experimentally via constitutively-active RAF gain-of-function suppression
of BAD-induced apoptosis (PMID:19667065). Negative regulation of apoptotic process is an established downstream consequence
of BRAF kinase activity through the BAD-Bcl-2 pro-survival axis (and complementary MEK-ERKβ90 kDa ribosomal S6 kinaseβBAD-S112
phosphorylation in murine BAD). Mechanically consolidated to ACCEPT with a uniform template across the 4 canonical BRAFβdownstream-BP
IDA/IMP rows in this batch (PMID:22065586 GO:0010628 IMP, PMID:22065586 GO:0070374 IDA, PMID:19667065 GO:0033138 IDA,
PMID:19667065 GO:0043066 IDA). Held back per-row items unchanged from the PMID:22065586 GO:0010628 row above. Note:
an existing IEA GO_REF:0000044 row on `GO:0043066` was already ACCEPTed in PR #456 β this row provides the direct experimental
anchor.'
supported_by:
- reference_id: PMID:19667065
supporting_text: 'expression of constitutively active RAF suppressed apoptosis induced by BAD and the inhibition of
colony formation caused by BAD could be prevented by RAF'
- term:
id: GO:0009887
label: animal organ morphogenesis
evidence_type: TAS
original_reference_id: PMID:9207797
review:
summary: 'TAS annotation from Wojnowski et al. 1997 (PMID:9207797), the foundational Braf-knockout paper showing that
Braf-/- mice die mid-gestation from vascular defects with increased endothelial precursor cells, dramatically enlarged
blood vessels, and apoptotic death of differentiated endothelial cells. The general term GO:0009887 (animal organ morphogenesis)
is too broad to capture this specific in vivo phenotype: the paper unambiguously demonstrates a role in blood vessel
/ vasculature development, not generic organ morphogenesis. GO:0001568 (blood vessel development) is the appropriate
replacement, capturing the vasculature-specific progression-to-mature-structure process the knockout phenotype defines.'
action: MODIFY
reason: 'The essence of the annotation is correct (BRAF is required for an in vivo developmental process per the Braf-/-
vascular-defects phenotype), but the term GO:0009887 (animal organ morphogenesis) is too general. PMID:9207797 specifically
demonstrates a role in vascular system formation (increased endothelial precursors, enlarged blood vessels, endothelial
apoptosis leading to mid-gestation vascular failure), which is more precisely captured by GO:0001568 (blood vessel development).
MODIFY to the more specific child term; this is a non-core developmental/tissue-specific role downstream of the canonical
BRAF kinase function and not promoted to core_functions.'
proposed_replacement_terms:
- id: GO:0001568
label: blood vessel development
- term:
id: GO:0004672
label: protein kinase activity
evidence_type: TAS
original_reference_id: PMID:2284096
review:
summary: 'TAS annotation from the foundational Sithanandam et al. 1990 paper that cloned the complete coding sequence
of human B-raf and detected B-raf protein kinase activity using isozyme-specific antibodies (PMID:2284096). BRAF is
a canonical Ser/Thr protein kinase phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade β directly demonstrated
experimentally elsewhere in this file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and already ACCEPTed
on the IEA row (GO_REF:0000120, PR #456) and via IBA propagation on the more specific child term GO:0004709 MAP3K activity
(PR #448).'
action: ACCEPT
reason: 'TAS evidence from the foundational 1990 BRAF cloning/kinase-detection paper (PMID:2284096) supports a canonical
core BRAF molecular function or core BRAF biological process directly demonstrated experimentally in this file (PMID:18567582
IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and already ACCEPTed via IEA (PR #456), IBA (PR #448), and Reactome TAS
(PR #440) propagation batches. Mechanically consolidated to ACCEPT with a uniform template across the 2 canonical kinase
TAS rows from PMID:2284096 (protein kinase activity, protein phosphorylation); the 2 PMID:9207797 Braf-knockout TAS
rows (animal organ morphogenesis, negative regulation of apoptotic process) are held back for separate per-row consideration
in a later batch because the in vivo vascular-development knockout context warrants a more specific term assessment.'
- term:
id: GO:0006468
label: protein phosphorylation
evidence_type: TAS
original_reference_id: PMID:2284096
review:
summary: 'TAS annotation from the foundational Sithanandam et al. 1990 paper that cloned the complete coding sequence
of human B-raf and detected B-raf protein kinase activity using isozyme-specific antibodies (PMID:2284096). Protein
phosphorylation is the canonical biological process of BRAF kinase activity β BRAF phosphorylates MEK1/MEK2 on activation-loop
serines (Ser218/Ser222 of MEK1) in the RAS-RAF-MEK-ERK cascade. Directly demonstrated experimentally elsewhere in this
file (PMID:18567582 IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and supported via IBA propagation on the MAP3K activity
/ MAPK cascade terms (PR #448).'
action: ACCEPT
reason: 'TAS evidence from the foundational 1990 BRAF cloning/kinase-detection paper (PMID:2284096) supports a canonical
core BRAF molecular function or core BRAF biological process directly demonstrated experimentally in this file (PMID:18567582
IDA, PMID:21441910 EXP, PMID:29433126 IDA/IMP) and already ACCEPTed via IEA (PR #456), IBA (PR #448), and Reactome TAS
(PR #440) propagation batches. Mechanically consolidated to ACCEPT with a uniform template across the 2 canonical kinase
TAS rows from PMID:2284096 (protein kinase activity, protein phosphorylation); the 2 PMID:9207797 Braf-knockout TAS
rows (animal organ morphogenesis, negative regulation of apoptotic process) are held back for separate per-row consideration
in a later batch because the in vivo vascular-development knockout context warrants a more specific term assessment.'
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: TAS
original_reference_id: PMID:9207797
review:
summary: 'TAS annotation from Wojnowski et al. 1997 (PMID:9207797) β Braf-knockout mice show apoptotic death of differentiated
endothelial cells leading to mid-gestation vascular defects, providing the first genetic evidence for a Raf-family role
in regulating programmed cell death. Supports the canonical BRAF anti-apoptotic activity already ACCEPTed via IEA propagation
(GO_REF:0000117, PR #456), which is mechanistically grounded in BRAF-driven MEK/ERK phosphorylation of pro-apoptotic
factors (BAD on Ser112/Ser155 via RSK; BIM via ERK-mediated proteasomal degradation).'
action: ACCEPT
reason: 'TAS evidence from PMID:9207797 supports the same canonical BRAF anti-apoptotic function already ACCEPTed via
IEA (GO_REF:0000117, PR #456) and consistent with the canonical RAS-RAF-MEK-ERK survival signaling captured in the Reactome
TAS batch (PR #440). The in vivo endothelial-apoptosis phenotype of Braf-/- mice provides genetic confirmation of the
cellular anti-apoptotic role. Retained as ACCEPT (mirroring the IEA row) rather than KEEP_AS_NON_CORE because the same
term is already at ACCEPT elsewhere in the file; the developmental tissue-specific aspect is captured in the paired
PMID:9207797 morphogenesis row (MODIFY β GO:0001568 blood vessel development) in this same batch.'
references:
- id: file:human/BRAF/BRAF-deep-research-falcon.md
title: Falcon deep research report for human BRAF
findings:
- statement: Falcon synthesis supports BRAF as the RAF-family MAP3K that directly phosphorylates and activates
MEK1/MEK2 in the ERK pathway.
supporting_text: BRAF is a RAF-family kinase whose primary role in the ERK pathway is to act as a MAP kinase kinase
kinase (MAP3K) that phosphorylates and activates MEK1/MEK2.
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000003
title: Gene Ontology annotation based on Enzyme Commission mapping
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by
conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
findings: []
- id: GO_REF:0000116
title: Automatic Gene Ontology annotation based on Rhea mapping
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:12194967
title: Di-Ras, a distinct subgroup of ras family GTPases with unique biochemical properties.
findings: []
- id: PMID:12620389
title: Novel raf kinase protein-protein interactions found by an exhaustive yeast two-hybrid analysis.
findings: []
- id: PMID:15161933
title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
findings: []
- id: PMID:15778465
title: Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer.
findings: []
- id: PMID:16810323
title: FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and
S6K2.
findings: []
- id: PMID:16858395
title: The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf.
findings:
- statement: The B-Raf-specific amino-terminal region is essential for calcium-dependent homo- and heterodimerization
of BRAF at the plasma membrane; increased intracellular calcium is necessary for dimerization and sufficient for
plasma membrane translocation
supporting_text: this amino-terminal B-Raf-specific region is essential for homo-dimerization of B-Raf and
hetero-dimerization of B-Raf and c-Raf at the plasma membrane, followed by phosphorylation of Thr118 in the
amino-terminal B-Raf-specific region
- id: PMID:16888650
title: Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and
FYN.
findings: []
- id: PMID:17380122
title: Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation.
findings: []
- id: PMID:17563371
title: IQGAP1 modulates activation of B-Raf.
findings:
- statement: IQGAP1 is a scaffold required for B-Raf activation by EGF; IQGAP1-null cells and cells expressing an
IQGAP1 mutant unable to bind B-Raf fail to stimulate B-Raf activity in response to EGF; IQGAP1 binding directly
enhances B-Raf kinase activity in vitro
supporting_text: EGF is unable to stimulate B-Raf activity in IQGAP1-null cells and in cells transfected with an
IQGAP1 mutant construct that is unable to bind B-Raf
- id: PMID:17979178
title: A novel tandem affinity purification strategy for the efficient isolation and characterisation of native
protein complexes.
findings: []
- id: PMID:18567582
title: IQGAP1 integrates Ca2+/calmodulin and B-Raf signaling.
findings:
- statement: IQGAP1 mediates crosstalk from Ca2+ and calmodulin signaling to B-Raf; Ca2+ promotes IQGAP1-B-Raf binding
while Ca2+/calmodulin abrogates it, and chelating intracellular Ca2+ enhances EGF-stimulated B-Raf activity in an
IQGAP1-dependent manner
supporting_text: Ca 2+ promotes the direct binding of IQGAP1 to B-Raf. This interaction is inhibited by calmodulin
in a Ca 2+ -regulated manner
- id: PMID:19667065
title: 'Identification of novel in vivo phosphorylation sites of the human proapoptotic protein BAD: pore-forming activity
of BAD is regulated by phosphorylation.'
findings:
- statement: Novel in vivo phosphorylation sites on the proapoptotic protein BAD were identified; BAD phosphorylation
regulates its pore-forming activity, linking kinases upstream of the MAPK cascade (including BRAF) to apoptotic
regulation
full_text_unavailable: true
- id: PMID:19710016
title: Diacylglycerol kinase eta augments C-Raf activity and B-Raf/C-Raf heterodimerization.
findings:
- statement: Diacylglycerol kinase eta (DGKeta) functions as a scaffold/adaptor that promotes B-Raf/C-Raf
heterodimerization in a kinase-activity-independent manner; DGKeta knockdown impairs EGF-stimulated
Ras/B-Raf/C-Raf/MEK/ERK signaling
supporting_text: DGKeta1 could activate the Ras/B-Raf/C-Raf/MEK/ERK pathway in a DGK activity-independent manner,
suggesting that DGKeta serves as a scaffold/adaptor protein
- id: PMID:19727074
title: A dimerization-dependent mechanism drives RAF catalytic activation.
findings:
- statement: RAF catalytic function is regulated by side-to-side kinase domain dimerization; the pseudokinase KSR also
forms side-to-side heterodimers with RAF to directly trigger RAF activation; side-to-side dimer interface
mutations abrogate oncogenic BRAF signaling
full_text_unavailable: true
- id: PMID:20130576
title: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.
findings:
- statement: ATP-competitive RAF inhibitors paradoxically prime wild-type RAF to activate the MAPK pathway through
drug-induced RAF dimerization in cells with upstream RAS activation
full_text_unavailable: true
- id: PMID:20141835
title: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.
findings:
- statement: Kinase-dead BRAF cooperates with oncogenic RAS to drive tumor progression through CRAF; RAF inhibitors
that selectively inhibit BRAF paradoxically activate this kinase-dead BRAF/oncogenic RAS/CRAF signaling axis
supporting_text: drugs that selectively inhibit BRAF activate RAS-dependent kinase-dead BRAF signaling through CRAF
- id: PMID:21441910
title: A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.
findings:
- statement: BRAF allosterically stimulates KSR2 kinase activity via side-to-side heterodimerization; this promotes
MEK phosphorylation by relaying a signal that releases the MEK activation segment
full_text_unavailable: true
- id: PMID:21478863
title: ERK and PDE4 cooperate to induce RAF isoform switching in melanoma.
findings: []
- id: PMID:21625473
title: A novel requirement for Janus kinases as mediators of drug resistance induced by fibroblast growth factor-2 in
human cancer cells.
findings: []
- id: PMID:22065586
title: Oncogenic Ras and B-Raf proteins positively regulate death receptor 5 expression through co-activation of ERK
and JNK signaling.
findings: []
- id: PMID:22169110
title: Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant
chronic myeloid leukemia.
findings: []
- id: PMID:22510884
title: Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling.
findings:
- statement: The kinase-domain dimer interface is pivotal for wild-type BRAF activity, whereas oncogenic BRAF(V600E)
and BRAF(G469A) are resistant to dimer-interface mutations and display extended protomer contacts and increased
homodimerization
supporting_text: the B-Raf(V600E), B-Raf(insT) and B-Raf(G469A) oncoproteins are remarkably resistant to mutations
in the DIF. However, compared with B-Raf(wt), B-Raf(V600E) displays extended protomer contacts, increased
homodimerisation and incorporation into larger protein complexes
- id: PMID:2284096
title: Complete coding sequence of a human B-raf cDNA and detection of B-raf protein kinase with isozyme specific
antibodies.
findings:
- statement: A 2.2 kb cDNA encoding the complete human BRAF coding sequence was isolated and contains all three
conserved regions CR1, CR2, and CR3 characteristic of RAF-family protein kinases
full_text_unavailable: true
- id: PMID:22939624
title: Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
findings: []
- id: PMID:23010278
title: Stimulation of the Na(+)-coupled glucose transporter SGLT1 by B-RAF.
findings:
- statement: Wild-type B-RAF stimulates Na+-coupled glucose transporter SGLT1 by increasing SGLT1 protein abundance at
the cell membrane without altering substrate affinity
full_text_unavailable: true
- id: PMID:23153539
title: Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in
BRAFV600E melanomas.
findings:
- statement: RAF inhibitors relieve profound ERK-dependent negative feedback in BRAF(V600E) melanomas, paradoxically
reactivating upstream RAS signaling; this feedback relief attenuates the antiproliferative effect of RAF
inhibitors
supporting_text: RAF inhibitors effectively inhibit ERK signaling only in tumors with mutant BRAF
- id: PMID:23680146
title: RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation.
findings:
- statement: RAF inhibitors activate wild-type RAF by relieving inhibitory autophosphorylation of the
phosphate-binding loop; activation is ATP-dependent and linked to RAF kinase activity itself
full_text_unavailable: true
- id: PMID:23934108
title: Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.
findings: []
- id: PMID:24255178
title: Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase
interactions.
findings: []
- id: PMID:24441586
title: Integrated RAS signaling defined by parallel NMR detection of effectors and regulators.
findings: []
- id: PMID:24746704
title: Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.
findings: []
- id: PMID:25155755
title: Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling.
findings:
- statement: Crystal structure of the BRAF-MEK complex reveals a kinase activity-independent scaffolding role for BRAF
in positioning MEK for phosphorylation within the MAPK signaling complex
full_text_unavailable: true
- id: PMID:25241761
title: Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in
a pathway network.
findings: []
- id: PMID:25437913
title: Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation.
findings:
- statement: Crystal structure of a BRAF kinase domain monomer reveals the off-state dimer interface; sulfonamide
inhibitors stabilize the monomer by displacing helix Ξ±C via AS-H1, the region targeted by potent BRAF oncogenic
mutations
full_text_unavailable: true
- id: PMID:25600339
title: Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result
in melanoma drug addiction.
findings: []
- id: PMID:26165597
title: The RAS-Binding Domain of Human BRAF Protein Serine/Threonine Kinase Exhibits Allosteric Conformational Changes
upon Binding HRAS.
findings: []
- id: PMID:26466569
title: RAF inhibitors that evade paradoxical MAPK pathway activation.
findings: []
- id: PMID:26496610
title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
findings: []
- id: PMID:27353360
title: The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.
findings: []
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and disease networks.
findings: []
- id: PMID:29433126
title: MEK drives BRAF activation through allosteric control of KSR proteins.
findings:
- statement: MEK binding to the KSR1 kinase domain asymmetrically drives BRAF-KSR1 heterodimerization, stimulating
BRAF catalytic activity toward free MEK molecules
supporting_text: MEK binding to the kinase domain of KSR1 asymmetrically drives BRAF-KSR1 heterodimerization,
resulting in the concomitant stimulation of BRAF catalytic activity towards free MEK molecules
- id: PMID:30194290
title: Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.
findings: []
- id: PMID:31024343
title: A YWHAZ Variant Associated With Cardiofaciocutaneous Syndrome Activates the RAF-ERK Pathway.
findings: []
- id: PMID:31980649
title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
findings: []
- id: PMID:32707033
title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
findings: []
- id: PMID:34591642
title: A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
findings: []
- id: PMID:35512704
title: Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
findings: []
- id: PMID:35839996
title: A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions.
findings: []
- id: PMID:36241744
title: HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative
stress.
findings: []
- id: PMID:36931259
title: A central chaperone-like role for 14-3-3 proteins in human cells.
findings: []
- id: PMID:37045861
title: Interactome dynamics of RAF1-BRAF kinase monomers and dimers.
findings: []
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional genomics.
findings: []
- id: PMID:9207797
title: Endothelial apoptosis in Braf-deficient mice.
findings:
- statement: Braf-/- mice die of vascular defects during mid-gestation; embryos show increased endothelial precursor
cells, dramatically enlarged blood vessels, and apoptotic death of differentiated endothelial cells, establishing
BRAF as critical for vascular system formation
full_text_unavailable: true
- id: Reactome:R-HSA-1295604
title: B-RAF dissociates from S110/S120 p-SPRY2
findings: []
- id: Reactome:R-HSA-1295634
title: SPRY2 is serine phosphorylated in response to MAPK activation
findings: []
- id: Reactome:R-HSA-5672950
title: '"Activator" RAF:YWHAB dimer binds RAS:GTP'
findings: []
- id: Reactome:R-HSA-5672951
title: Inactive RAFs bind YWHAB
findings: []
- id: Reactome:R-HSA-5672960
title: YWHAB dimer dissociates from dephosphorylated RAF
findings: []
- id: Reactome:R-HSA-5672961
title: PP2A dephosphorylates inactive RAFs
findings: []
- id: Reactome:R-HSA-5672966
title: RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers
findings: []
- id: Reactome:R-HSA-5672969
title: Phosphorylation of RAF
findings: []
- id: Reactome:R-HSA-5672972
title: MAP2Ks and MAPKs bind to the activated RAF complex
findings: []
- id: Reactome:R-HSA-5672973
title: MAP2Ks phosphorylate MAPKs
findings: []
- id: Reactome:R-HSA-5672978
title: RAF phosphorylates MAP2K dimer
findings: []
- id: Reactome:R-HSA-5672980
title: Dissociation of RAS:RAF complex
findings: []
- id: Reactome:R-HSA-5674130
title: MAP2Ks and MAPKs are phosphorylated at the endosome membrane
findings: []
- id: Reactome:R-HSA-5674132
title: WDR83:LAMTOR2:LAMTOR3 binds MAPK components
findings: []
- id: Reactome:R-HSA-5674140
title: PAQR3 binds inactive RAFs
findings: []
- id: Reactome:R-HSA-5675198
title: Activated MAPKs phosphorylate BRAF
findings: []
- id: Reactome:R-HSA-5675417
title: PEBP1 binds activated RAF1
findings: []
- id: Reactome:R-HSA-5675431
title: PP2A dephosphorylates RAF1
findings: []
- id: Reactome:R-HSA-5675433
title: PP5 dephosphorylates RAF1 S338
findings: []
- id: Reactome:R-HSA-6802908
title: RAS mutants bind inactive RAF
findings: []
- id: Reactome:R-HSA-6802910
title: Activated MAP2Ks phosphorylate MAPKs downstream of high kinase activity BRAF mutants
findings: []
- id: Reactome:R-HSA-6802911
title: High kinase activity BRAF complexes phosphorylate MAP2Ks
findings: []
- id: Reactome:R-HSA-6802912
title: High kinase activity BRAF mutants bind MAP2Ks and MAPKs
findings: []
- id: Reactome:R-HSA-6802914
title: RAS:GTP:moderate kinase activity p-RAF complexes bind MAP2Ks and MAPKs
findings: []
- id: Reactome:R-HSA-6802915
title: Moderate kinase activity BRAF mutants bind RAS:GTP
findings: []
- id: Reactome:R-HSA-6802916
title: RAF is phosphorylated downstream of moderate kinase activity BRAF mutants
findings: []
- id: Reactome:R-HSA-6802918
title: Activated MAP2Ks phosphorylate MAPKs downstream of inactive BRAF mutants
findings: []
- id: Reactome:R-HSA-6802919
title: RAS:GTP:moderate kinase activity p-RAF complexes phosphorylate MAP2Ks
findings: []
- id: Reactome:R-HSA-6802921
title: Activated MAP2Ks phosphorylate MAPKs downstream of moderate kinase activity BRAF mutants
findings: []
- id: Reactome:R-HSA-6802922
title: Activated MAP2Ks phosphorylate MAPKs downstream of oncogenic RAS
findings: []
- id: Reactome:R-HSA-6802924
title: RAF is phosphorylated downstream of oncogenic RAS
findings: []
- id: Reactome:R-HSA-6802925
title: Mutant RAS:p-RAF complexes bind MAP2Ks and MAPKs
findings: []
- id: Reactome:R-HSA-6802926
title: Mutant RAS:p-RAF complexes phosphorylate MAP2Ks
findings: []
- id: Reactome:R-HSA-6802930
title: Dimerization of BRAF V600E splice variants contributes to BRAF inhibitor resistance
findings: []
- id: Reactome:R-HSA-6802937
title: Inactive BRAF mutants bind mutant RAS:GTP
findings: []
- id: Reactome:R-HSA-6802938
title: Inhibitors bind and inhibit highly active BRAF mutants
findings: []
- id: Reactome:R-HSA-6802941
title: RAF is paradoxically phosphorylated downstream of kinase-inactive RAF
findings: []
- id: Reactome:R-HSA-6802942
title: RAS:GTP:p-RAF complexes paradoxically bind MAP2Ks and MAPKs
findings: []
- id: Reactome:R-HSA-6802943
title: RAS:GTP:inactive p-RAF complexes phosphorylate MAP2Ks
findings: []
- id: Reactome:R-HSA-6803227
title: Dissociation of high activity BRAF complexes
findings: []
- id: Reactome:R-HSA-6803230
title: Dissociation of moderate activity BRAF complexes
findings: []
- id: Reactome:R-HSA-6803233
title: Dissociation of oncogenic RAS:RAF complex
findings: []
- id: Reactome:R-HSA-6803234
title: Dissociation of paradoxically activated RAS:BRAF complexes
findings: []
- id: Reactome:R-HSA-6803240
title: Homo- or heterodimerization of RAF downstream of mutant RAS
findings: []
- id: Reactome:R-HSA-8936676
title: Moderate kinase activity BRAF mutants:RAS:GTP homo/heterodimerize
findings: []
- id: Reactome:R-HSA-8936731
title: Inactive BRAF mutants:mutant RAS:GTP bind RAF1
findings: []
- id: Reactome:R-HSA-9610152
title: Activated BRAF recruits MAP2Ks and MAPKs to the endosome
findings: []
- id: Reactome:R-HSA-9610153
title: Activated BRAF phosphorylates MAP2K dimers downstream of RAP1 and NGF
findings: []
- id: Reactome:R-HSA-9610154
title: Dissociation of phosphorylated MAP2Ks and MAPKs
findings: []
- id: Reactome:R-HSA-9610156
title: MAP2Ks phosphorylate MAPKs downstream of BRAF and NGF
findings: []
- id: Reactome:R-HSA-9610163
title: BRAF autophosphorylates downstream of RAP1 and NGF
findings: []
- id: Reactome:R-HSA-9653108
title: Raf dimer inhibitors bind RAF heterodimers
findings: []
- id: Reactome:R-HSA-9656209
title: Dissociation of RAS:RAF1 mutant complex
findings: []
- id: Reactome:R-HSA-9656211
title: MAP2Ks and MAPKs bind to the activated mutant RAF1 complex
findings: []
- id: Reactome:R-HSA-9656212
title: Phosphorylation of RAF1 mutants
findings: []
- id: Reactome:R-HSA-9656213
title: RAF1 mutants show enhanced heterodimerization with BRAF
findings: []
- id: Reactome:R-HSA-9656214
title: MAP2Ks phosphorylate MAPKs downstream of RAF1 mutants
findings: []
- id: Reactome:R-HSA-9656215
title: RAF1 mutant complexes phosphorylate MAP2K dimer
findings: []
- id: Reactome:R-HSA-9657599
title: Dual mechanism MAP2K inhibitors bind MAP2Ks
findings: []
- id: Reactome:R-HSA-9657603
title: Dual mechanism MAPK inhibitors bind MAPKs
findings: []
- id: Reactome:R-HSA-9657606
title: Single mechanism MAP2K inhibitors bind phosphorylated MAP2Ks
findings: []
- id: Reactome:R-HSA-9657608
title: Single mechanism MAPK inhibitors bind phosphorylated MAPK
findings: []
- id: Reactome:R-HSA-9658445
title: MRAS:SHOC2:PPP1CC dephosphorylates inactive RAFs
findings: []
- id: Reactome:R-HSA-9660536
title: SHOC2 M173I disrupts the SHOC2:MRAS:PP1 complex
findings: []
- id: Reactome:R-HSA-9660538
title: Mutant MRAS:SHOC2:PPP1CC complexes dephosphorylate inactive RAFs
findings: []
- id: file:human/BRAF/BRAF-uniprot.txt
title: UniProt record for human BRAF (P15056)
findings:
- statement: BRAF phosphorylates MAP2K1 (MEK1) and thereby activates the MAP kinase signal transduction pathway.
supporting_text: Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway
- statement: BRAF is an ATP-dependent protein serine/threonine kinase (EC 2.7.11.1).
supporting_text: L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
core_functions:
- description: BRAF is the canonical RAF-family MAP kinase kinase kinase (MAP3K) of the RAS-RAF-MEK-ERK cascade. After
RAS-GTP-driven membrane recruitment and side-to-side dimerization (BRAF homodimers and the more potent BRAF-RAF1
heterodimers), BRAF phosphorylates and activates MAP2K1/MAP2K2 (MEK1/MEK2) β the committed step that propagates
mitogenic signaling to ERK1/ERK2.
supported_by:
- reference_id: file:human/BRAF/BRAF-uniprot.txt
supporting_text: Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway
- reference_id: PMID:29433126
supporting_text: BRAF phosphorylation of MEK1
molecular_function:
id: GO:0004709
label: MAP kinase kinase kinase activity
directly_involved_in:
- id: GO:0000165
label: MAPK cascade
- id: GO:0070374
label: positive regulation of ERK1 and ERK2 cascade
locations:
- id: GO:0005829
label: cytosol
- id: GO:0005886
label: plasma membrane
- description: BRAF is an ATP-dependent protein serine/threonine kinase. Its intrinsic catalytic activity, demonstrated
by direct in vitro kinase assays, phosphorylates substrate serine/threonine residues (most importantly the
activation-loop serines of MEK1/MEK2); this enzymatic activity is the molecular basis for its MAP3K function and for
its oncogenic activation by the V600E mutation.
supported_by:
- reference_id: file:human/BRAF/BRAF-uniprot.txt
supporting_text: L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
- reference_id: PMID:21441910
supporting_text: kinase activity
molecular_function:
id: GO:0004674
label: protein serine/threonine kinase activity
directly_involved_in:
- id: GO:0000165
label: MAPK cascade
locations:
- id: GO:0005829
label: cytosol
- id: GO:0005886
label: plasma membrane
proposed_new_terms: []
suggested_questions:
- question: Does BRAF homodimerization versus BRAF-RAF1 heterodimerization yield qualitatively or quantitatively
distinct MEK activation outputs, and what cellular signals or post-translational modifications tip the balance in
vivo?
- question: How is the stoichiometry and dynamics of the autoinhibited cytosolic BRAF-MEK-14-3-3 complex regulated
during growth factor stimulation, and does the complex dissociate as a unit or do components exchange independently
upon RAS activation?
- question: What is the full complement of direct BRAF substrates beyond MEK1/2 in normal physiological contexts, and do
non-MEK targets such as BAD contribute to BRAF function in vascular development?
- question: Can the BRAF amino-terminal B-Raf-specific region (mediating calcium-dependent dimerization) be targeted
pharmacologically to modulate wild-type BRAF activity without triggering paradoxical RAF inhibitor-type pathway
activation?
suggested_experiments:
- description: Cryo-EM reconstitution of the active BRAF-RAF1 heterodimer and the BRAF-KSR1-MEK ternary complex on
nanodisc membranes in the presence of RAS-GTP to determine how membrane context and substrate engagement reshape the
active conformation.
hypothesis: RAS-GTP at the membrane induces a distinct active-dimer conformation compared to drug-stabilized dimers,
and KSR1-MEK positioning within the ternary complex explains the allosteric stimulation of BRAF catalytic activity.
experiment_type: structural
- description: Phosphoproteomic profiling of isogenic cells with conditional BRAF knockout versus BRAF(V600E) knock-in
under matched growth conditions to identify direct BRAF-dependent phosphorylation events beyond MEK1/2.
hypothesis: BRAF has physiological substrates beyond MEK1/2 that contribute to its essential role in endothelial
survival and vascular development, and these are distinct from the MEK-dependent oncogenic signaling in V600E
tumors.
experiment_type: biochemical
- description: Calcium-imaging combined with BRAF FRET-based dimerization reporters in primary endothelial cells to
establish the kinetics and threshold of calcium-dependent BRAF membrane translocation and dimerization.
hypothesis: The B-Raf-specific amino-terminal region converts transient calcium signals into sustained BRAF
dimerization at the plasma membrane, providing a calcium-dependent amplification mechanism for MAPK signaling in
endothelial cells.
experiment_type: cell_biology