BRAF

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.

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.

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.

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 — 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.

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.

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), also KEEP_AS_NON_CORE. ORGANELLES check (2026-10-24): the PAINT node PTN000584576 (PTHR44329-paint.tsv) is seeded for mitochondrion by mouse Araf (MGI:88065, IDA PMID:12931191) and mouse Braf (MGI:88190, IDA PMID:16116448). The Braf seed is a Bag1-knockout study reporting most B-Raf immunoreactivity of postmitotic motoneurons at mitochondria and its loss of mitochondrial contact without Bag1, so the organelle claim is supported as a recruited, Bag1-dependent pool at the mitochondrial surface. Stays at the root: BRAF has no transit peptide or membrane anchor, and no cached study fractionates it to the outer membrane or tests protease accessibility; peripheral recruitment is one line, so GO:0005741 is not added.

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 — 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.

Summary: IEA annotation from GO_REF:0000003 (UniProt keyword KW-0723 Serine/threonine-protein kinase). BRAF is a canonical Ser/Thr kinase — 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.

Summary: IEA annotation from GO_REF:0000002 (InterPro2GO) for ATP binding. BRAF binds ATP via the kinase-domain glycine-rich loop and DFG motif — 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.

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.

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) — 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.

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) — 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.

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 — 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.

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.

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 — 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).

Summary: IEA annotation from GO_REF:0000116 for protein serine kinase activity — the most specific MF child of GO:0004674. BRAF phosphorylates MEK1/MEK2 on serine residues — 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.

Summary: IPI for BRAF binding to 14-3-3 protein(s) (YWHAB). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (YWHAB), a canonical phospho-dependent BRAF interaction. Yeast two-hybrid screen of Raf-interacting proteins. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to 14-3-3 protein(s) (YWHAZ). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (YWHAZ), a canonical phospho-dependent BRAF interaction. Proteomic screen of 14-3-3-binding proteins. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to 14-3-3 protein(s) (SFN / 14-3-3 sigma). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (SFN / 14-3-3 sigma), a canonical phospho-dependent BRAF interaction. Proteomic screen of 14-3-3 sigma partners, which lists B-RAF among interactors. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: 14-3-3 protein binding

Summary: IPI from a study showing that FGF-2 induces a multiprotein complex of B-Raf, PKCepsilon and S6K2 in small cell lung cancer cells.

Reason: WITH/FROM partners are protein kinases (PRKCE, RPS6KA2/S6K2, MAP3K1); the paper describes a B-Raf/PKCepsilon/S6K2 signalling complex, so 'protein kinase binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02156 (Protein kinase C epsilon type), so only the protein kinase binding replacement applies to it.

Proposed replacements: protein kinase binding

Summary: IPI whose cached paper concerns glucocorticoid-induced dissociation of a TCR-associated LCK/FYN complex; BRAF is not mentioned in the cached text.

Reason: Deferring to the IntAct curator: the WITH/FROM partner is MAP3K1, a protein kinase, and BRAF may have been detected in the complex or used as a control in a part of the paper not visible here. Mapped by partner to 'protein kinase binding'; low confidence, worth spot-checking. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein kinase binding

Summary: IPI showing that RGS12 acts as a scaffold that associates with TrkA, activated H-Ras, B-Raf and MEK2 to sustain NGF-induced ERK activation.

Reason: WITH/FROM partner is RGS12 (rat), described in the paper as a selective Ras/Raf/MEK scaffold, so 'scaffold protein binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: scaffold protein binding

Summary: IPI characterising the direct interaction between the scaffold protein IQGAP1 and B-Raf, which modulates B-Raf activation.

Reason: WITH/FROM partner is IQGAP1, a MAPK-pathway scaffold protein; BRAF already carries 'scaffold protein binding' elsewhere in this review. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: scaffold protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2; plus 14-3-3 isoforms, HSP90AB1 and ARAF). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2; plus 14-3-3 isoforms, HSP90AB1 and ARAF), BRAF's substrates. Tandem-affinity purification of Raf complexes recovered the canonical RAF partners, so the row is split into the matching terms. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P08238 (Heat shock protein HSP 90-beta), so only the Hsp90 protein binding replacement applies to it.

Proposed replacements: Hsp90 protein binding

Summary: IPI for BRAF binding to another RAF paralog (RAF1, ARAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1, ARAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper shows that RAF inhibitors induce dimerization of wild-type RAF. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P04049 (RAF proto-oncogene serine/threonine-protein kinase), so only the protein heterodimerization activity replacement applies to it.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to another RAF paralog (RAF1/CRAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1/CRAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper shows that BRAF-selective drugs drive RAS-dependent BRAF binding to CRAF. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to MEK (MEK1 (non-human)). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MEK1 (non-human)), BRAF's substrates. The paper also describes KSR2-BRAF heterodimers that relay a signal to MEK. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to RAS (NRAS). BRAF is a RAS effector whose RAS-binding domain (RBD) binds GTP-loaded RAS at the membrane, a core step in RAF activation.

Reason: WITH/FROM partner is a RAS small GTPase (NRAS); RAS-GTP binding through the RBD is a core BRAF molecular function. The paper shows that ERK phosphorylation of BRAF Ser151 inhibits the NRAS-BRAF interaction. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: small GTPase binding

Summary: IPI from a study of FGF-2-induced drug resistance, which involves a PKCepsilon/B-RAF/S6K2 complex.

Reason: WITH/FROM partner is PKCepsilon (PRKCE), a protein kinase that forms a complex with B-RAF, so 'protein kinase binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein kinase binding

Summary: IPI for BRAF binding to another RAF paralog (RAF1/CRAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1/CRAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper describes RAS-dependent paradoxical activation of BRAF and CRAF by off-target inhibitors, which occurs through RAF dimers. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to another RAF paralog (RAF1/CRAF, mouse Raf1 and Ksr1). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1/CRAF, mouse Raf1 and Ksr1); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper examines the dimer interface requirement in wild-type and V600E B-Raf. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P04049 (RAF proto-oncogene serine/threonine-protein kinase), so only the protein heterodimerization activity replacement applies to it.

Proposed replacements: protein heterodimerization activity

Summary: IPI from a quantitative survey of HSP90-client interactions, which found that kinases are the dominant HSP90 client class.

Reason: WITH/FROM partner is HSP90AB1; BRAF (especially V600E) is an established HSP90 client kinase. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: Hsp90 protein binding

Summary: IPI whose cached paper concerns relief of ERK-dependent feedback by RAF inhibitors in BRAF V600E melanoma; the TRAF3 interaction is not described in the cached text.

Reason: Deferring to the IntAct curator: the WITH/FROM partner is TRAF3, an E3 ubiquitin ligase, and the interaction may come from supplementary data or a control. Mapped by partner to 'ubiquitin protein ligase binding'; low confidence, worth spot-checking. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: ubiquitin protein ligase binding

Summary: IPI for BRAF binding to another RAF paralog (RAF1/CRAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1/CRAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper concerns how RAF inhibitors activate MAPK signalling, which involves RAF dimers. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to MEK (MAP2K1, plus RAF1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, plus RAF1), BRAF's substrates. The paper compares MEK activation states in BRAF- vs KRAS-driven tumours. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P04049 (RAF proto-oncogene serine/threonine-protein kinase), so only the protein heterodimerization activity replacement applies to it.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to 14-3-3 protein(s) (YWHAB). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (YWHAB), a canonical phospho-dependent BRAF interaction. Hippo-pathway interactome screen. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to RAS (HRAS). BRAF is a RAS effector whose RAS-binding domain (RBD) binds GTP-loaded RAS at the membrane, a core step in RAF activation.

Reason: WITH/FROM partner is a RAS small GTPase (HRAS); RAS-GTP binding through the RBD is a core BRAF molecular function. NMR study of RAS-effector binding, including RAF kinases. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2), BRAF's substrates. The paper concerns RAF-mediated MEK activation. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, plus RAF1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, plus RAF1), BRAF's substrates. The crystal structure of the BRAF-MEK complex shows a kinase-activity-independent scaffolding role for BRAF. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P04049 (RAF proto-oncogene serine/threonine-protein kinase), so only the protein heterodimerization activity replacement applies to it.

Proposed replacements: protein heterodimerization activity

Summary: IPI from an in situ proximity ligation assay profiling endogenous interactions, with ARAF and AKT1 as partners.

Reason: WITH/FROM partners are protein kinases (ARAF, AKT1), so 'protein kinase binding' is the informative term for this screen. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P10398 (Serine/threonine-protein kinase A-Raf), so only the protein kinase binding replacement applies to it.

Proposed replacements: protein kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1), BRAF's substrates. The crystal structure of a BRAF kinase-domain monomer was used to explain allosteric inhibition; MEK1 is the partner. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2), BRAF's substrates. The paper concerns resistance to combined BRAF/MEK targeting. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to RAS (HRAS). BRAF is a RAS effector whose RAS-binding domain (RBD) binds GTP-loaded RAS at the membrane, a core step in RAF activation.

Reason: WITH/FROM partner is a RAS small GTPase (HRAS); RAS-GTP binding through the RBD is a core BRAF molecular function. The paper shows that the BRAF RBD changes conformation allosterically when it binds HRAS. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to another RAF paralog (RAF1/CRAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1/CRAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper describes RAF inhibitors that avoid paradoxical activation, a dimer-dependent process. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to MEK (MAP2K1, plus YWHAZ). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, plus YWHAZ), BRAF's substrates. Quantitative interactome (HeLa AP-MS). GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P63104 (14-3-3 protein zeta/delta), so only the 14-3-3 protein binding replacement applies to it.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K2, plus HRAS, ARAF, YWHAE/YWHAZ and RPTOR). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K2, plus HRAS, ARAF, YWHAE/YWHAZ and RPTOR), BRAF's substrates. BioPlex AP-MS screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01112 (GTPase HRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to RAS (NRAS, HRAS). BRAF is a RAS effector whose RAS-binding domain (RBD) binds GTP-loaded RAS at the membrane, a core step in RAF activation.

Reason: WITH/FROM partner is a RAS small GTPase (NRAS, HRAS); RAS-GTP binding through the RBD is a core BRAF molecular function. RAS-isoform interactome screen. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01111 (GTPase NRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

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 — 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 — and specific MF terms should be preferred per CLAUDE.md curation guidelines.

Reason: Generic 'protein binding' should not be retained for BRAF's well-characterized RAF-kinase, RAS-effector, dimerization, substrate-binding, and chaperone biology. Curate a partner-specific informative molecular-function term when the evidence supports one; otherwise remove the bare GO:0005515 assertion.

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus NRAS and 14-3-3 isoforms). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus NRAS and 14-3-3 isoforms), BRAF's substrates. Kinase interaction-network screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01111 (GTPase NRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus HRAS, RAF1/ARAF and 14-3-3 isoforms). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus HRAS, RAF1/ARAF and 14-3-3 isoforms), BRAF's substrates. BioPlex dual-cell-line screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01112 (GTPase HRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to RAS (NRAS, HRAS). BRAF is a RAS effector whose RAS-binding domain (RBD) binds GTP-loaded RAS at the membrane, a core step in RAF activation.

Reason: WITH/FROM partner is a RAS small GTPase (NRAS, HRAS); RAS-GTP binding through the RBD is a core BRAF molecular function. Head-and-neck cancer protein network screen. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01111 (GTPase NRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

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 — 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 — and specific MF terms should be preferred per CLAUDE.md curation guidelines.

Reason: Generic 'protein binding' should not be retained for BRAF's well-characterized RAF-kinase, RAS-effector, dimerization, substrate-binding, and chaperone biology. Curate a partner-specific informative molecular-function term when the evidence supports one; otherwise remove the bare GO:0005515 assertion.

Summary: IPI for BRAF binding to RAS (HRAS). BRAF is a RAS effector whose RAS-binding domain (RBD) binds GTP-loaded RAS at the membrane, a core step in RAF activation.

Reason: WITH/FROM partner is a RAS small GTPase (HRAS); RAS-GTP binding through the RBD is a core BRAF molecular function. Proteomic study of isoform- and nucleotide-dependent RAS interactors. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: small GTPase binding

Summary: IPI from a study showing that the E3 ligase HERC2 forms complexes with RAF proteins and regulates C-RAF ubiquitylation.

Reason: WITH/FROM partner is HERC2, a HECT E3 ubiquitin ligase that the paper shows forms complexes with RAF proteins, so 'ubiquitin protein ligase binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: ubiquitin protein ligase binding

Summary: IPI for BRAF binding to 14-3-3 protein(s) (YWHAB, SFN, YWHAE, YWHAZ). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (YWHAB, SFN, YWHAE, YWHAZ), a canonical phospho-dependent BRAF interaction. Study of the chaperone-like role of 14-3-3 proteins. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P31946 (14-3-3 protein beta/alpha), so only the 14-3-3 protein binding replacement applies to it.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to another RAF paralog (RAF1/CRAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1/CRAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. Interactome study of RAF1-BRAF monomers and dimers. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to 14-3-3 protein(s) (YWHAB). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (YWHAB), a canonical phospho-dependent BRAF interaction. Large-scale multimodal cell-map interactome. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: 14-3-3 protein binding

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 — more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 — 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).

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 — more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 — 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).

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 — kinase-inhibitor-induced trans-activation of MAPK signaling via RAF dimer formation — 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 — more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 — 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).

Summary: IPI annotation supporting BRAF homodimerization, derived from Röring 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 — more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 — 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).

Summary: IPI annotation supporting BRAF homodimerization, derived from Haling et al. 2014 Cancer Cell — 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 — more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 — 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).

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 — more so than the generic GO:0005515 'protein binding' rows already demoted in PR #437 — 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).

Summary: IPI annotation for GO:0042802 identical protein binding, derived from Mo et al. 2022 Cell (PMID:35512704 — 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 — 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.

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) is also KEEP_AS_NON_CORE. ORGANELLES check (2026-10-24), as a synthesis row: the projection source is mouse Braf (P28028), whose mitochondrion row in QuickGO is an MGI IDA on PMID:16116448 (B-Raf immunoreactivity at motoneuron mitochondria, lost in Bag1 knockouts), not a propagated annotation, so the projection is not circular and the organelle claim stands as a recruited surface pool. Stays at the root for the reasons given on the IBA row: no anchor, no transit peptide, no outer-membrane fractionation.

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 — 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).

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 — 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).

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).

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 — 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).

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.

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.

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.

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.

Summary: EXP annotation for protein serine kinase activity from PMID:21441910 (Brennan et al. 2011 Nature — 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) — "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 — 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).

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) — "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 — 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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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) — "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 — 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).

Summary: IMP annotation for GO:0004708 MAP kinase kinase activity from Lavoie et al. 2018 Nature (PMID:29433126 — 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 — the MAP2Ks — 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

Summary: IDA annotation for MAPK cascade from PMID:18567582 (Ren et al. 2008 J Biol Chem — 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) — "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 — 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).

Summary: IDA annotation for protein serine/threonine kinase activity from PMID:18567582 (Ren et al. 2008 J Biol Chem — 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 — phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade. PMID:17563371 (Ren et al. 2007 PNAS — IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem — 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).

Summary: IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem — 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).

Summary: IPI showing that the scaffold IQGAP1 integrates Ca2+/calmodulin and B-Raf signalling.

Reason: WITH/FROM partner is IQGAP1, a MAPK scaffold protein, so 'scaffold protein binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: scaffold protein binding

Summary: IDA annotation from PMID:18567582 (Ren et al. 2008 J Biol Chem). BRAF was studied as an EGF-stimulated effector — 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 — 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).

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-Raf–IQGAP1 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).

Summary: IPI for BRAF binding to 14-3-3 protein(s) (YWHAZ). BRAF is a well-established 14-3-3 client; 14-3-3 dimers bind phospho-S365 and phospho-S729 of BRAF to hold the autoinhibited monomer and to stabilise the active dimer.

Reason: WITH/FROM partner(s) are 14-3-3 isoforms (YWHAZ), a canonical phospho-dependent BRAF interaction. The paper describes a YWHAZ variant associated with cardiofaciocutaneous syndrome that activates RAF-MAPK signalling. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF.

Proposed replacements: 14-3-3 protein binding

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 — 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 — and specific MF terms should be preferred per CLAUDE.md curation guidelines.

Reason: Generic 'protein binding' should not be retained for BRAF's well-characterized RAF-kinase, RAS-effector, dimerization, substrate-binding, and chaperone biology. Curate a partner-specific informative molecular-function term when the evidence supports one; otherwise remove the bare GO:0005515 assertion.

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

Summary: IPI from a study of the FNIP1/FNIP2 co-chaperones of HSP90, with BRAF detected as an interacting client kinase.

Reason: WITH/FROM partners are FNIP1/FNIP2, HSP90 co-chaperones; BRAF is an HSP90 client, so 'protein-folding chaperone binding' is the closest informative term. Deferring to the curator on the interaction itself (the cached text is abstract-only). GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q8TF40 (Folliculin-interacting protein 1), so only the protein-folding chaperone binding replacement applies to it.

Proposed replacements: protein-folding chaperone binding

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 — 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).

Summary: NOT (negated) IPI annotation for GO:0031267 small GTPase binding from Kontani et al. 2002 J Biol Chem (PMID:12194967 — 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 — 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.

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).

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).

Summary: IDA annotation from PMID:23010278 (Pakladok et al. 2012, Biochem Biophys Res Commun — 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 — the RAS-RAF-MEK-ERK kinase cascade and cytosol/plasma-membrane localization — 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).

Summary: IDA annotation from PMID:23010278 (Pakladok et al. 2012, Biochem Biophys Res Commun — 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 — the RAS-RAF-MEK-ERK kinase cascade and cytosol/plasma-membrane localization — 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).

Summary: IDA annotation for protein kinase activity from PMID:17563371 (Ren et al. 2007 PNAS — 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) — 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 — phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade. PMID:17563371 (Ren et al. 2007 PNAS — IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem — 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).

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.

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 — 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 BRAF→downstream-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.

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 — phosphorylating MEK1/MEK2 in the RAS-RAF-MEK-ERK cascade. PMID:17563371 (Ren et al. 2007 PNAS — IQGAP1 modulates B-Raf activation; demonstrates B-Raf kinase activity in vitro), PMID:18567582 (Ren et al. 2008 J Biol Chem — 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).

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

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-ERK→90 kDa ribosomal S6 kinase→BAD-S112 phosphorylation in murine BAD). Mechanically consolidated to ACCEPT with a uniform template across the 4 canonical BRAF→downstream-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 — this row provides the direct experimental anchor.

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

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 — 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.

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 — 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.

Summary: TAS annotation from Wojnowski et al. 1997 (PMID:9207797) — 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 → GO:0001568 blood vessel development) in this same batch.

Summary: IPI from a study showing that FGF-2 induces a multiprotein complex of B-Raf, PKCepsilon and S6K2 in small cell lung cancer cells.

Reason: WITH/FROM partners are protein kinases (PRKCE, RPS6KA2/S6K2, MAP3K1); the paper describes a B-Raf/PKCepsilon/S6K2 signalling complex, so 'protein kinase binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q13233 (Mitogen-activated protein kinase kinase kinase 1), so only the protein kinase binding replacement applies to it.

Proposed replacements: protein kinase binding

Summary: IPI from a study showing that FGF-2 induces a multiprotein complex of B-Raf, PKCepsilon and S6K2 in small cell lung cancer cells.

Reason: WITH/FROM partners are protein kinases (PRKCE, RPS6KA2/S6K2, MAP3K1); the paper describes a B-Raf/PKCepsilon/S6K2 signalling complex, so 'protein kinase binding' is the informative term. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q15349 (Ribosomal protein S6 kinase alpha-2), so only the protein kinase binding replacement applies to it.

Proposed replacements: protein kinase binding

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:P10398 from a Raf-associated SF-TAP protein-complex pilot study, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2; plus 14-3-3 isoforms, HSP90AB1 and ARAF). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2; plus 14-3-3 isoforms, HSP90AB1 and ARAF), BRAF's substrates. Tandem-affinity purification of Raf complexes recovered the canonical RAF partners, so the row is split into the matching terms. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P62258 from a Raf-associated SF-TAP protein-complex pilot study.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P63104 from a Raf-associated SF-TAP protein-complex pilot study.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2; plus 14-3-3 isoforms, HSP90AB1 and ARAF). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2; plus 14-3-3 isoforms, HSP90AB1 and ARAF), BRAF's substrates. Tandem-affinity purification of Raf complexes recovered the canonical RAF partners, so the row is split into the matching terms. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to another RAF paralog (RAF1, ARAF). BRAF forms side-to-side kinase-domain heterodimers with CRAF/ARAF, the key mechanism of normal RAF activation and of paradoxical activation by RAF inhibitors.

Reason: WITH/FROM partner(s) are RAF paralogs (RAF1, ARAF); the paper concerns RAF dimerisation, so 'protein heterodimerization activity' is the informative replacement. The paper shows that RAF inhibitors induce dimerization of wild-type RAF. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P10398 (Serine/threonine-protein kinase A-Raf), so only the protein heterodimerization activity replacement applies to it.

Proposed replacements: protein heterodimerization activity

Summary: This newly backfilled generic protein-binding row links human BRAF to mouse KSR1 from PMID:22510884.

Reason: The cached full text supports B-Raf and Raf-1 dimer-interface biology, but it does not expose the KSR1-specific experimental record underlying this IntAct row; that support may be confined to supplemental interaction data outside the cache. Use UNDECIDED rather than guessing whether the row should be modified to GO:0046982 protein heterodimerization activity.

Summary: This newly backfilled IPI row records a BRAF-RAF1 RAF-family dimer interaction from a RAF dimerization study.

Reason: The generic protein-binding term should be replaced by GO:0046982 protein heterodimerization activity because the supporting entity is a RAF-family or KSR-family dimerization partner and the cited study assayed the side-to-side dimerization/transactivation mechanism that regulates BRAF output to MEK.

Proposed replacements: protein heterodimerization activity

Summary: IPI for BRAF binding to MEK (MAP2K1, plus RAF1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, plus RAF1), BRAF's substrates. The paper compares MEK activation states in BRAF- vs KRAS-driven tumours. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2), BRAF's substrates. The paper concerns RAF-mediated MEK activation. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, plus RAF1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, plus RAF1), BRAF's substrates. The crystal structure of the BRAF-MEK complex shows a kinase-activity-independent scaffolding role for BRAF. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI from an in situ proximity ligation assay profiling endogenous interactions, with ARAF and AKT1 as partners.

Reason: WITH/FROM partners are protein kinases (ARAF, AKT1), so 'protein kinase binding' is the informative term for this screen. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P31749 (RAC-alpha serine/threonine-protein kinase), so only the protein kinase binding replacement applies to it.

Proposed replacements: protein kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, MAP2K2). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, MAP2K2), BRAF's substrates. The paper concerns resistance to combined BRAF/MEK targeting. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI for BRAF binding to MEK (MAP2K1, plus YWHAZ). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1, plus YWHAZ), BRAF's substrates. Quantitative interactome (HeLa AP-MS). GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: IPI from a study of the FNIP1/FNIP2 co-chaperones of HSP90, with BRAF detected as an interacting client kinase.

Reason: WITH/FROM partners are FNIP1/FNIP2, HSP90 co-chaperones; BRAF is an HSP90 client, so 'protein-folding chaperone binding' is the closest informative term. Deferring to the curator on the interaction itself (the cached text is abstract-only). GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q9P278 (Folliculin-interacting protein 2), so only the protein-folding chaperone binding replacement applies to it.

Proposed replacements: protein-folding chaperone binding

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:P10398 from the BioPlex 2.0 AP-MS interactome survey, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: IPI for BRAF binding to MEK (MAP2K2, plus HRAS, ARAF, YWHAE/YWHAZ and RPTOR). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K2, plus HRAS, ARAF, YWHAE/YWHAZ and RPTOR), BRAF's substrates. BioPlex AP-MS screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P62258 from the BioPlex 2.0 AP-MS interactome survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P63104 from the BioPlex 2.0 AP-MS interactome survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:Q8N122 from the BioPlex 2.0 AP-MS interactome survey, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: This newly backfilled IPI row records a BRAF-KSR1 RAF-family dimer interaction from a RAF dimerization study.

Reason: The generic protein-binding term should be replaced by GO:0046982 protein heterodimerization activity because the supporting entity is a RAF-family or KSR-family dimerization partner and the cited study assayed the side-to-side dimerization/transactivation mechanism that regulates BRAF output to MEK.

Proposed replacements: protein heterodimerization activity

Summary: This newly backfilled IPI row reports BRAF proximity to HRAS from a RAS-interaction study.

Reason: BRAF is a direct effector of activated RAS-family small GTPases through its Ras-binding domain. Replace generic GO:0005515 with GO:0031267 small GTPase binding; this captures the direct RAS-effector molecular function without manufacturing a downstream biological-process annotation.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus 14-3-3 isoforms, HSP90AB1, RAF1/ARAF and RPTOR). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus 14-3-3 isoforms, HSP90AB1, RAF1/ARAF and RPTOR), BRAF's substrates. EGFR-network AP-MS screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P08238 (Heat shock protein HSP 90-beta), so only the Hsp90 protein binding replacement applies to it.

Proposed replacements: Hsp90 protein binding

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:P10398 from an AP-MS map of EGFR-network rewiring in KRAS(G13D) colorectal cancer cells, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P31946 from an AP-MS map of EGFR-network rewiring in KRAS(G13D) colorectal cancer cells.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P31947 from an AP-MS map of EGFR-network rewiring in KRAS(G13D) colorectal cancer cells.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus 14-3-3 isoforms, HSP90AB1, RAF1/ARAF and RPTOR). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus 14-3-3 isoforms, HSP90AB1, RAF1/ARAF and RPTOR), BRAF's substrates. EGFR-network AP-MS screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P62258 from an AP-MS map of EGFR-network rewiring in KRAS(G13D) colorectal cancer cells.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P63104 from an AP-MS map of EGFR-network rewiring in KRAS(G13D) colorectal cancer cells.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus 14-3-3 isoforms, HSP90AB1, RAF1/ARAF and RPTOR). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus 14-3-3 isoforms, HSP90AB1, RAF1/ARAF and RPTOR), BRAF's substrates. EGFR-network AP-MS screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:Q8N122 from an AP-MS map of EGFR-network rewiring in KRAS(G13D) colorectal cancer cells, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P31946 from a kinome-scale AP-MS interaction survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus NRAS and 14-3-3 isoforms). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus NRAS and 14-3-3 isoforms), BRAF's substrates. Kinase interaction-network screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P62258 from a kinome-scale AP-MS interaction survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P63104 from a kinome-scale AP-MS interaction survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus NRAS and 14-3-3 isoforms). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus NRAS and 14-3-3 isoforms), BRAF's substrates. Kinase interaction-network screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:P04049 from the BioPlex 3.0 and HCT116 proteome-scale AP-MS interactome survey, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: This newly backfilled IPI row records a BRAF physical interaction with UniProtKB:P10398 from the BioPlex 3.0 and HCT116 proteome-scale AP-MS interactome survey, but the asserted term is the uninformative generic GO:0005515 protein binding.

Reason: GO:0005515 should not be retained when it only restates that a physical interaction was reported. The row is being removed because the term adds no curatable molecular function beyond the interaction record itself; this does not mean the reported interaction is false. No evidence in this source/entity combination justifies replacing the row with a specific BRAF molecular function such as 14-3-3 protein binding, small GTPase binding, or RAF-family heterodimerization activity.

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P31946 from the BioPlex 3.0 and HCT116 proteome-scale AP-MS interactome survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus HRAS, RAF1/ARAF and 14-3-3 isoforms). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus HRAS, RAF1/ARAF and 14-3-3 isoforms), BRAF's substrates. BioPlex dual-cell-line screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P62258 from the BioPlex 3.0 and HCT116 proteome-scale AP-MS interactome survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P63104 from the BioPlex 3.0 and HCT116 proteome-scale AP-MS interactome survey.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2, plus HRAS, RAF1/ARAF and 14-3-3 isoforms). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2, plus HRAS, RAF1/ARAF and 14-3-3 isoforms), BRAF's substrates. BioPlex dual-cell-line screen; the row is mapped to terms for the canonical partners. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row reports BRAF proximity to HRAS from a head-and-neck cancer cell-map AP-MS survey.

Reason: BRAF is a direct effector of activated RAS-family small GTPases through its Ras-binding domain. Replace generic GO:0005515 with GO:0031267 small GTPase binding; this captures the direct RAS-effector molecular function without manufacturing a downstream biological-process annotation.

Proposed replacements: small GTPase binding

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:O14920.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:O14965.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:O15297.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:O43524.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:O75874.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1), BRAF's substrates. This high-throughput screen of wild-type and mutant proteins mainly reports mutation-directed neo-PPIs (e.g. BRAF V600E/KEAP1); only the canonical partners are carried into the replacement terms, and the other partners were not adjudicated. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01111 (GTPase NRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1), BRAF's substrates. This high-throughput screen of wild-type and mutant proteins mainly reports mutation-directed neo-PPIs (e.g. BRAF V600E/KEAP1); only the canonical partners are carried into the replacement terms, and the other partners were not adjudicated. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P01112 (GTPase HRas), so only the small GTPase binding replacement applies to it.

Proposed replacements: small GTPase binding

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P04049.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P04637.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P07196.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P08238.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P10398.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P16885.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P17174.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P18074.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P21399.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P25311.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P27986.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P27987.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P28715.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P31749.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P31946.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P31947.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P35221.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1), BRAF's substrates. This high-throughput screen of wild-type and mutant proteins mainly reports mutation-directed neo-PPIs (e.g. BRAF V600E/KEAP1); only the canonical partners are carried into the replacement terms, and the other partners were not adjudicated. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:P36507 (Dual specificity mitogen-activated protein kinase kinase 2), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P40259.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P40337.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P42772.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P48736.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P49407.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P49840.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P57735.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P61024.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P61224.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P62258.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:P63104.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: IPI for BRAF binding to MEK (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1). MEK1/MEK2 are the direct substrates of BRAF and also form stable BRAF-MEK complexes.

Reason: WITH/FROM partner(s) include MEK1/MEK2 (MAP2K1/MAP2K2 and about 60 others, including 14-3-3 isoforms, HRAS/NRAS, RAF1/ARAF and KEAP1), BRAF's substrates. This high-throughput screen of wild-type and mutant proteins mainly reports mutation-directed neo-PPIs (e.g. BRAF V600E/KEAP1); only the canonical partners are carried into the replacement terms, and the other partners were not adjudicated. GO:0005515 'protein binding' is uninformative; the replacement term captures what the interaction means for BRAF. GOA now lists this interaction as one row per partner; this row's partner is UniProtKB:Q02750 (Dual specificity mitogen-activated protein kinase kinase 1), so only the mitogen-activated protein kinase kinase binding replacement applies to it.

Proposed replacements: mitogen-activated protein kinase kinase binding

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q07817.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q07864.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q12967.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q13164.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q13618.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q14145.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q15759.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q16254.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q16659.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q6P1J9.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q7Z589.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q8IYM1.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q8N122.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q8WXI9.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q92560.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q92843.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q9BRP1.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q9GZV4.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q9NX70.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row comes from the mutation-directed qHT-dS neoPPI screen and records a generic BRAF protein-binding assertion with UniProtKB:Q9UMX1.

Reason: PMID:35512704 systematically compares wild-type and cancer-mutant alleles to find variant-enabled neo-protein-protein interactions, with BRAF V600E-KEAP1 as the mechanistic case study. These rows should not be promoted to ordinary wild-type BRAF molecular-function annotations, and the generic GO:0005515 term is itself uninformative. Remove the generic binding assertion rather than flattening a mutant-directed interaction screen into BRAF core function.

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P31947 from a 14-3-3 interactome study.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P62258 from a 14-3-3 interactome study.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding

Summary: This newly backfilled IPI row records a BRAF interaction with the 14-3-3 family member UniProtKB:P63104 from a 14-3-3 interactome study.

Reason: BRAF binding to 14-3-3 dimers at regulatory phosphoserines is a specific, well-established RAF regulatory activity, so the generic GO:0005515 row should be replaced by GO:0071889 14-3-3 protein binding. This keeps the interaction as a specific non-catalytic molecular function instead of a bare physical-interaction placeholder.

Proposed replacements: 14-3-3 protein binding