A-Raf (ARAF) is one of the three RAF-family serine/threonine protein kinases (with BRAF and RAF1/CRAF) that act as MAP kinase kinase kinases in the RAS-RAF-MEK-ERK (MAPK/ERK) cascade. It has an N-terminal RAS-binding domain and cysteine-rich C1-like domain (CR1), a Ser/Thr-rich regulatory region carrying the inhibitory 14-3-3 site Ser-214 (CR2), and a C-terminal protein kinase domain (CR3). In resting cells ARAF is held in an autoinhibited cytosolic complex with 14-3-3 proteins and the HSP90/CDC37 chaperone; RAS-GTP recruits it to the plasma membrane, where Ser-214 dephosphorylation (by PP2A or the SHOC2-MRAS-PP1C complex) and side-to-side homo- or heterodimerization with BRAF or CRAF activate it to phosphorylate the activation loops of MEK1/MEK2 (MAP2K1/MAP2K2). ARAF is the least catalytically active RAF paralog, but it sustains RAS-driven ERK signalling in some contexts and can confer resistance to BRAF/CRAF-selective inhibitors. A fraction of ARAF localises to mitochondria, where it restrains apoptosis largely independently of its kinase activity, notably by sequestering the pro-apoptotic kinase MST2. Activating somatic ARAF mutations occur in lung adenocarcinoma, Langerhans cell histiocytosis and central conducting lymphatic anomaly. A short splice isoform (DA-Raf1) lacking the kinase domain acts as a dominant-negative RAS antagonist.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for MAPK cascade from PAINT node PTN001147804 (RAF family), seeded by experimentally annotated RAF-family members including human BRAF and RAF orthologs from rodents, fly and worm. ARAF is a bona fide member of this clade and acts at the MAP3K tier of the RAS-RAF-MEK-ERK cascade. Reason: ARAF sits inside the RAF clade that carries the MAP3K/MAPK-cascade function; there is no evidence of loss of function in ARAF (it is the weakest but still catalytically competent RAF paralog). Core process. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md Wild-type ARAF immunoprecipitates generated phosphorylated MEK1 file:human/ARAF/ARAF-uniprot.txt Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA protein kinase activity from InterPro kinase-domain signatures (IPR001245, IPR008271). Reason: Correct but general; ARAF has an intact protein kinase domain with Ser/Thr kinase activity. The more informative term GO:0004709 MAP kinase kinase kinase activity is accepted separately. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md Wild-type ARAF immunoprecipitates generated phosphorylated MEK1 |
| GO:0004672 protein kinase activity | TAS PMID:3029685 The complete coding sequence of the human A-raf-1 oncogene a... | ACCEPT | Summary: TAS protein kinase activity citing the 1987 cloning of the human A-raf-1 cDNA, which described its transforming activity and homology to protein kinases. Reason: Consistent with the established Ser/Thr kinase activity of ARAF; general parent of the core MAP3K term. Supporting Evidence: PMID:3029685 The complete 606 amino acid sequence of the human A-raf oncogene has been deduced |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:19667065 Identification of novel in vivo phosphorylation sites of the... | ACCEPT | Summary: IDA protein serine/threonine kinase activity from a study identifying RAF kinases as in vivo BAD-phosphorylating kinases (Rapp laboratory). Reason: The cached abstract speaks of RAF kinases generically, but the curator read the full text (PMC2788853), from a laboratory that routinely assays purified A-RAF. ARAF Ser/Thr kinase activity is in any case well established (MEK1/2 phosphorylation). Supporting Evidence: PMID:19667065 Our results indicate that RAF kinases represent, besides protein kinase A, PAK, and Akt/protein kinase B, in vivo BAD-phosphorylating kinases. file:human/ARAF/ARAF-deep-research-falcon.md Wild-type ARAF immunoprecipitates generated phosphorylated MEK1 |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: IEA protein serine/threonine kinase activity from the EC 2.7.11.1 mapping. Reason: Correct: ARAF is EC 2.7.11.1, a Ser/Thr protein kinase. Supporting Evidence: file:human/ARAF/ARAF-uniprot.txt EC=2.7.11.1 |
| GO:0004709 MAP kinase kinase kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA MAP kinase kinase kinase activity from PAINT node PTN001147804 (RAF family). ARAF phosphorylates MEK1/MEK2 on their activation loops, the defining MAP3K reaction. Reason: Core molecular function. ARAF is within the RAF clade and ARAF-specific experiments show MEK1 phosphorylation by wild-type but not kinase-dead ARAF; it binds MEK2 directly through its kinase domain. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md Wild-type ARAF immunoprecipitates generated phosphorylated MEK1 PMID:11909642 A-Raf was identified as a novel partner that interacts with MEK2 |
| GO:0005515 protein binding | IPI PMID:11909642 Identification of interaction between MEK2 and A-Raf-1. | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from a directed yeast two-hybrid screen with MEK2 as bait, confirmed by in vitro binding, mapping the interaction to the ARAF kinase domain. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:11909642 A-Raf was identified as a novel partner that interacts with MEK2 |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding TIMM44, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and TIMM44 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. TIMM44/TIMM50 partners are consistent with reported mitochondrial import of a fraction of ARAF, which is captured by the mitochondrion CC rows rather than by a binding MF. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding PRPF6, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and PRPF6 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding NUDT14, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and NUDT14 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding ASS1, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and ASS1 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | MODIFY | Summary: IPI for ARAF binding HRAS, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. RAS-GTP binds the ARAF RAS-binding domain/CRD and recruits ARAF to the plasma membrane, the initiating step of RAF activation. Reason: The WITH/FROM partner (HRAS) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031267 small GTPase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: small GTPase binding Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding CPS1, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and CPS1 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding RABGGTB, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and RABGGTB does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | MODIFY | Summary: IPI for ARAF binding RRAS2, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. RAS-GTP binds the ARAF RAS-binding domain/CRD and recruits ARAF to the plasma membrane, the initiating step of RAF activation. Reason: The WITH/FROM partner (RRAS2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031267 small GTPase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: small GTPase binding Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding EFEMP1, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and EFEMP1 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding TIMM50, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and TIMM50 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. TIMM44/TIMM50 partners are consistent with reported mitochondrial import of a fraction of ARAF, which is captured by the mitochondrion CC rows rather than by a binding MF. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding NELFCD, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and NELFCD does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. NELFCD binding (UniProt SUBUNIT) is reproduced in several Y2H screens but has no established functional consequence that maps to an informative MF term. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding PBK/TOPK, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and PBK/TOPK does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: IPI for ARAF binding COPS3, from an exhaustive yeast two-hybrid screen using the A-Raf/C-Raf N-terminal regulatory domain (RBD+CRD) as bait. Reason: GO:0005515 'protein binding' is uninformative, and COPS3 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:12620389 The cysteine-rich zinc-binding domain (CRD) of Raf was found to interact with all 20 proteins |
| GO:0005515 protein binding | IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ... | MODIFY | Summary: IPI for ARAF binding 14-3-3 sigma/SFN, from a TAP/MudPIT proteomic survey of 14-3-3 sigma partners that lists A-RAF among interactors. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 sigma/SFN) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:15778465 implicated in oncogenic signaling (APC, A-RAF, B-RAF, and c-RAF) |
| GO:0005515 protein binding | IPI PMID:17979178 A novel tandem affinity purification strategy for the effici... | MODIFY | Summary: IPI for ARAF binding BRAF, from SF-TAP purification of Raf-associated complexes from HEK293 cells. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:17979178 dissection of interaction patterns from the Raf binding partners MEK1 and 14-3-3 |
| GO:0005515 protein binding | IPI PMID:19933840 Regulation of IRSp53-dependent filopodial dynamics by antago... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from a 14-3-3 interaction study centred on IRSp53 (ARAF presumably recovered as a 14-3-3 client). ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:20052757 Molecular and clinical analysis of RAF1 in Noonan syndrome a... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from a RAF1 Noonan syndrome study of S259 dephosphorylation and 14-3-3 dissociation (ARAF presumably assayed as a comparator). ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:20052757 mutant RAF1 then dissociated from 14-3-3 |
| GO:0005515 protein binding | IPI PMID:20130576 RAF inhibitors prime wild-type RAF to activate the MAPK path... | MODIFY | Summary: IPI for ARAF binding BRAF, from a study showing that RAF inhibitors induce dimerization of wild-type RAF isoforms. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:20130576 Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MODIFY | Summary: IPI for ARAF binding 14-3-3 epsilon/YWHAE, from a large-scale human MAP kinase interactome (Y2H plus co-IP). ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 epsilon/YWHAE) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from a large-scale human MAP kinase interactome (Y2H plus co-IP). ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IPI for ARAF binding IRAK2, from an innate-immunity (type I interferon) AP-MS interactome. Reason: GO:0005515 'protein binding' is uninformative, and IRAK2 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IPI for ARAF binding TIRAP, from an innate-immunity (type I interferon) AP-MS interactome. Reason: GO:0005515 'protein binding' is uninformative, and TIRAP does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IPI for ARAF binding IRF7, from an innate-immunity (type I interferon) AP-MS interactome. Reason: GO:0005515 'protein binding' is uninformative, and IRF7 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from a human liver proteome-scale yeast two-hybrid network. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: IPI for ARAF binding NELFCD, from a human liver proteome-scale yeast two-hybrid network. Reason: GO:0005515 'protein binding' is uninformative, and NELFCD does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. NELFCD binding (UniProt SUBUNIT) is reproduced in several Y2H screens but has no established functional consequence that maps to an informative MF term. |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | MODIFY | Summary: IPI for ARAF binding HSP90AB1, from a quantitative LUMIER survey of HSP90/CDC37 clients across the human kinome. ARAF, like most RAF-family kinases, is an HSP90/CDC37 chaperone client. Reason: The WITH/FROM partner (HSP90AB1) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0051879 Hsp90 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:22939624 Unexpectedly, many more kinases than transcription factors bound HSP90. |
| GO:0005515 protein binding | IPI PMID:24441586 Integrated RAS signaling defined by parallel NMR detection o... | MODIFY | Summary: IPI for ARAF binding HRAS, from NMR-based measurement of RAS binding to effector RBDs including RAF kinases. RAS-GTP binds the ARAF RAS-binding domain/CRD and recruits ARAF to the plasma membrane, the initiating step of RAF activation. Reason: The WITH/FROM partner (HRAS) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031267 small GTPase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: small GTPase binding Supporting Evidence: PMID:24441586 specifically altering interactions with RAL GTPase-specific GEFs and RAF kinases |
| GO:0005515 protein binding | IPI PMID:24746704 Disruption of CRAF-mediated MEK activation is required for e... | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from a study of CRAF-mediated MEK activation in KRAS-mutant tumours. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | MODIFY | Summary: IPI for ARAF binding HSP90AB1, from a quantitative chaperone/co-chaperone interaction network (LUMIER/AP-MS). ARAF, like most RAF-family kinases, is an HSP90/CDC37 chaperone client. Reason: The WITH/FROM partner (HSP90AB1) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0051879 Hsp90 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: Hsp90 protein binding |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | MODIFY | Summary: IPI for ARAF binding BRAF, from an in situ proximity ligation assay survey of endogenous PPIs in HeLa cells. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MODIFY | Summary: IPI for ARAF binding 14-3-3 sigma/SFN, from kinase-centred AP-MS interaction maps from a TRAIL-apoptosis screen. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 sigma/SFN) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from kinase-centred AP-MS interaction maps from a TRAIL-apoptosis screen. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MODIFY | Summary: IPI for ARAF binding 14-3-3 epsilon/YWHAE, from kinase-centred AP-MS interaction maps from a TRAIL-apoptosis screen. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 epsilon/YWHAE) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from kinase-centred AP-MS interaction maps from a TRAIL-apoptosis screen. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | REMOVE | Summary: IPI for ARAF binding TIMM50, from kinase-centred AP-MS interaction maps from a TRAIL-apoptosis screen. Reason: GO:0005515 'protein binding' is uninformative, and TIMM50 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. TIMM44/TIMM50 partners are consistent with reported mitochondrial import of a fraction of ARAF, which is captured by the mitochondrion CC rows rather than by a binding MF. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: IPI for ARAF binding BRAF, from the BioPlex 2.0 AP-MS interactome. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI for ARAF binding HSP90AB1, from AP-MS rewiring analysis of the EGFR network in KRAS(G13D) colorectal cancer cells. ARAF, like most RAF-family kinases, is an HSP90/CDC37 chaperone client. Reason: The WITH/FROM partner (HSP90AB1) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0051879 Hsp90 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: Hsp90 protein binding |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI for ARAF binding BRAF, from AP-MS rewiring analysis of the EGFR network in KRAS(G13D) colorectal cancer cells. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI for ARAF binding 14-3-3 sigma/SFN, from AP-MS rewiring analysis of the EGFR network in KRAS(G13D) colorectal cancer cells. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 sigma/SFN) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from AP-MS rewiring analysis of the EGFR network in KRAS(G13D) colorectal cancer cells. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from AP-MS rewiring analysis of the EGFR network in KRAS(G13D) colorectal cancer cells. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: IPI for ARAF binding HSP90AB1, from a kinase-centred AP-MS/BioID interaction network of human kinases. ARAF, like most RAF-family kinases, is an HSP90/CDC37 chaperone client. Reason: The WITH/FROM partner (HSP90AB1) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0051879 Hsp90 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: Hsp90 protein binding |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from a kinase-centred AP-MS/BioID interaction network of human kinases. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: IPI for ARAF binding 14-3-3 epsilon/YWHAE, from a kinase-centred AP-MS/BioID interaction network of human kinases. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 epsilon/YWHAE) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from a kinase-centred AP-MS/BioID interaction network of human kinases. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI for ARAF binding BRAF, from the BioPlex 3.0 AP-MS interactome. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | MODIFY | Summary: IPI for ARAF binding HRAS, from a breast-cancer AP-MS interaction landscape. RAS-GTP binds the ARAF RAS-binding domain/CRD and recruits ARAF to the plasma membrane, the initiating step of RAF activation. Reason: The WITH/FROM partner (HRAS) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031267 small GTPase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: small GTPase binding |
| GO:0005515 protein binding | IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... | MODIFY | Summary: IPI for ARAF binding HRAS, from a head-and-neck-cancer AP-MS network map. RAS-GTP binds the ARAF RAS-binding domain/CRD and recruits ARAF to the plasma membrane, the initiating step of RAF activation. Reason: The WITH/FROM partner (HRAS) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031267 small GTPase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: small GTPase binding |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: IPI for ARAF binding MEK2/MAP2K2, from the OpenCell endogenous-tagging IP-MS resource. MEK1/MEK2 are the direct substrates of RAF-family MAP3Ks and form stable RAF-MEK complexes; ARAF binds MEK2 through its kinase domain. Reason: The WITH/FROM partner (MEK2/MAP2K2) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031434 mitogen-activated protein kinase kinase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: mitogen-activated protein kinase kinase binding |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: IPI for ARAF binding 14-3-3 epsilon/YWHAE, from the OpenCell endogenous-tagging IP-MS resource. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 epsilon/YWHAE) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from the OpenCell endogenous-tagging IP-MS resource. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | MODIFY | Summary: IPI for ARAF binding BRAF, from a high-throughput screen for mutation-directed neo-PPIs in cancer. ARAF forms side-to-side kinase-domain heterodimers with BRAF (and CRAF), the key step in RAF activation. Reason: The WITH/FROM partner (BRAF) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0046982 protein heterodimerization activity (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | Summary: IPI for ARAF binding SMAD4, from a high-throughput screen for mutation-directed neo-PPIs in cancer. Reason: GO:0005515 'protein binding' is uninformative, and SMAD4 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:35839996 A Proteomic Approach Identifies Isoform-Specific and Nucleot... | MODIFY | Summary: IPI for ARAF binding HRAS, from an isoform- and nucleotide-dependent RAS interactome. RAS-GTP binds the ARAF RAS-binding domain/CRD and recruits ARAF to the plasma membrane, the initiating step of RAF activation. Reason: The WITH/FROM partner (HRAS) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0031267 small GTPase binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: small GTPase binding |
| GO:0005515 protein binding | IPI PMID:36241744 HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway... | REMOVE | Summary: IPI for ARAF binding HERC2, from a HERC2 study in which A-RAF and B-RAF were detected in HERC2 immunoprecipitates, attributed to RAF heterodimerisation with C-RAF. Reason: GO:0005515 'protein binding' is uninformative, and HERC2 does not belong to a partner class with a defined role in ARAF function, so no specific MF replacement is supported by this evidence. Removal does not imply that the reported interaction is false. The paper attributes co-precipitation of A-RAF to RAF heterodimerisation with C-RAF, the actual HERC2 substrate, and reports that HERC2 depletion did not change A-RAF levels. Supporting Evidence: PMID:36241744 A-RAF and B-RAF were also detected in HERC2 immunoprecipitated complexes |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: IPI for ARAF binding 14-3-3 sigma/SFN, from an interactome map of all human 14-3-3 paralogs. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 sigma/SFN) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: IPI for ARAF binding 14-3-3 epsilon/YWHAE, from an interactome map of all human 14-3-3 paralogs. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 epsilon/YWHAE) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: IPI for ARAF binding 14-3-3 zeta/YWHAZ, from an interactome map of all human 14-3-3 paralogs. ARAF is a phospho-dependent 14-3-3 client: 14-3-3 dimers bind phospho-S214 and phospho-S582 to hold autoinhibited ARAF and stabilise active RAF dimers. Reason: The WITH/FROM partner (14-3-3 zeta/YWHAZ) places this interaction in a well-characterised RAF partner class, so the uninformative GO:0005515 'protein binding' is replaced by GO:0071889 14-3-3 protein binding (term choice consistent with the BRAF review). Deferring to the curator on the underlying interaction evidence. Proposed replacements: 14-3-3 protein binding |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA ATP binding from protein kinase ATP-binding-site InterPro signatures. Reason: ARAF has a canonical ATP-binding kinase domain (K336 ATP-binding lysine; K336M is kinase dead). Supporting Evidence: file:human/ARAF/ARAF-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytoplasm (is_active_in) propagated across the RAF/TKL clade. Reason: ARAF is a cytoplasmic kinase: inactive in cytosolic 14-3-3 complexes and active at the cytoplasmic face of the plasma membrane. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA mitochondrion (is_active_in) from PTN000584576, seeded by mouse Raf1/Braf mitochondrial annotations. Reason: A fraction of ARAF localises to mitochondria, where it sequesters MST2 in a largely kinase-independent anti-apoptotic role; TIMM44/TIMM50 were recovered as ARAF Y2H partners. Genuine but not the site of the canonical MAP3K function. Examined as a synthesis row (ORGANELLES, 2026-10-24); the PAINT node PTN000584576 is seeded for GO:0005739 by mouse Araf and Braf (MGI:88065, MGI:88190), whose mitochondrion rows are IDA (Araf from the liver mitochondrial BAD/glucokinase complex study PMID:12931191, Braf from PMID:16116448); ARAF descends from that node, and its own organelle claim is independently supported by rat liver mitochondria purified on Nycodenz (cytochrome c and COX IV enriched, ERK-1 and RACK-1 absent) with protease-protected A-RAF and immunogold label over mitochondria (PMID:10848612), and by A-Raf/MST2 at mitochondria in tumour cells (reviewed in PMID:21779496). The organelle claim stands. Stays at the root because the sub-compartment lines disagree - the 2000 study places a protease-protected pool in the intermembrane space and possibly the matrix and says its results imply but do not prove import, while the MST2-sequestration and BAD-related anti-apoptotic roles need the cytosolic face - and ARAF has no recognised presequence or membrane anchor. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md ARAF also has important non-catalytic functions, particularly sequestration of the pro-apoptotic kinase MST2 at mitochondria. PMID:10848612 The purified mitochondrial fractions were highly enriched with cytochrome oxidase IV and cytochrome c (Table 2 ), while ERK-1 and RACK-1 were absent. PMID:10848612 A-RAF remained present in mitochondria treated with either protease K or osmotic shock or in mitochondrion-mitoplast preparations. PMID:21779496 Both A-Raf and MST2 are localized at the mitochondria in tumor cell lines as well as primary tumors. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA mitochondrion transferred from mouse Araf via Ensembl Compara (GO_REF:0000107). Reason: Same as the IBA mitochondrion row: mitochondrial ARAF is documented (MST2 sequestration) but is a secondary location. Examined as a synthesis row (ORGANELLES, 2026-10-24); the Ensembl projection comes from mouse Araf (P04627), whose mitochondrion row is an MGI IDA from PMID:12931191, not a propagated annotation, so the projection is not circular; the organelle claim is independently supported for A-RAF (PMID:10848612, PMID:21779496). Stays at the root for the reasons given on the IBA row (disagreeing sub-compartment lines). Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md ARAF also has important non-catalytic functions, particularly sequestration of the pro-apoptotic kinase MST2 at mitochondria. PMID:10848612 The purified mitochondrial fractions were highly enriched with cytochrome oxidase IV and cytochrome c (Table 2 ), while ERK-1 and RACK-1 were absent. PMID:10848612 A-RAF remained present in mitochondria treated with either protease K or osmotic shock or in mitochondrion-mitoplast preparations. PMID:21779496 Both A-Raf and MST2 are localized at the mitochondria in tumor cell lines as well as primary tumors. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytosol (is_active_in) from PTN000584576, seeded by RAF1 and BRAF. Reason: Inactive ARAF resides in the cytosol bound to 14-3-3 and HSP90; consistent with Reactome events. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5672951 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-5672951 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: Reactome:R-HSA-5672951 S214 and S582 in ARAF |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5672960 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-5672960 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5672961 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-5672961 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5672966 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-5672966 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5672969 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-5672969 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5674140 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-5674140 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9653108 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-9653108 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9658445 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-9658445 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9660536 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-9660536 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9660538 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-9660538 (RAF activation/regulation pathway), in which ARAF participates in its cytosolic state. Reason: ARAF is cytosolic in its inactive, 14-3-3-bound state, which is the starting point of the Reactome RAF activation events; consistent with the IBA cytosol row. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md In the canonical model, inactive RAF is predominantly a cytosolic, 14-3-3-stabilized monomer. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: IDA plasma membrane from Human Protein Atlas immunofluorescence (GO_REF:0000052). Reason: Active ARAF is recruited by RAS-GTP to the inner plasma membrane where RAF dimers phosphorylate MEK; plasma membrane is the principal site of its MAP3K activity. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md RAS-GTP recruits ARAF through CR1 to the plasma membrane |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: IEA signal transduction from the RAS-binding domain signature (IPR003116). Reason: Correct but very general; ARAF is a RAS effector transducing mitogenic signals. The informative process is GO:0000165 MAPK cascade, accepted separately. Supporting Evidence: file:human/ARAF/ARAF-uniprot.txt Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. |
| GO:0032006 regulation of TOR signaling | IMP PMID:22609986 PRR5L degradation promotes mTORC2-mediated PKC-Ξ΄ phosphoryla... | KEEP AS NON CORE | Summary: IMP regulation of TOR signaling: ARAF knockdown blocked Galpha12-induced RFFL upregulation, PRR5L polyubiquitination and mTORC2-dependent PKCdelta hydrophobic-motif phosphorylation. Reason: Experimentally supported (and reflected in the UniProt FUNCTION line), but the effect is an indirect downstream output of ARAF MAP3K activity through MEK-ERK-driven RFFL expression rather than a direct action of ARAF on TOR signaling components. Supporting Evidence: PMID:22609986 LPA acts preferentially through GΞ±12 to regulate RFFL expression, PRR5L polyubiquitination, and PKCΞ΄ HM phosphorylation through an ARAF-MEK-ERK pathway. PMID:22609986 Knockdown of ARAF, but not BRAF or CRAF, by siRNAs inhibited GΞ±12QL-mediated upregulation of RFFL expression and polyubiquitination of PRR5L |
| GO:0032434 regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:22609986 PRR5L degradation promotes mTORC2-mediated PKC-Ξ΄ phosphoryla... | KEEP AS NON CORE | Summary: IMP regulation of proteasomal ubiquitin-dependent protein catabolic process, from the same Galpha12-ARAF-RFFL-PRR5L study. Reason: ARAF knockdown blocked RFFL induction and PRR5L polyubiquitination, so the annotation reflects real data, but ARAF acts several steps upstream (via MEK-ERK and RFFL expression). Retained as a non-core, indirect regulatory role. Supporting Evidence: PMID:22609986 As depicted in Figure 7C, LPA acts through GΞ±12 to specifically activate ARAF, which in turn upregulates RFFL, leading to the polyubiquitination and destabilization of PRR5L |
| GO:0033138 positive regulation of peptidyl-serine phosphorylation | IDA PMID:19667065 Identification of novel in vivo phosphorylation sites of the... | MODIFY | Summary: IDA positive regulation of peptidyl-serine phosphorylation, from the study showing that RAF kinases phosphorylate BAD serines in vivo. Reason: RAF kinases directly phosphorylate BAD serines (inhibited by the RAF inhibitor BAY 43-9006 but not by MEK inhibitors), so the kinase performs rather than regulates peptidyl-serine phosphorylation. MODIFY to GO:0018105 peptidyl-serine phosphorylation, consistent with the BRAF review of the same paper. Non-core. Proposed replacements: peptidyl-serine phosphorylation Supporting Evidence: PMID:19667065 RAF-induced phosphorylation of BAD was reduced to control levels using the RAF inhibitor BAY 43-9006. This phosphorylation was not prevented by MEK inhibitors. |
| GO:0036211 protein modification process | TAS PMID:3029685 The complete coding sequence of the human A-raf-1 oncogene a... | MODIFY | Summary: TAS protein modification process citing the A-raf-1 cloning paper. Reason: Very general. ARAF modifies proteins by phosphorylation; GO:0006468 protein phosphorylation is the appropriate process term for a protein kinase. Proposed replacements: protein phosphorylation Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md Wild-type ARAF immunoprecipitates generated phosphorylated MEK1 |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:19667065 Identification of novel in vivo phosphorylation sites of the... | KEEP AS NON CORE | Summary: IDA negative regulation of apoptotic process: constitutively active RAF suppressed BAD-induced apoptosis. Reason: Anti-apoptotic activity of RAF kinases (BAD phosphorylation; ARAF-specific kinase-independent MST2 sequestration) is supported but secondary to the MAP3K role. Supporting Evidence: PMID:19667065 Consistently, expression of constitutively active RAF suppressed apoptosis induced by BAD |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA negative regulation of apoptotic process from an ARBA machine-learning rule. Reason: Consistent with experimental data for ARAF (MST2 sequestration at mitochondria; BAD phosphorylation by RAF kinases); non-core. Supporting Evidence: file:human/ARAF/ARAF-deep-research-falcon.md ARAF also has important non-catalytic functions, particularly sequestration of the pro-apoptotic kinase MST2 at mitochondria. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA protein serine kinase activity from the Rhea mapping (RHEA:17989). Reason: ARAF phosphorylates serine residues (e.g. MEK1 S218/S222 activation loop); correct. Supporting Evidence: file:human/ARAF/ARAF-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP |
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Download this section (compressed HTML)Q: Should the kinase-independent, anti-apoptotic sequestration of MST2/STK3 at mitochondria be captured with a specific MF (e.g. a protein kinase inhibitor/sequestering activity) once ARAF-specific primary evidence is curated?
Q: Are BAD, PFKFB2 and SMAD2 physiologically relevant direct ARAF substrates in vivo, or are they in vitro or paralog-shared RAF activities that should remain non-core?
Q: How much of ARAF-dependent ERK signalling is catalytic (as MEK kinase) versus allosteric (as a dimer partner that transactivates BRAF/CRAF)?
Experiment: Compare purified full-length ARAF, BRAF and CRAF (as 14-3-3-bound dimers) in MEK1/MEK2 kinase assays, with kinase-dead and dimer-interface (R362H) ARAF mutants, to separate catalytic from allosteric contributions.
Experiment: Use ARAF-only (BRAF/CRAF-null) isogenic cells with kinase-dead or mitochondria-excluded ARAF to test which cellular phenotypes (ERK output, MST2-dependent apoptosis) depend on catalysis versus localization.
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