RAF1 (Raf-1 proto-oncogene, serine/threonine kinase)

Gene

• Entrez ID: 5894
• Gene name: Raf-1 proto-oncogene, serine/threonine kinase
• Gene symbol: RAF1
• Synonyms: CMD1NN, CRAF, NS5, Raf-1, c-Raf
• Chromosome: 3
• Chromosome location: 3p25.2
• Summary: This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs3730271	A>C,G,T	Pathogenic, likely-pathogenic, uncertain-significance	Non coding transcript variant, coding sequence variant, missense variant
rs11549992	G>A	Likely-benign, uncertain-significance, conflicting-interpretations-of-pathogenicity	Non coding transcript variant, 5 prime UTR variant, missense variant, coding sequence variant
rs80338796	G>A,C	Pathogenic, likely-pathogenic	Non coding transcript variant, missense variant, coding sequence variant
rs80338797	G>C,T	Pathogenic, likely-pathogenic	Non coding transcript variant, missense variant, coding sequence variant, genic downstream transcript variant
rs80338798	C>T	Pathogenic	Non coding transcript variant, missense variant, coding sequence variant, genic downstream transcript variant
rs80338799	G>A,C	Pathogenic, likely-pathogenic	Non coding transcript variant, missense variant, coding sequence variant, genic downstream transcript variant
rs121434594	G>A,C,T	Pathogenic, likely-pathogenic	Non coding transcript variant, missense variant, coding sequence variant
rs145611571	C>A,T	Uncertain-significance, likely-benign, conflicting-interpretations-of-pathogenicity	Missense variant, 5 prime UTR variant, coding sequence variant, non coding transcript variant
rs200856000	C>T	Conflicting-interpretations-of-pathogenicity, likely-benign	Coding sequence variant, non coding transcript variant, missense variant, 5 prime UTR variant
rs368796800	C>T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Coding sequence variant, non coding transcript variant, missense variant
rs370243307	A>G	Conflicting-interpretations-of-pathogenicity, likely-benign, uncertain-significance	Coding sequence variant, non coding transcript variant, missense variant
rs397516813	C>G	Likely-pathogenic, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516815	T>C	Likely-pathogenic, pathogenic	Genic downstream transcript variant, non coding transcript variant, coding sequence variant, missense variant
rs397516822	T>C	Pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516823	A>G	Conflicting-interpretations-of-pathogenicity, likely-benign, benign-likely-benign	Non coding transcript variant, coding sequence variant, intron variant, synonymous variant
rs397516825	T>C	Likely-pathogenic, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516826	C>A,G	Likely-pathogenic, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516827	G>A,C,T	Likely-pathogenic, uncertain-significance, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516828	G>A,C	Pathogenic-likely-pathogenic, not-provided, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516829	A>T	Pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs397516830	A>C,G,T	Likely-pathogenic, pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs587777586	A>G	Pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant, non coding transcript variant
rs587777587	G>A,C	Pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant, non coding transcript variant
rs587777588	C>T	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs587782971	A>G	Likely-pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs587782972	C>A	Likely-pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs727503384	G>C	Likely-pathogenic	Missense variant, intron variant, coding sequence variant, non coding transcript variant
rs727505017	A>G,T	Pathogenic, likely-pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs730881002	T>C,G	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant, downstream transcript variant, genic downstream transcript variant
rs730881003	A>G	Pathogenic, likely-pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant, non coding transcript variant
rs730881009	T>G	Likely-pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs730881010	T>A,C	Pathogenic-likely-pathogenic, likely-pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs771344560	T>C	Benign, conflicting-interpretations-of-pathogenicity	Genic downstream transcript variant, intron variant
rs869025501	G>A,T	Uncertain-significance, likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs876657965	GC>AT	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Missense variant, non coding transcript variant, coding sequence variant, 5 prime UTR variant
rs886039607	C>G	Pathogenic, likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs1057517813	A>C	Likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs1057518155	T>G	Likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs1057519815	C>G	Likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs1057524239	G>C	Conflicting-interpretations-of-pathogenicity	Genic downstream transcript variant, missense variant, non coding transcript variant, coding sequence variant
rs1085307553	T>C,G	Likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs1553609795	T>C	Uncertain-significance, pathogenic	Genic downstream transcript variant, non coding transcript variant, missense variant, coding sequence variant
rs1553609996	A>C,G	Uncertain-significance, likely-pathogenic	Genic downstream transcript variant, non coding transcript variant, missense variant, coding sequence variant
rs1553610155	C>A,G	Uncertain-significance, likely-pathogenic	Genic downstream transcript variant, non coding transcript variant, missense variant, coding sequence variant
rs1575573330	G>C	Likely-pathogenic	Non coding transcript variant, missense variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT004026	hsa-miR-7-5p	Luciferase reporter assay, Microarray, qRT-PCR, Western blot, Reporter assay;qRT-PCR;Microarray;Other	19073608
MIRT004026	hsa-miR-7-5p	PAR-CLIP	21572407
MIRT004026	hsa-miR-7-5p	Luciferase reporter assay, Western blot	24603851
MIRT004418	hsa-miR-125b-5p	Western blot, Western blot;Other	19825990
MIRT006077	hsa-miR-195-5p	Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	21350001
MIRT006077	hsa-miR-195-5p	Flow, Immunofluorescence, qRT-PCR, Western blot	23760062
MIRT006078	hsa-miR-497-5p	Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	21350001
MIRT044977	hsa-miR-186-5p	CLASH	23622248
MIRT046343	hsa-miR-23b-3p	CLASH	23622248
MIRT053089	hsa-miR-16-5p	Luciferase reporter assay, Western blot	23507142
MIRT532154	hsa-miR-4799-5p	PAR-CLIP	22012620
MIRT532155	hsa-miR-6881-3p	PAR-CLIP	22012620
MIRT532156	hsa-miR-6780a-3p	PAR-CLIP	22012620
MIRT532157	hsa-miR-6516-3p	PAR-CLIP	22012620
MIRT532158	hsa-miR-7111-3p	PAR-CLIP	22012620
MIRT532159	hsa-miR-3682-5p	PAR-CLIP	22012620
MIRT532160	hsa-miR-520f-5p	PAR-CLIP	22012620
MIRT541099	hsa-miR-4291	PAR-CLIP	21572407
MIRT541100	hsa-miR-6789-5p	PAR-CLIP	21572407
MIRT541101	hsa-miR-6077	PAR-CLIP	21572407
MIRT541102	hsa-miR-486-3p	PAR-CLIP	21572407
MIRT541103	hsa-miR-4254	PAR-CLIP	21572407
MIRT541104	hsa-miR-4660	PAR-CLIP	21572407
MIRT541105	hsa-miR-3690	PAR-CLIP	21572407
MIRT541106	hsa-miR-6736-3p	PAR-CLIP	21572407
MIRT541107	hsa-miR-7157-5p	PAR-CLIP	21572407
MIRT541108	hsa-miR-4310	PAR-CLIP	21572407
MIRT541109	hsa-miR-6813-5p	PAR-CLIP	21572407
MIRT541110	hsa-miR-6085	PAR-CLIP	21572407
MIRT541111	hsa-miR-6743-5p	PAR-CLIP	21572407
MIRT541112	hsa-miR-4688	PAR-CLIP	21572407
MIRT542736	hsa-miR-3134	PAR-CLIP	21572407
MIRT542737	hsa-miR-8082	PAR-CLIP	21572407
MIRT542738	hsa-miR-4534	PAR-CLIP	21572407
MIRT726794	hsa-miR-19b-3p	HITS-CLIP	22473208
MIRT726795	hsa-miR-19a-3p	HITS-CLIP	22473208
MIRT731714	hsa-miR-132-3p	Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	26452132
MIRT733010	hsa-miR-7-1-3p	Microarray, qRT-PCR, Western blot	27448964
MIRT734728	hsa-miR-125a-5p	Luciferase reporter assay, qRT-PCR, Western blot	27982429

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000165	Process	MAPK cascade	TAS
GO:0000186	Process	Activation of MAPKK activity	IDA	10644344
GO:0001666	Process	Response to hypoxia	IEA
GO:0002223	Process	Stimulatory C-type lectin receptor signaling pathway	TAS
GO:0004672	Function	Protein kinase activity	IBA	21873635
GO:0004674	Function	Protein serine/threonine kinase activity	IDA	19667065
GO:0004709	Function	MAP kinase kinase kinase activity	IEA
GO:0005515	Function	Protein binding	IPI	7644510, 7760835, 7791872, 7882972, 7935795, 7939632, 8085158, 8332187, 8601312, 8670882, 8756332, 9144171, 9624170, 10433554, 10523642, 11697890, 11909642, 12620389, 14688280, 15778465, 15935327, 16239230, 16306228, 16330544, 16405965, 16837009, 17097642, 17229891, 17724343, 1797917
GO:0005524	Function	ATP binding	IEA
GO:0005737	Component	Cytoplasm	IDA	17724343
GO:0005737	Component	Cytoplasm	ISS
GO:0005739	Component	Mitochondrion	IBA	21873635
GO:0005741	Component	Mitochondrial outer membrane	TAS	8929532
GO:0005794	Component	Golgi apparatus	IPI	17724343
GO:0005829	Component	Cytosol	IBA	21873635
GO:0005829	Component	Cytosol	IDA	16009725
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	IBA	21873635
GO:0005886	Component	Plasma membrane	IDA	17724343
GO:0005886	Component	Plasma membrane	IDA	16009725
GO:0005886	Component	Plasma membrane	TAS
GO:0006468	Process	Protein phosphorylation	IEA
GO:0006915	Process	Apoptotic process	TAS	8929532
GO:0007165	Process	Signal transduction	TAS	8063729
GO:0007190	Process	Activation of adenylate cyclase activity	IDA	15385642
GO:0007507	Process	Heart development	IEA
GO:0008179	Function	Adenylate cyclase binding	IEA
GO:0008285	Process	Negative regulation of cell population proliferation	IDA	9765203
GO:0010856	Function	Adenylate cyclase activator activity	IEA
GO:0016607	Component	Nuclear speck	IDA
GO:0019899	Function	Enzyme binding	IPI	23509299
GO:0030154	Process	Cell differentiation	IEA
GO:0030168	Process	Platelet activation	TAS
GO:0030878	Process	Thyroid gland development	IEA
GO:0031143	Component	Pseudopodium	IEA
GO:0031267	Function	Small GTPase binding	IPI	12194967
GO:0031333	Process	Negative regulation of protein-containing complex assembly	IDA	19667065
GO:0031434	Function	Mitogen-activated protein kinase kinase binding	IEA
GO:0033138	Process	Positive regulation of peptidyl-serine phosphorylation	IDA	19667065
GO:0034220	Process	Ion transmembrane transport	TAS
GO:0035019	Process	Somatic stem cell population maintenance	IEA
GO:0035023	Process	Regulation of Rho protein signal transduction	TAS	16649144
GO:0035773	Process	Insulin secretion involved in cellular response to glucose stimulus	IEA
GO:0035994	Process	Response to muscle stretch	IEA
GO:0042060	Process	Wound healing	TAS	15943972
GO:0042802	Function	Identical protein binding	IPI	17979178, 20130576, 22169110, 22510884
GO:0042981	Process	Regulation of apoptotic process	TAS	21779496
GO:0043066	Process	Negative regulation of apoptotic process	IDA	19667065
GO:0043154	Process	Negative regulation of cysteine-type endopeptidase activity involved in apoptotic process	TAS	21779496
GO:0044877	Function	Protein-containing complex binding	IEA
GO:0045104	Process	Intermediate filament cytoskeleton organization	IEA
GO:0045595	Process	Regulation of cell differentiation	TAS	21779496
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IEA
GO:0046872	Function	Metal ion binding	IEA
GO:0048011	Process	Neurotrophin TRK receptor signaling pathway	IEA
GO:0048538	Process	Thymus development	IEA
GO:0060324	Process	Face development	IEA
GO:0071550	Process	Death-inducing signaling complex assembly	IEA
GO:0106310	Function	Protein serine kinase activity	IEA
GO:0106311	Function	Protein threonine kinase activity	IEA
GO:1902042	Process	Negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	IEA
GO:2000145	Process	Regulation of cell motility	TAS	21779496

Other IDs

• MIM: 164760
• HGNC: 9829
• e!Ensembl: ENSG00000132155

Protein

• UniProt ID: P04049
• Protein name: RAF proto-oncogene serine/threonine-protein kinase (EC 2.7.11.1) (Proto-oncogene c-RAF) (cRaf) (Raf-1)
• Protein function: Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.
• PDB: 1C1Y, 1FAQ, 1FAR, 1GUA, 1RFA, 3CU8, 3IQJ, 3IQU, 3IQV, 3KUC, 3KUD, 3NKX, 3O8I, 3OMV, 4FJ3, 4G0N, 4G3X, 4IEA, 4IHL, 6NTC, 6NTD, 6PTS, 6PTW, 6VJJ, 6XGU, 6XGV, 6XHA, 6XHB, 6XI7, 7JHP
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF02196	RBD	57 → 129	Raf-like Ras-binding domain	Domain
  PF00130	C1_1	139 → 187	Phorbol esters/diacylglycerol binding domain (C1 domain)	Domain
  PF07714	PK_Tyr_Ser-Thr	349 → 606	Protein tyrosine and serine/threonine kinase	Domain

• Sequence:

  MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRV
  FLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAAS
  LIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKV
  PTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF
  NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNL
  SPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSF
  GTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIV
  TQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL
  TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYE
  LMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFP
  QILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF

• Sequence length: 648