Reviewed, UniProtKB/Swiss-Prot P04049 (RAF1_HUMAN)

Names and origin

Protein names

Recommended name:
    RAF proto-oncogene serine/threonine-protein kinase
    EC=2.7.11.1
Alternative name(s):
    C-RAF
      Short name=cRaf
    Raf-1

Gene names

Name:	RAF1
Synonyms:	RAF

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	648 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Part of the Ras-dependent signaling pathway from receptors to the nucleus. Protects cells from apoptosis mediated by STK3. Ref.10 Ref.16
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Binds 2 zinc ions per subunit.
Subunit structure	Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC). Interacts with Ras proteins; the interaction is antagonized by RIN1. Weakly interacts with RIT1 By similarity. Interacts with STK3; the interaction inhibits its pro-apoptotic activity. Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232').
Tissue specificity	In skeletal muscle, isoform 1 is more abundant than isoform 2. Ref.8
Post-translational modification	Phosphorylated upon DNA damage, probably by ATM or ATR. Phosphorylation at Thr-269 increases its kinase activity. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Ref.7 Ref.9 Ref.11 Ref.14 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23
Involvement in disease	Defects in RAF1 are the cause of Noonan syndrome type 5 (NS5) [MIM:611553]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Ref.29 Ref.30 Defects in RAF1 are the cause of LEOPARD syndrome type 2 (LEOPARD syndrome-2) [MIM:611554]. LEOPARD syndrome is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness.
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily. Contains 1 phorbol-ester/DAG-type zinc finger. Contains 1 protein kinase domain. Contains 1 RBD (Ras-binding) domain.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Phorbol-ester binding Zinc-finger
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	Ras protein signal transduction Inferred from Experiment. Source: Reactome apoptosis Traceable author statement. Source: ProtInc cell proliferation Traceable author statement. Source: ProtInc protein amino acid phosphorylation Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome mitochondrial outer membrane Traceable author statement. Source: ProtInc plasma membrane Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW diacylglycerol binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.26 Inferred from physical interaction. Source: UniProtKB protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW receptor signaling protein activity Inferred from electronic annotation. Source: InterPro zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCT3	P49368	3	EBI-365996,EBI-356673
COPS3	Q9UNS2	2	EBI-365996,EBI-350590
CPS1	P31327	2	EBI-365996,EBI-536811
HRAS	P01112	5	EBI-365996,EBI-350145
HSP90AB1	P08238	1	EBI-365996,EBI-352572
HSPA5	P11021	3	EBI-365996,EBI-354921
INTS10	Q9NVR2	2	EBI-365996,EBI-536703
MAP2K1	Q02750	1	EBI-365996,EBI-492564
OIP5	O43482	3	EBI-365996,EBI-536879
PAK2	Q13177	2	EBI-365996,EBI-1045887
PKM2	P14618	3	EBI-365996,EBI-353408
RAP1A	P62834	2	EBI-365996,EBI-491414
RCAN1	P53805-2	3	EBI-365996,EBI-1541912
TIMM50	Q3ZCQ8	3	EBI-365996,EBI-355175
YWHAB	P31946	4	EBI-365996,EBI-359815
YWHAG	P61981	1	EBI-365996,EBI-359832
YWHAH	Q04917	1	EBI-365996,EBI-306940
YWHAQ	P27348	1	EBI-365996,EBI-359854
YWHAZ	P63104	2	EBI-365996,EBI-347088

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P04049-1)

Also known as: 6C;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P04049-2)

Also known as: 1A;

The sequence of this isoform differs from the canonical sequence as follows:
     278-278: E → ENNNLSASPRAWSRRFCLRGR

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 648

648

RAF proto-oncogene serine/threonine-protein kinase

PRO_0000086596

Regions

Domain

56 – 131

76

RBD

Domain

349 – 609

261

Protein kinase

Zinc finger

138 – 184

47

Phorbol-ester/DAG-type

Nucleotide binding

355 – 363

9

ATP By similarity

Sites

Active site

468

1

Proton acceptor

Metal binding

139

1

Zinc 1

Metal binding

152

1

Zinc 2

Metal binding

155

1

Zinc 2

Metal binding

165

1

Zinc 1

Metal binding

168

1

Zinc 1

Metal binding

173

1

Zinc 2

Metal binding

176

1

Zinc 2

Metal binding

184

1

Zinc 1

Binding site

375

1

ATP By similarity

Amino acid modifications

Modified residue

43

1

Phosphoserine Ref.9 Ref.22

Modified residue

244

1

Phosphoserine Ref.22

Modified residue

252

1

Phosphoserine Ref.19

Modified residue

257

1

Phosphoserine Ref.21

Modified residue

258

1

Phosphothreonine Ref.21

Modified residue

259

1

Phosphoserine; by PKC Ref.9 Ref.14 Ref.18 Ref.22

Modified residue

268

1

Phosphothreonine; by autocatalysis Ref.9

Modified residue

269

1

Phosphothreonine; by PKA Ref.7

Modified residue

294

1

Phosphoserine Ref.17

Modified residue

301

1

Phosphoserine Ref.17

Modified residue

338

1

Phosphoserine; by PAK2 and PAK3

Modified residue

499

1

Phosphoserine; by PKC Ref.9

Modified residue

621

1

Phosphoserine Ref.9 Ref.20

Modified residue

642

1

Phosphoserine Ref.23

Natural variations

Alternative sequence

278

1

E → ENNNLSASPRAWSRRFCLRG R in isoform 2.

VSP_034649

Natural variant

256

1

R → S in NS5. Ref.29

VAR_037807

Natural variant

257

1

S → L in NS5 and LEOPARD sndrome-2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. Ref.29 Ref.30

VAR_037808

Natural variant

259

1

S → A in an ovarian serous carcinoma sample; somatic mutation. Ref.31

VAR_041037

Natural variant

259

1

S → F in NS5. Ref.29

VAR_037809

Natural variant

260

1

T → I in hypertrophic cardiomyopathy. Ref.29

VAR_037810

Natural variant

260

1

T → R in NS5. Ref.29

VAR_037811

Natural variant

261

1

P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. Ref.30

VAR_037812

Natural variant

261

1

P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. Ref.29

VAR_037813

Natural variant

261

1

P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. Ref.29 Ref.30

VAR_037814

Natural variant

263

1

V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. Ref.30

VAR_037815

Natural variant

308

1

P → L: dbSNP rs5746220. Ref.2 Ref.3

VAR_018840

Natural variant

335

1

Q → H in a lung adenocarcinoma sample; somatic mutation. Ref.31

VAR_041038

Natural variant

486

1

D → G in NS5. Ref.29

VAR_037816

Natural variant

486

1

D → N in NS5; has reduced or absent kinase activity. Ref.29

VAR_037817

Natural variant

491

1

T → I in NS5; has reduced or absent kinase activity. Ref.29

VAR_037818

Natural variant

491

1

T → R in NS5. Ref.29

VAR_037819

Natural variant

612

1

S → T in NS5. Ref.29

VAR_037820

Natural variant

613

1

L → V in NS5 and LEOPARD syndrome-2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. Ref.29 Ref.30

VAR_037821

Experimental info

Mutagenesis

259

1

S → A: Increased ERK activation. Ref.18

Sequence conflict

240

1

F → L in AAA60247. Ref.6

Sequence conflict

542

1

M → I in AAA60247. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

648

Helix Strand Turn

Details...

Beta strand

57 – 62

6

Turn

63 – 65

3

Beta strand

66 – 71

6

Helix

78 – 87

10

Turn

88 – 90

3

Helix

93 – 95

3

Beta strand

96 – 102

7

Helix

103 – 105

3

Beta strand

106 – 112

7

Helix

118 – 121

4

Beta strand

125 – 130

6

Beta strand

142 – 144

3

Beta strand

155 – 159

5

Beta strand

161 – 164

4

Turn

166 – 169

4

Beta strand

177 – 182

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (6C) [UniParc]. Last modified November 1, 1986. Version 1. Checksum: EF821B5349711BC3	FASTA	648	73,052
	10 20 30 40 50 60 MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD PSKTSNTIRV 70 80 90 100 110 120 FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR LLHEHKGKKA RLDWNTDAAS 130 140 150 160 170 180 LIGEELQVDF LDHVPLTTHN FARKTFLKLA FCDICQKFLL NGFRCQTCGY KFHEHCSTKV 190 200 210 220 230 240 PTMCVDWSNI RQLLLFPNST IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF 250 260 270 280 290 300 NTSSPSSEGS LSQRQRSTST PNVHMVSTTL PVDSRMIEDA IRSHSESASP SALSSSPNNL 310 320 330 340 350 360 SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY YWEIEASEVM LSTRIGSGSF 370 380 390 400 410 420 GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT RHVNILLFMG YMTKDNLAIV 430 440 450 460 470 480 TQWCEGSSLY KHLHVQETKF QMFQLIDIAR QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL 490 500 510 520 530 540 TVKIGDFGLA TVKSRWSGSQ QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE 550 560 570 580 590 600 LMTGELPYSH INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP 610 620 630 640 QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF
	Isoform 2 (1A). Checksum: BD64D7A649342F5D	FASTA	668	75,395
	10 20 30 40 50 60 MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD PSKTSNTIRV 70 80 90 100 110 120 FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR LLHEHKGKKA RLDWNTDAAS 130 140 150 160 170 180 LIGEELQVDF LDHVPLTTHN FARKTFLKLA FCDICQKFLL NGFRCQTCGY KFHEHCSTKV 190 200 210 220 230 240 PTMCVDWSNI RQLLLFPNST IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF 250 260 270 280 290 300 NTSSPSSEGS LSQRQRSTST PNVHMVSTTL PVDSRMIENN NLSASPRAWS RRFCLRGRDA 310 320 330 340 350 360 IRSHSESASP SALSSSPNNL SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY 370 380 390 400 410 420 YWEIEASEVM LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT 430 440 450 460 470 480 RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR QTAQGMDYLH 490 500 510 520 530 540 AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ QVEQPTGSVL WMAPEVIRMQ 550 560 570 580 590 600 DNNPFSFQSD VYSYGIVLYE LMTGELPYSH INNRDQIIFM VGRGYASPDL SKLYKNCPKA 610 620 630 640 650 660 MKRLVADCVK KVKEERPLFP QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The complete coding sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene." Bonner T.I., Oppermann H., Seeburg P., Kerby S.B., Gunnell M.A., Young A.C., Rapp U.R. Nucleic Acids Res. 14:1009-1015(1986) [PubMed: 3003687] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT LEU-308.
[3]	NIEHS SNPs program Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LEU-308.
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Pancreas.
[6]	"Structure and biological activity of human homologs of the raf/mil oncogene." Bonner T.I., Kerby S.B., Sutrave P., Gunnell M.A., Mark G., Rapp U.R. Mol. Cell. Biol. 5:1400-1407(1985) [PubMed: 2993863] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 228-648.
[7]	"Phosphorylation of Raf by ceramide-activated protein kinase." Yao B., Zhang Y., Delikat S., Mathias S., Basu S., Kolesnick R. Nature 378:307-310(1995) [PubMed: 7477354] [Abstract] Cited for: PROTEIN SEQUENCE OF 254-278, PHOSPHORYLATION AT THR-269.
[8]	"An alternatively spliced c-mil/raf mRNA is predominantly expressed in chicken muscular tissues and conserved among vertebrate species." Dozier C., Ansieau S., Ferreira E., Coll J., Stehelin D. Oncogene 6:1307-1311(1991) [PubMed: 1886707] [Abstract] Cited for: PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, TISSUE SPECIFICITY. Tissue: Placenta.
[9]	"Identification of the major phosphorylation sites of the Raf-1 kinase." Morrison D.K., Heidecker G., Rapp U.R., Copeland T.D. J. Biol. Chem. 268:17309-17316(1993) [PubMed: 8349614] [Abstract] Cited for: PHOSPHORYLATION AT SER-43; SER-259; THR-268; SER-499 AND SER-621.
[10]	"14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction." Dubois T., Rommel C., Howell S., Steinhussen U., Soneji Y., Morrice N., Moelling K., Aitken A. J. Biol. Chem. 272:28882-28888(1997) [PubMed: 9360956] [Abstract] Cited for: INTERACTION WITH YWHAZ, FUNCTION.
[11]	"The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338." King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., Marshall M.S. Nature 396:180-183(1998) [PubMed: 9823899] [Abstract] Cited for: PHOSPHORYLATION.
[12]	Erratum King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., Marshall M.S. Nature 406:439-439(2000)
[13]	"The RAS effector RIN1 directly competes with RAF and is regulated by 14-3-3 proteins." Wang Y., Waldron R.T., Dhaka A., Patel A., Riley M.M., Rozengurt E., Colicelli J. Mol. Cell. Biol. 22:916-926(2002) [PubMed: 11784866] [Abstract] Cited for: COMPETITION WITH RIN1.
[14]	"LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway." Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K. J. Biol. Chem. 279:23151-23157(2004) [PubMed: 15047712] [Abstract] Cited for: PHOSPHORYLATION AT SER-259.
[15]	Erratum Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K. J. Biol. Chem. 282:2752-2752(2007)
[16]	"Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1." O'Neill E., Rushworth L., Baccarini M., Kolch W. Science 306:2267-2270(2004) [PubMed: 15618521] [Abstract] Cited for: INTERACTION WITH STK3, FUNCTION.
[17]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-294 AND SER-301, MASS SPECTROMETRY. Tissue: Epithelium.
[18]	"A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity." Rodriguez-Viciana P., Oses-Prieto J., Burlingame A., Fried M., McCormick F. Mol. Cell 22:217-230(2006) [PubMed: 16630891] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH PP1CA; PPP1CB; PPP1CC; SHOC2 AND MRAS, PHOSPHORYLATION AT SER-259, MUTAGENESIS OF SER-259.
[19]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-252, MASS SPECTROMETRY.
[20]	"Evaluation of the low-specificity protease elastase for large-scale phosphoproteome analysis." Wang B., Malik R., Nigg E.A., Korner R. Anal. Chem. 80:9526-9533(2008) [PubMed: 19007248] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-621, MASS SPECTROMETRY.
[21]	"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis." Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257 AND THR-258, MASS SPECTROMETRY.
[22]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-244 AND SER-259, MASS SPECTROMETRY.
[23]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-642, MASS SPECTROMETRY.
[24]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[25]	"The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue." Nassar N., Horn G., Herrmann C., Scherer A., McCormick F., Wittinghofer A. Nature 375:554-560(1995) [PubMed: 7791872] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 51-131.
[26]	"Ras/Rap effector specificity determined by charge reversal." Nassar N., Horn G., Herrmann C., Block C., Janknecht R., Wittinghofer A. Nat. Struct. Biol. 3:723-729(1996) [PubMed: 8756332] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 56-131.
[27]	"Solution structure of the Ras-binding domain of c-Raf-1 and identification of its Ras interaction surface." Emerson S.D., Madison V.S., Palermo R.E., Waugh D.S., Scheffler J.E., Tsao K.L., Kiefer S.E., Liu S.P., Fry D.C. Biochemistry 34:6911-6918(1995) [PubMed: 7766599] [Abstract] Cited for: STRUCTURE BY NMR OF 55-132.
[28]	"The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site." Mott H.R., Carpenter J.W., Zhong S., Ghosh S., Bell R.M., Campbell S.L. Proc. Natl. Acad. Sci. U.S.A. 93:8312-8317(1996) [PubMed: 8710867] [Abstract] Cited for: STRUCTURE BY NMR OF 136-187.
[29]	"Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy." Pandit B., Sarkozy A., Pennacchio L.A., Carta C., Oishi K., Martinelli S., Pogna E.A., Schackwitz W., Ustaszewska A., Landstrom A., Bos J.M., Ommen S.R., Esposito G., Lepri F., Faul C., Mundel P., Lopez Siguero J.P., Tenconi R. , Selicorni A., Rossi C., Mazzanti L., Torrente I., Marino B., Digilio M.C., Zampino G., Ackerman M.J., Dallapiccola B., Tartaglia M., Gelb B.D. Nat. Genet. 39:1007-1012(2007) [PubMed: 17603483] [Abstract] Cited for: VARIANTS NS5 SER-256; PHE-259; ARG-260; LEU-261; SER-261; ASN-486; GLY-486; ILE-491; ARG-491 AND THR-612, VARIANT HYPERTROPHIC CARDIOMYOPATHY ILE-260, VARIANT LEOPARD SYNDROME-2 VAL-613, VARIANT NS5/LEOPARD SYNDROME-2 LEU-257, CHARACTERIZATION OF VARIANTS NS5 SER-261; ASN-486 AND ILE-491, CHARACTERIZATION OF VARIANT LEOPARD SYNDROME-2 VAL-613.
[30]	"Germline gain-of-function mutations in RAF1 cause Noonan syndrome." Razzaque M.A., Nishizawa T., Komoike Y., Yagi H., Furutani M., Amo R., Kamisago M., Momma K., Katayama H., Nakagawa M., Fujiwara Y., Matsushima M., Mizuno K., Tokuyama M., Hirota H., Muneuchi J., Higashinakagawa T., Matsuoka R. Nat. Genet. 39:1013-1017(2007) [PubMed: 17603482] [Abstract] Cited for: VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613, CHARACTERIZATION OF VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613.
[31]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ALA-259 AND HIS-335.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

X03484 mRNA. Translation: CAA27204.1.
AY271661 Genomic DNA. Translation: AAP03432.1.
AK312248 mRNA. Translation: BAG35180.1.
EU332868 Genomic DNA. Translation: ABY87557.1.
CH471055 Genomic DNA. Translation: EAW64134.1.
BC018119 mRNA. Translation: AAH18119.1.
L00212 , L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA. Translation: AAA60247.1.
X54851 Genomic DNA. No translation available.

IPI

IPI00021786.
IPI00900312.

PIR

TVHUF6. A00637.
S60341.

RefSeq

NP_002871.1.

UniGene

Hs.159130

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1C1Y	X-ray	1.90	B	55-131	[»]
1FAQ	NMR	-	A	136-187	[»]
1FAR	NMR	-	A	136-187	[»]
1GUA	X-ray	2.00	B	51-131	[»]
1RFA	NMR	-	A	55-132	[»]
3CU8	X-ray	2.40	P/Q	256-264	[»]

DisProt

DP00171.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:1048N.

IntAct

P04049. 30 interactions.

STRING

P04049.

PTM databases

PhosphoSite

P04049.

Proteomic databases

PRIDE

P04049.

Genome annotation databases

Ensembl

ENST00000251849; ENSP00000251849; ENSG00000132155; Homo sapiens. [Genome view]
ENST00000415519; ENSP00000401697; ENSG00000132155; Homo sapiens. [Genome view]
ENST00000416093; ENSP00000391265; ENSG00000132155; Homo sapiens. [Genome view]
ENST00000423275; ENSP00000401088; ENSG00000132155; Homo sapiens. [Genome view]
ENST00000432427; ENSP00000398591; ENSG00000132155; Homo sapiens. [Genome view]
ENST00000442415; ENSP00000401888; ENSG00000132155; Homo sapiens. [Genome view]

GeneID

5894.

KEGG

hsa:5894.

UCSC

uc003bxf.2. human.

Organism-specific databases

CTD

5894.

GeneCards

GC03M012600.

H-InvDB

HIX0003068.

HGNC

HGNC:9829. RAF1.

HPA

CAB019291.
HPA002640.

MIM

164760. gene.
611553. phenotype.
611554. phenotype.

Orphanet

500. LEOPARD syndrome.
648. Noonan syndrome.

PharmGKB

PA142671136.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P04049.

HOVERGEN

P04049.

OMA

DGPSCIS.

Enzyme and pathway databases

BRENDA

2.7.10.2. 247.
2.7.11.1. 247.

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
ceramidepathway. Ceramide signaling pathway.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
endothelinpathway. Endothelins.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
igf1_pathway. IGF1 pathway.
il2_1pathway. IL2-mediated signaling events.
p38_mk2pathway. p38 signaling mediated by MAPKAP kinases.
tcrraspathway. Ras signaling in the CD4+ TCR pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_11061. Signalling by NGF.
REACT_16888. Signaling by PDGF.
REACT_18266. Axon guidance.
REACT_498. Signaling by Insulin receptor.
REACT_9417. Signaling by EGFR.

Gene expression databases

ArrayExpress

P04049.

Bgee

P04049.

CleanEx

HS_RAF1.

Genevestigator

P04049.

GermOnline

ENSG00000132155. Homo sapiens.

Family and domain databases

InterPro

IPR020454. DAG/PE_bd.
IPR002219. Prot_Kinase_C-like_PE/DAG_bd.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR003116. Raf-like_ras_bd.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
[Graphical view]

Pfam

PF00130. C1_1. 1 hit.
PF00069. Pkinase. 1 hit.
PF02196. RBD. 1 hit.
[Graphical view]

PRINTS

PR00008. DAGPEDOMAIN.

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00109. C1. 1 hit.
SM00455. RBD. 1 hit.
[Graphical view]

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50898. RBD. 1 hit.
PS00479. ZF_DAG_PE_1. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

BindingDB

P04049.

DrugBank

DB00398. Sorafenib.

NextBio

22930.

PMAP-CutDB

P04049.

SOURCE

Search...

Entry information

Entry name

RAF1_HUMAN

Accession

Primary (citable) accession number: P04049
Secondary accession number(s): B0LPH8 , B2R5N3, Q15278, Q9UC20

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1986
Last sequence update:	November 1, 1986
Last modified:	November 3, 2009
This is version 131 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.