GENTAUR Molecular Products.

 RAF1_BOVIN              Reviewed;         648 AA.
 A7E3S4; A7YY51;
 02-SEP-2008, integrated into UniProtKB/Swiss-Prot.
 11-SEP-2007, sequence version 1.
 12-SEP-2018, entry version 87.
 RecName: Full=RAF proto-oncogene serine/threonine-protein kinase;
          EC=2.7.11.1;
 AltName: Full=Proto-oncogene c-RAF;
          Short=cRaf;
 AltName: Full=Raf-1;
 Name=RAF1 {ECO:0000312|EMBL:ABS45011.1};
 Bos taurus (Bovine).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
 Mammalia; Eutheria; Laurasiatheria; Cetartiodactyla; Ruminantia;
 Pecora; Bovidae; Bovinae; Bos.
 NCBI_TaxID=9913;
 [1] {ECO:0000305, ECO:0000312|EMBL:ABS45011.1}
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
 PubMed=16305752; DOI=10.1186/1471-2164-6-166;
 Harhay G.P., Sonstegard T.S., Keele J.W., Heaton M.P., Clawson M.L.,
 Snelling W.M., Wiedmann R.T., Van Tassell C.P., Smith T.P.L.;
 "Characterization of 954 bovine full-CDS cDNA sequences.";
 BMC Genomics 6:166-166(2005).
 [2] {ECO:0000305, ECO:0000312|EMBL:AAI51320.1}
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
 STRAIN=Hereford {ECO:0000312|EMBL:AAI51320.1};
 TISSUE=Heart ventricle {ECO:0000312|EMBL:AAI51320.1};
 NIH - Mammalian Gene Collection (MGC) project;
 Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases.
 -!- 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 (By similarity). {ECO:0000250}.
 -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
     {ECO:0000250|UniProtKB:P04049}.
 -!- COFACTOR:
     Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
       Evidence={ECO:0000250|UniProtKB:P04049};
     Note=Binds 2 Zn(2+) ions per subunit.
     {ECO:0000250|UniProtKB:P04049};
 -!- ACTIVITY REGULATION: Regulation is a highly complex process
     involving membrane recruitment, protein-protein interactions,
     dimerization, and phosphorylation/dephosphorylation events. Ras-
     GTP recruits RAF1 to the membrane, thereby promoting its
     activation. The inactive conformation of RAF1 is maintained by
     autoinhibitory interactions occurring between the N-terminal
     regulatory and the C-terminal catalytic domains and by the binding
     of a 14-3-3 protein that contacts two phosphorylation sites, Ser-
     259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A
     cooperate to release autoinhibition and the subsequent
     phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491,
     and Ser-494, yields a fully active kinase. Through a negative
     feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on
     Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by
     MAPK1/ERK2, which yields an inactive, desensitized kinase. The
     signaling-competent conformation of RAF1 is finally re-established
     by the coordinated action of PIN1, a prolyl isomerase that
     converts pSer and pThr residues from the cis to the trans
     conformation, which is preferentially recognized and
     dephosphorylated by PPP2R1A. Activated by homodimerization and
     heterodimerization (with BRAF). Also regulated through association
     with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP,
     PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1
     from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin
     facilitates the displacement of 14-3-3 from RAF1 by activated Ras,
     thereby promoting cell membrane localization and phosphorylation
     of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent,
     but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates
     Src-mediated RAF1 activation (By similarity). {ECO:0000250}.
 -!- SUBUNIT: Monomer. Homodimer. Heterodimerizes with BRAF and this
     heterodimer possesses a highly increased kinase activity compared
     to the respective homodimers or monomers. Heterodimerization is
     mitogen-regulated and enhanced by 14-3-3 proteins. MAPK1/ERK2
     activation can induce a negative feedback that promotes the
     dissociation of the heterodimer. 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. Interacts (via N-
     terminus) with RGS14 (via RBD domains); the interaction mediates
     the formation of a ternary complex with BRAF, a ternary complex
     inhibited by GNAI1. Probably forms a complex composed of
     chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and
     client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does
     not contain co-chaperones STIP1/HOP and PTGES3/p23. Interacts with
     STK3/MST2; the interaction inhibits its pro-apoptotic activity.
     Interacts (when phosphorylated at Ser-259) with YWHAZ
     (unphosphorylated at 'Thr-232'). Interacts with MAP2K1/MEK1 and
     MAP2K2/MEK2. Interacts with MAP3K5/ASF1 (via N-terminus) and this
     interaction inhibits the proapoptotic function of MAP3K5/ASK1.
     Interacts with PAK1 (via kinase domain). The phosphorylated form
     interacts with PIN1. The Ser-338 and Ser-339 phosphorylated form
     (by PAK1) interacts with BCL2. Interacts with PEBP1/RKIP and this
     interaction is enhanced if RAF1 is phosphorylated on residues Ser-
     338, Ser-339, Tyr-340 and Tyr-341. Interacts with ADCY2, ADCY5,
     ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B,
     SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin. Interacts with
     ROCK2. In its active form, interacts with PRMT5. Interacts with
     FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1.
     Interacts with PDE8A; the interaction promotes RAF1 activity.
     Interacts with MFHAS1. {ECO:0000250|UniProtKB:P04049,
     ECO:0000250|UniProtKB:P11345, ECO:0000250|UniProtKB:Q99N57}.
 -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane
     {ECO:0000250}. Mitochondrion {ECO:0000250}. Nucleus {ECO:0000250}.
     Note=Colocalizes with RGS14 and BRAF in both the cytoplasm and
     membranes. Phosphorylation at Ser-259 impairs its membrane
     accumulation. Recruited to the cell membrane by the active Ras
     protein. Phosphorylation at Ser-338 and Ser-339 by PAK1 is
     required for its mitochondrial localization. Retinoic acid-induced
     Ser-621 phosphorylated form of RAF1 is predominantly localized at
     the nucleus (By similarity). {ECO:0000250}.
 -!- ALTERNATIVE PRODUCTS:
     Event=Alternative splicing; Named isoforms=2;
     Name=1 {ECO:0000269|PubMed:16305752};
       IsoId=A7E3S4-1; Sequence=Displayed;
     Name=2;
       IsoId=A7E3S4-2; Sequence=VSP_052844;
 -!- PTM: Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and
     Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-
     43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in
     its inactivation. 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. Phosphorylation at Ser-338 by PAK1 and
     PAK5 and Ser-339 by PAK1 is required for its mitochondrial
     localization (By similarity). Phosphorylation at Ser-621 in
     response to growth factor treatment stabilizes the protein,
     possibly by preventing proteasomal degradation. Phosphorylation at
     Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked
     to the methylation potential of cells. Treatment of cells with HGF
     in the presence of the methylation inhibitor 5'-
     methylthioadenosine (MTA) results in increased phosphorylation at
     Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-
     301 and Ser-338. Dephosphorylation at SER-338 by PPP5C results in
     a decreased of activity (By similarity). {ECO:0000250}.
 -!- PTM: Methylated at Arg-563 in response to EGF treatment. This
     modification leads to destabilization of the protein, possibly
     through proteasomal degradation. {ECO:0000250}.
 -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
     protein kinase family. RAF subfamily. {ECO:0000255}.
 -----------------------------------------------------------------------
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 EMBL; BT030695; ABS45011.1; -; mRNA.
 EMBL; BC151319; AAI51320.1; -; mRNA.
 RefSeq; NP_001095975.1; NM_001102505.1. [A7E3S4-2]
 RefSeq; XP_005223216.2; XM_005223159.2. [A7E3S4-1]
 RefSeq; XP_015324294.1; XM_015468808.1. [A7E3S4-1]
 UniGene; Bt.4968; -.
 ProteinModelPortal; A7E3S4; -.
 SMR; A7E3S4; -.
 IntAct; A7E3S4; 1.
 STRING; 9913.ENSBTAP00000005930; -.
 iPTMnet; A7E3S4; -.
 PaxDb; A7E3S4; -.
 GeneID; 521196; -.
 KEGG; bta:107131151; -.
 KEGG; bta:521196; -.
 CTD; 5894; -.
 HOGENOM; HOG000252972; -.
 HOVERGEN; HBG001886; -.
 InParanoid; A7E3S4; -.
 KO; K04366; -.
 ChiTaRS; RAF1; cattle.
 Proteomes; UP000009136; Unplaced.
 GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
 GO; GO:0005829; C:cytosol; IBA:GO_Central.
 GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
 GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
 GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO; GO:0004709; F:MAP kinase kinase kinase activity; IBA:GO_Central.
 GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; IBA:GO_Central.
 GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
 GO; GO:0007275; P:multicellular organism development; IBA:GO_Central.
 GO; GO:0043066; P:negative regulation of apoptotic process; IBA:GO_Central.
 GO; GO:0009968; P:negative regulation of signal transduction; IBA:GO_Central.
 GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IBA:GO_Central.
 CDD; cd00029; C1; 1.
 InterPro; IPR020454; DAG/PE-bd.
 InterPro; IPR011009; Kinase-like_dom_sf.
 InterPro; IPR002219; PE/DAG-bd.
 InterPro; IPR000719; Prot_kinase_dom.
 InterPro; IPR017441; Protein_kinase_ATP_BS.
 InterPro; IPR003116; RBD_dom.
 InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 InterPro; IPR008271; Ser/Thr_kinase_AS.
 InterPro; IPR029071; Ubiquitin-like_domsf.
 Pfam; PF00130; C1_1; 1.
 Pfam; PF07714; Pkinase_Tyr; 1.
 Pfam; PF02196; RBD; 1.
 PRINTS; PR00008; DAGPEDOMAIN.
 SMART; SM00109; C1; 1.
 SMART; SM00455; RBD; 1.
 SMART; SM00220; S_TKc; 1.
 SUPFAM; SSF54236; SSF54236; 1.
 SUPFAM; SSF56112; SSF56112; 1.
 PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
 PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
 PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
 PROSITE; PS50898; RBD; 1.
 PROSITE; PS00479; ZF_DAG_PE_1; 1.
 PROSITE; PS50081; ZF_DAG_PE_2; 1.
 2: Evidence at transcript level;
 Alternative splicing; ATP-binding; Cell membrane; Complete proteome;
 Cytoplasm; Kinase; Membrane; Metal-binding; Methylation;
 Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein;
 Proto-oncogene; Reference proteome; Serine/threonine-protein kinase;
 Transferase; Zinc; Zinc-finger.
 CHAIN         1    648       RAF proto-oncogene serine/threonine-
                              protein kinase.
                              /FTId=PRO_0000348937.
 DOMAIN       56    131       RBD. {ECO:0000255|PROSITE-
                              ProRule:PRU00262}.
 DOMAIN      349    609       Protein kinase. {ECO:0000255|PROSITE-
                              ProRule:PRU00159}.
 ZN_FING     138    184       Phorbol-ester/DAG-type.
                              {ECO:0000255|PROSITE-ProRule:PRU00226}.
 NP_BIND     355    363       ATP. {ECO:0000250|UniProtKB:P12931,
                              ECO:0000255|PROSITE-ProRule:PRU00159}.
 REGION      331    349       Interaction with PEBP1/RKIP.
                              {ECO:0000250}.
 ACT_SITE    468    468       Proton acceptor.
                              {ECO:0000250|UniProtKB:P04049,
                              ECO:0000255|PROSITE-ProRule:PRU00159,
                              ECO:0000255|PROSITE-ProRule:PRU10027}.
 METAL       139    139       Zinc 1. {ECO:0000250|UniProtKB:P04049}.
 METAL       152    152       Zinc 2. {ECO:0000250|UniProtKB:P04049}.
 METAL       155    155       Zinc 2. {ECO:0000250|UniProtKB:P04049}.
 METAL       165    165       Zinc 1. {ECO:0000250|UniProtKB:P04049}.
 METAL       168    168       Zinc 1. {ECO:0000250|UniProtKB:P04049}.
 METAL       173    173       Zinc 2. {ECO:0000250|UniProtKB:P04049}.
 METAL       176    176       Zinc 2. {ECO:0000250|UniProtKB:P04049}.
 METAL       184    184       Zinc 1. {ECO:0000250|UniProtKB:P04049}.
 BINDING     375    375       ATP. {ECO:0000250|UniProtKB:P12931,
                              ECO:0000255|PROSITE-ProRule:PRU00159}.
 MOD_RES      29     29       Phosphoserine; by MAPK1.
                              {ECO:0000250|UniProtKB:Q99N57}.
 MOD_RES      43     43       Phosphoserine; by PKA and MAPK1.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     233    233       Phosphoserine; by PKA.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     252    252       Phosphoserine.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     259    259       Phosphoserine; by PKA, PKC and PKB/AKT1.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     269    269       Phosphothreonine; by PKA.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     289    289       Phosphoserine; by MAPK1.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     296    296       Phosphoserine; by MAPK1.
                              {ECO:0000250|UniProtKB:Q99N57}.
 MOD_RES     301    301       Phosphoserine; by MAPK1.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     338    338       Phosphoserine; by PAK1, PAK2, PAK3 and
                              PAK5. {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     339    339       Phosphoserine; by PAK1, PAK2 and PAK3.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     340    340       Phosphotyrosine; by SRC.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     341    341       Phosphotyrosine; by SRC.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     471    471       Phosphoserine.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     491    491       Phosphothreonine.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     494    494       Phosphoserine.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     497    497       Phosphoserine; by PKC.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     499    499       Phosphoserine; by PKC.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     563    563       Symmetric dimethylarginine; by PRMT5.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     621    621       Phosphoserine.
                              {ECO:0000250|UniProtKB:P04049}.
 MOD_RES     642    642       Phosphoserine; by MAPK1.
                              {ECO:0000250|UniProtKB:P04049}.
 VAR_SEQ     278    278       E -> ENNSLNASPRAWSRRFCVRGR (in isoform
                              2). {ECO:0000303|Ref.2}.
                              /FTId=VSP_052844.
 SEQUENCE   648 AA;  72874 MW;  283F6CEBFD9274E4 CRC64;
 MEHIQGAWKT ISNGFGFKDT VFDGTSCISP TIVQQFGYQR RASDDGKLTD PSKTSNTIRV
 FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR LLHEHKGKKA RLDWNTDAAS
 LIGEELQVDF LDHVPLTTHN FARKTFLKLA FCDICQKFLL NGFRCQTCGY KFHEHCSTKV
 PTMCVDWSNI RQLLLFPNST VGDGGVPALP SLTMRRMRES VSRIPPGSQH RYSTPHAFTF
 SASSPSSEGS LSQRQRSTST PNVHMVSATL PVDSRMIEDA IRSHSESGSP SALSSSPNNL
 SPTGWSQPKT PAPAQRERAP GSSTQEKNKI RPRGQRDSSY YWEIEASEVM LSTRIGSGSF
 GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT RHVNILLFMG YMTKDNLAIV
 TQWCEGSSLY KHLHVQETKF QMFQLIDIAR QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL
 TVKIGDFGLA TVKSRWSGSQ QVEQPTGSIL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE
 LMTGELPYSH INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP
 QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF

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