ID KSR1_MOUSE Reviewed; 873 AA. AC Q61097; Q61648; Q78DX8; DT 21-DEC-2004, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 195. DE RecName: Full=Kinase suppressor of Ras 1; DE Short=mKSR1; DE EC=2.7.11.1 {ECO:0000269|PubMed:21441104}; DE AltName: Full=Protein Hb; GN Name=Ksr1; Synonyms=Ksr; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8521512; DOI=10.1016/0092-8674(95)90204-x; RA Therrien M., Chang H.C., Solomon N.M., Karim F.D., Wassarman D.A., RA Rubin G.M.; RT "KSR, a novel protein kinase required for RAS signal transduction."; RL Cell 83:879-888(1995). RN [2] RP NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2), INTERACTION WITH MAPK, MUTAGENESIS RP OF GLY-572; ARG-589; ARG-615; ASP-700 AND CYS-809, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=10891492; DOI=10.1128/mcb.20.15.5529-5539.2000; RA Mueller J., Cacace A.M., Lyons W.E., McGill C.B., Morrison D.K.; RT "Identification of B-KSR1, a novel brain-specific isoform of KSR1 that RT functions in neuronal signaling."; RL Mol. Cell. Biol. 20:5529-5539(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Pelan S.; RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 49-474 (ISOFORMS 1/2). RC STRAIN=BALB/cJ; RX PubMed=7626882; DOI=10.1007/bf00364794; RA Nehls M., Luno K., Schorpp M., Pfeifer D., Krause S., Matysiak-Scholze U., RA Dierbach H., Boehm T.; RT "YAC/P1 contigs defining the location of 56 microsatellite markers and RT several genes across a 3.4cM interval on mouse chromosome 11."; RL Mamm. Genome 6:321-331(1995). RN [5] RP FUNCTION, INTERACTION WITH MAP2K1; MAP2K2; HSP90AA1; YWHAB AND CDC37, RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF 56-LEU--ARG-57; GLY-580; RP ARG-589; ARG-615 AND CYS-809. RX PubMed=10409742; DOI=10.1128/mcb.19.8.5523; RA Stewart S., Sundaram M., Zhang Y., Lee J., Han M., Guan K.L.; RT "Kinase suppressor of Ras forms a multiprotein signaling complex and RT modulates MEK localization."; RL Mol. Cell. Biol. 19:5523-5534(1999). RN [6] RP INTERACTION WITH MARK3 AND 14-3-3, PHOSPHORYLATION AT SER-297 AND SER-392, RP MUTAGENESIS OF SER-297; SER-392; ILE-397 AND VAL-401, AND SUBCELLULAR RP LOCATION. RX PubMed=11741534; DOI=10.1016/s1097-2765(01)00383-5; RA Mueller J., Ory S., Copeland T., Piwnica-Worms H., Morrison D.K.; RT "C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, RT KSR1."; RL Mol. Cell 8:983-993(2001). RN [7] RP REVIEW. RX PubMed=12007434; DOI=10.1016/s0960-9822(02)00831-x; RA Roy F., Therrien M.; RT "MAP kinase module: the Ksr connection."; RL Curr. Biol. 12:R325-R327(2002). RN [8] RP FUNCTION, INTERACTION WITH PPP2R1A AND PPP2CA, DEPHOSPHORYLATION BY PPP2CA, RP AND SUBCELLULAR LOCATION. RX PubMed=12932319; DOI=10.1016/s0960-9822(03)00535-9; RA Ory S., Zhou M., Conrads T.P., Veenstra T.D., Morrison D.K.; RT "Protein phosphatase 2A positively regulates Ras signaling by RT dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites."; RL Curr. Biol. 13:1356-1364(2003). RN [9] RP INTERACTION WITH MARK3, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-297 RP AND SER-392, AND MUTAGENESIS OF LEU-382; LEU-387; ARG-389; THR-390; RP GLU-391; SER-392; VAL-393; PRO-394; SER-395; ASP-396; ILE-397; PRO-400; RP VAL-401; ARG-403 AND PRO-413. RX PubMed=12941695; DOI=10.1093/emboj/cdg426; RA Mueller J., Ritt D.A., Copeland T.D., Morrison D.K.; RT "Functional analysis of C-TAK1 substrate binding and identification of PKP2 RT as a new C-TAK1 substrate."; RL EMBO J. 22:4431-4442(2003). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320; SER-392 AND SER-518, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Kidney, Lung, and Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [11] RP FUNCTION, INTERACTION WITH AKAP13; MAP2K1 AND BRAF, IDENTIFICATION BY MASS RP SPECTROMETRY, PHOSPHORYLATION AT SER-838, AND MUTAGENESIS OF SER-838. RX PubMed=21102438; DOI=10.1038/ncb2130; RA Smith F.D., Langeberg L.K., Cellurale C., Pawson T., Morrison D.K., RA Davis R.J., Scott J.D.; RT "AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade."; RL Nat. Cell Biol. 12:1242-1249(2010). RN [12] RP STRUCTURE BY NMR OF 331-378 IN COMPLEX WITH ZINC. RX PubMed=11786023; DOI=10.1006/jmbi.2001.5263; RA Zhou M., Horita D.A., Waugh D.S., Byrd R.A., Morrison D.K.; RT "Solution structure and functional analysis of the cysteine-rich C1 domain RT of kinase suppressor of Ras (KSR)."; RL J. Mol. Biol. 315:435-446(2002). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH BRAF AND MAP2K1, AND RP MUTAGENESIS OF ALA-587. RX PubMed=21441104; DOI=10.1073/pnas.1102554108; RA Hu J., Yu H., Kornev A.P., Zhao J., Filbert E.L., Taylor S.S., Shaw A.S.; RT "Mutation that blocks ATP binding creates a pseudokinase stabilizing the RT scaffolding function of kinase suppressor of Ras, CRAF and BRAF."; RL Proc. Natl. Acad. Sci. U.S.A. 108:6067-6072(2011). RN [14] {ECO:0007744|PDB:2LPE} RP STRUCTURE BY NMR OF 25-170, INTERACTION WITH BRAF AND MAP2K1, DOMAIN, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 56-LEU-ARG-57; ILE-71 AND LEU-78. RX PubMed=23250398; DOI=10.1126/scisignal.2003289; RA Koveal D., Schuh-Nuhfer N., Ritt D., Page R., Morrison D.K., Peti W.; RT "A CC-SAM, for coiled coil-sterile alpha motif, domain targets the scaffold RT KSR-1 to specific sites in the plasma membrane."; RL Sci. Signal. 5:RA94-RA94(2012). CC -!- FUNCTION: Part of a multiprotein signaling complex which promotes CC phosphorylation of Raf family members and activation of downstream MAP CC kinases (PubMed:10409742, PubMed:12932319, PubMed:21102438, CC PubMed:21441104). Independently of its kinase activity, acts as CC MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; CC upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and CC promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or CC MAP2K2/MEK2 (By similarity). Promotes activation of MAPK1 and/or MAPK3, CC both in response to EGF and to cAMP (PubMed:21102438). Its kinase CC activity is unsure (PubMed:21441104). Some protein kinase activity has CC been detected in vitro, however the physiological relevance of this CC activity is unknown (PubMed:21441104). {ECO:0000250|UniProtKB:Q8IVT5, CC ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:12932319, CC ECO:0000269|PubMed:21102438, ECO:0000269|PubMed:21441104}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:21441104}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:21441104}; CC -!- SUBUNIT: Homodimer (By similarity). Heterodimerizes (via N-terminus) CC with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent CC manner (By similarity). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 CC (PubMed:10891492, PubMed:10409742, PubMed:21441104). Binding to CC MAP2K1/MEK1 releases the intramolecular inhibitory interaction between CC KSR1 N-terminus and kinase domains which is required for the subsequent CC RSK1 dimerization with BRAF (By similarity). Identified in a complex CC with AKAP13, MAP2K1 and BRAF (PubMed:21102438, PubMed:23250398). CC Interacts with AKAP13 and BRAF (PubMed:21102438). Interacts with RAF CC and MAPK/ERK, in a Ras-dependent manner (PubMed:10891492). Interacts CC with 14-3-3 proteins including YWHAB (PubMed:10409742, CC PubMed:11741534). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37 CC (PubMed:10409742). The binding of 14-3-3 proteins to phosphorylated CC KSR1 prevents the membrane localization (PubMed:10409742). Interacts CC with MARK3/C-TAK1 (PubMed:11741534, PubMed:12941695). Interacts with CC PPP2R1A and PPP2CA (PubMed:12932319). Interacts with VRK2 (By CC similarity). {ECO:0000250|UniProtKB:Q8IVT5, CC ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:10891492, CC ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, CC ECO:0000269|PubMed:12941695, ECO:0000269|PubMed:21102438, CC ECO:0000269|PubMed:21441104, ECO:0000269|PubMed:23250398}. CC -!- INTERACTION: CC Q61097; Q60875: Arhgef2; NbExp=5; IntAct=EBI-1536336, EBI-772191; CC Q61097; P15056: BRAF; Xeno; NbExp=3; IntAct=EBI-1536336, EBI-365980; CC Q61097; P15531: NME1; Xeno; NbExp=7; IntAct=EBI-1536336, EBI-741141; CC Q61097; Q86Y07-1: VRK2; Xeno; NbExp=8; IntAct=EBI-1536336, EBI-1207633; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742, CC ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, CC ECO:0000269|PubMed:12941695, ECO:0000269|PubMed:23250398}. Membrane CC {ECO:0000269|PubMed:10409742}; Peripheral membrane protein CC {ECO:0000269|PubMed:10409742}. Cell membrane CC {ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, CC ECO:0000269|PubMed:23250398}; Peripheral membrane protein CC {ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, CC ECO:0000269|PubMed:23250398}. Cell projection, ruffle membrane CC {ECO:0000269|PubMed:23250398}. Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q8IVT5}. Note=In unstimulated cells, where the CC phosphorylated form is bound to a 14-3-3 protein, sequestration in the CC cytoplasm occurs. Following growth factor treatment, the protein is CC free for membrane translocation, and it moves from the cytoplasm to the CC cell periphery. {ECO:0000305|PubMed:12932319}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q61097-1; Sequence=Displayed; CC Name=2; Synonyms=B-KSR1; CC IsoId=Q61097-2; Sequence=VSP_012232, VSP_012233; CC -!- TISSUE SPECIFICITY: Expressed in brain, spleen and testis. Isoform 1 is CC highly expressed spleen and weakly in testis, and isoform 2 is highly CC expressed in brain and weakly in testis. {ECO:0000269|PubMed:10891492}. CC -!- DOMAIN: The protein kinase domain is predicted to be catalytically CC inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1 CC and MAP2K2 membrane localization. The domain is required but not CC sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation CC (PubMed:10409742). {ECO:0000255, ECO:0000269|PubMed:10409742}. CC -!- DOMAIN: The N-terminal region mediates interaction with BRAF CC (PubMed:23250398). Also mediates membrane localization CC (PubMed:23250398). {ECO:0000269|PubMed:23250398}. CC -!- PTM: Phosphorylated on Ser-297 and, to a higher extent, on Ser-392 by CC MARK3 (PubMed:11741534, PubMed:12941695). Dephosphorylated on Ser-392 CC by PPP2CA (PubMed:12932319). Phosphorylated KSR1 is cytoplasmic and CC dephosphorylated KSR1 is membrane-associated (Probable). Phosphorylated CC by PKA at Ser-838. Phosphorylation at Ser-838 is required for cAMP- CC dependent activation of MAPK1 and/or MAPK3 (PubMed:21102438). CC {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:10891492, CC ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, CC ECO:0000269|PubMed:12941695, ECO:0000269|PubMed:21102438, ECO:0000305}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. {ECO:0000305}. CC -!- CAUTION: Although it belongs to the protein kinase superfamily, the CC ATP-binding motif VAIK has an arginine instead of a lysine residue CC suggesting that KSR1 cannot bind ATP and therefore lacks protein kinase CC activity. However, KSR1 is capable of binding ATP (PubMed:21441104). CC Has protein kinase activity towards MAP2K1 in presence of RAF1/c-RAF in CC vitro (PubMed:21441104). {ECO:0000269|PubMed:21441104, ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U43585; AAC52382.1; -; mRNA. DR EMBL; AL592551; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; X81634; CAA57288.1; -; mRNA. DR CCDS; CCDS25117.1; -. [Q61097-1] DR PIR; I48379; I48379. DR RefSeq; NP_001335136.1; NM_001348207.1. DR RefSeq; NP_038599.1; NM_013571.3. [Q61097-1] DR RefSeq; XP_006532398.1; XM_006532335.3. [Q61097-2] DR PDB; 1KBE; NMR; -; A=331-378. DR PDB; 1KBF; NMR; -; A=331-378. DR PDB; 2LPE; NMR; -; A=25-170. DR PDBsum; 1KBE; -. DR PDBsum; 1KBF; -. DR PDBsum; 2LPE; -. DR AlphaFoldDB; Q61097; -. DR BMRB; Q61097; -. DR SMR; Q61097; -. DR BioGRID; 201048; 239. DR CORUM; Q61097; -. DR IntAct; Q61097; 9. DR MINT; Q61097; -. DR STRING; 10090.ENSMUSP00000018478; -. DR iPTMnet; Q61097; -. DR PhosphoSitePlus; Q61097; -. DR EPD; Q61097; -. DR jPOST; Q61097; -. DR MaxQB; Q61097; -. DR PaxDb; 10090-ENSMUSP00000018478; -. DR PeptideAtlas; Q61097; -. DR ProteomicsDB; 263568; -. [Q61097-1] DR ProteomicsDB; 263569; -. [Q61097-2] DR Pumba; Q61097; -. DR Antibodypedia; 2110; 503 antibodies from 33 providers. DR DNASU; 16706; -. DR Ensembl; ENSMUST00000018478.11; ENSMUSP00000018478.5; ENSMUSG00000018334.19. [Q61097-1] DR GeneID; 16706; -. DR KEGG; mmu:16706; -. DR UCSC; uc033fyo.1; mouse. [Q61097-1] DR AGR; MGI:105051; -. DR CTD; 8844; -. DR MGI; MGI:105051; Ksr1. DR VEuPathDB; HostDB:ENSMUSG00000018334; -. DR eggNOG; KOG0193; Eukaryota. DR GeneTree; ENSGT00940000156066; -. DR HOGENOM; CLU_006812_0_0_1; -. DR InParanoid; Q61097; -. DR OMA; HAIPHKW; -. DR OrthoDB; 4560496at2759; -. DR PhylomeDB; Q61097; -. DR TreeFam; TF317006; -. DR Reactome; R-MMU-5673000; RAF activation. DR Reactome; R-MMU-5674135; MAP2K and MAPK activation. DR Reactome; R-MMU-5675221; Negative regulation of MAPK pathway. DR BioGRID-ORCS; 16706; 2 hits in 79 CRISPR screens. DR ChiTaRS; Ksr1; mouse. DR EvolutionaryTrace; Q61097; -. DR PRO; PR:Q61097; -. DR Proteomes; UP000000589; Chromosome 11. DR RNAct; Q61097; Protein. DR Bgee; ENSMUSG00000018334; Expressed in hindlimb stylopod muscle and 182 other cell types or tissues. DR ExpressionAtlas; Q61097; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI. DR GO; GO:0016020; C:membrane; ISO:MGI. DR GO; GO:0032991; C:protein-containing complex; ISO:MGI. DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0071889; F:14-3-3 protein binding; IPI:UniProtKB. DR GO; GO:0005524; F:ATP binding; IMP:UniProtKB. DR GO; GO:0051879; F:Hsp90 protein binding; IPI:UniProtKB. DR GO; GO:0005078; F:MAP-kinase scaffold activity; IDA:MGI. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; IPI:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:UniProtKB. DR GO; GO:0019933; P:cAMP-mediated signaling; IMP:UniProtKB. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:MGI. DR GO; GO:0007265; P:Ras protein signal transduction; IMP:UniProtKB. DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:UniProtKB. DR GO; GO:0043405; P:regulation of MAP kinase activity; IMP:UniProtKB. DR CDD; cd20872; C1_KSR1; 1. DR CDD; cd14152; STKc_KSR1; 1. DR Gene3D; 3.30.60.20; -; 1. DR Gene3D; 6.10.140.1120; -; 1. DR Gene3D; 1.10.150.50; Transcription Factor, Ets-1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR046349; C1-like_sf. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR002219; PE/DAG-bd. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR013761; SAM/pointed_sf. DR InterPro; IPR046861; SAM_KSR1_N. DR InterPro; IPR046933; SAM_KSR1_N_sf. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR23257:SF716; KINASE SUPPRESSOR OF RAS 1; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR Pfam; PF20406; SAM_KSR1_N; 1. DR SMART; SM00109; C1; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF57889; Cysteine-rich domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS00479; ZF_DAG_PE_1; 1. DR PROSITE; PS50081; ZF_DAG_PE_2; 1. DR Genevisible; Q61097; MM. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; KW Cell projection; Cytoplasm; Endoplasmic reticulum; Kinase; Membrane; KW Metal-binding; Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger. FT CHAIN 1..873 FT /note="Kinase suppressor of Ras 1" FT /id="PRO_0000086230" FT DOMAIN 563..833 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT ZN_FING 333..377 FT /note="Phorbol-ester/DAG-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226" FT REGION 1..170 FT /note="Mediates association with membranes" FT /evidence="ECO:0000269|PubMed:23250398" FT REGION 1..24 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 174..230 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 251..281 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 416..473 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 506..544 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 202..220 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 424..473 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 514..529 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 683 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 334 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 346 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 349 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 359 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 362 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 367 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 370 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 377 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11786023" FT BINDING 569..577 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 685 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q6VAB6" FT BINDING 700 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q6VAB6" FT MOD_RES 256 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8IVT5" FT MOD_RES 260 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8IVT5" FT MOD_RES 297 FT /note="Phosphoserine; by MARK3" FT /evidence="ECO:0000269|PubMed:11741534, FT ECO:0000269|PubMed:12941695" FT MOD_RES 320 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 337 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8IVT5" FT MOD_RES 392 FT /note="Phosphoserine; by MARK3" FT /evidence="ECO:0000269|PubMed:12941695" FT MOD_RES 411 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8IVT5" FT MOD_RES 518 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 838 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:21102438" FT VAR_SEQ 474 FT /note="P -> PAAYFIHHRQQFIFP (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_012232" FT VAR_SEQ 848..873 FT /note="DINSSKVMPRFERFGLGTLESGNPKM -> EL (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_012233" FT MUTAGEN 56..57 FT /note="LR->GS: No effect on the interaction with MAP2K1, FT MAP2K2 and YWHAE. Abolishes interaction with BRAF. FT Abolishes location at membrane ruffles." FT /evidence="ECO:0000269|PubMed:10409742, FT ECO:0000269|PubMed:23250398" FT MUTAGEN 71 FT /note="I->A: Impairs interaction with BRAF and association FT with membrane ruffles; when associated with A-78." FT /evidence="ECO:0000269|PubMed:23250398" FT MUTAGEN 78 FT /note="L->A: Impairs interaction with BRAF and association FT with membrane ruffles; when associated with A-78." FT /evidence="ECO:0000269|PubMed:23250398" FT MUTAGEN 297 FT /note="S->A: Constitutive targeting to the plasma membrane; FT when associated with A-392." FT /evidence="ECO:0000269|PubMed:11741534" FT MUTAGEN 382 FT /note="L->A: No effect on interaction with MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 387 FT /note="L->A: Reduces interaction with MARK3. Reduces FT phosphorylation of S-392 by MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 389 FT /note="R->A: Reduces phosphorylation of S-392 by MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 390 FT /note="T->A: No effect on phosphorylation of S-392 by FT MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 391 FT /note="E->A: No effect on phosphorylation of S-392 by FT MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 392 FT /note="S->A: Constitutive targeting to the plasma membrane; FT when associated with A-297. No effect on interaction with FT MARK3. Abolishes phosphorylation by MARK3." FT /evidence="ECO:0000269|PubMed:11741534, FT ECO:0000269|PubMed:12941695" FT MUTAGEN 393 FT /note="V->A: Reduces phosphorylation of S-392 by MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 394 FT /note="P->A: No effect on phosphorylation of S-392 by FT MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 395 FT /note="S->A: No effect on phosphorylation of S-392 by FT MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 396 FT /note="D->A: No effect on phosphorylation of S-392 by FT MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 397 FT /note="I->A: Decrease in MARK3 binding; when associated FT with A-401. Abolishes interaction with MARK3. Reduces FT phosphorylation of S-392 by MARK3." FT /evidence="ECO:0000269|PubMed:11741534, FT ECO:0000269|PubMed:12941695" FT MUTAGEN 400 FT /note="P->A: No effect on interaction with MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 401 FT /note="V->A: Decrease in MARK3 binding; when associated FT with A-397. No effect on interaction with MARK3." FT /evidence="ECO:0000269|PubMed:11741534, FT ECO:0000269|PubMed:12941695" FT MUTAGEN 403 FT /note="R->A: No effect on interaction with MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 413 FT /note="P->A: No effect on interaction with MARK3." FT /evidence="ECO:0000269|PubMed:12941695" FT MUTAGEN 572 FT /note="G->E: Decrease in MEK binding." FT /evidence="ECO:0000269|PubMed:10891492" FT MUTAGEN 580 FT /note="G->E: Partial decrease in MAP2K1 and MAP2K2 binding. FT No effect on the interaction with YWHAE." FT /evidence="ECO:0000269|PubMed:10409742" FT MUTAGEN 587 FT /note="A->F: Loss of ATP binding and reduces MAPK1 and FT MAPK3 phosphorylation levels. Loss of kinase activity FT towards MAP2K1 in vitro. Abnormal constitutive interaction FT with CRAF. No effect on the interaction with BRAF and FT MAP2K1." FT /evidence="ECO:0000269|PubMed:21441104" FT MUTAGEN 587 FT /note="A->V: No effect on ATP binding and MAPK1 and MAPK3 FT phosphorylation levels. No effect on the interaction with FT MAP2K1." FT /evidence="ECO:0000269|PubMed:21441104" FT MUTAGEN 589 FT /note="R->M: Severe decrease in MAP2K1 and MAP2K2 binding. FT No effect on the interaction with YWHAE." FT /evidence="ECO:0000269|PubMed:10409742, FT ECO:0000269|PubMed:10891492" FT MUTAGEN 615 FT /note="R->H: Severe decrease in MAP2K1 and MAP2K2 binding. FT No effect on the interaction with YWHAE." FT /evidence="ECO:0000269|PubMed:10409742, FT ECO:0000269|PubMed:10891492" FT MUTAGEN 700 FT /note="D->V: Decrease in MEK binding." FT /evidence="ECO:0000269|PubMed:10891492" FT MUTAGEN 809 FT /note="C->Y: Associates almost exclusively with the FT membrane. Loss of MAP2K2 and MAP2K2 binding and recruitment FT to the membrane. Loss of MAP kinase-mediated inhibition of FT ELK1 phosphorylation. No effect on the interaction with FT YWHAE." FT /evidence="ECO:0000269|PubMed:10409742, FT ECO:0000269|PubMed:10891492" FT MUTAGEN 838 FT /note="S->A: Abolishes one phosphorylation site. Decreases FT phosphorylation by PKA." FT /evidence="ECO:0000269|PubMed:21102438" FT TURN 30..32 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 33..36 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 37..39 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 47..58 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 65..82 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 83..85 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 88..90 FT /evidence="ECO:0007829|PDB:2LPE" FT TURN 94..96 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 101..103 FT /evidence="ECO:0007829|PDB:2LPE" FT TURN 108..110 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 111..114 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 118..121 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 130..133 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 138..146 FT /evidence="ECO:0007829|PDB:2LPE" FT TURN 147..149 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 153..162 FT /evidence="ECO:0007829|PDB:2LPE" FT HELIX 163..167 FT /evidence="ECO:0007829|PDB:2LPE" FT STRAND 336..339 FT /evidence="ECO:0007829|PDB:1KBE" FT STRAND 347..349 FT /evidence="ECO:0007829|PDB:1KBE" FT STRAND 356..359 FT /evidence="ECO:0007829|PDB:1KBE" FT TURN 360..363 FT /evidence="ECO:0007829|PDB:1KBE" FT STRAND 364..369 FT /evidence="ECO:0007829|PDB:1KBE" FT TURN 371..373 FT /evidence="ECO:0007829|PDB:1KBE" SQ SEQUENCE 873 AA; 96755 MW; EAEEB23FAE715D94 CRC64; MDRAALRAAA MGEKKEGGGG GAAADGGAGA AVSRALQQCG QLQKLIDISI GSLRGLRTKC SVSNDLTQQE IRTLEAKLVK YICKQQQSKL SVTPSDRTAE LNSYPRFSDW LYIFNVRPEV VQEIPQELTL DALLEMDEAK AKEMLRRWGA STEECSRLQQ ALTCLRKVTG LGGEHKMDSG WSSTDARDSS LGPPMDMLSS LGRAGASTQG PRSISVSALP ASDSPVPGLS EGLSDSCIPL HTSGRLTPRA LHSFITPPTT PQLRRHAKLK PPRTPPPPSR KVFQLLPSFP TLTRSKSHES QLGNRIDDVT PMKFELPHGS PQLVRRDIGL SVTHRFSTKS WLSQVCNVCQ KSMIFGVKCK HCRLKCHNKC TKEAPACRIT FLPLARLRRT ESVPSDINNP VDRAAEPHFG TLPKALTKKE HPPAMNLDSS SNPSSTTSST PSSPAPFLTS SNPSSATTPP NPSPGQRDSR FSFPDISACS QAAPLSSTAD STRLDDQPKT DVLGVHEAEA EEPEAGKSEA EDDEEDEVDD LPSSRRPWRG PISRKASQTS VYLQEWDIPF EQVELGEPIG QGRWGRVHRG RWHGEVAIRL LEMDGHNQDH LKLFKKEVMN YRQTRHENVV LFMGACMNPP HLAIITSFCK GRTLHSFVRD PKTSLDINKT RQIAQEIIKG MGYLHAKGIV HKDLKSKNVF YDNGKVVITD FGLFGISGVV REERRENQLK LSHDWLCYLA PEIVREMIPG RDEDQLPFSK AADVYAFGTV WYELQARDWP FKHQPAEALI WQIGSGEGVR RVLASVSLGK EVGEILSACW AFDLQERPSF SLLMDMLERL PKLNRRLSHP GHFWKSADIN SSKVMPRFER FGLGTLESGN PKM //