ID KSR1_HUMAN Reviewed; 923 AA. AC Q8IVT5; F8WEA9; H7BYU0; Q13476; DT 21-DEC-2004, integrated into UniProtKB/Swiss-Prot. DT 03-SEP-2014, sequence version 3. DT 02-SEP-2026, entry version 197. DE RecName: Full=Kinase suppressor of Ras 1; DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q61097}; GN Name=KSR1; Synonyms=KSR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-628 (ISOFORM 3). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] OF 243-899 (ISOFORM 2). 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 [4] RP INTERACTION WITH MAP2K1; MAP2K2; HSP90AA1; 14-3-3 AND CDC37, SUBCELLULAR RP LOCATION, AND DOMAIN. 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 [5] 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 [6] RP INTERACTION WITH MARK3. 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 [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-311, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-270 AND SER-334, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-270, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-270; THR-274; SER-334; RP SER-406 AND SER-569, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-406, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [13] RP SUBCELLULAR LOCATION, AND INTERACTION WITH VRK2. RX PubMed=20679487; DOI=10.1128/mcb.01581-09; RA Fernandez I.F., Blanco S., Lozano J., Lazo P.A.; RT "VRK2 inhibits mitogen-activated protein kinase signaling and inversely RT correlates with ErbB2 in human breast cancer."; RL Mol. Cell. Biol. 30:4687-4697(2010). RN [14] RP INTERACTION WITH AKAP13 AND BRAF, AND IDENTIFICATION BY MASS SPECTROMETRY. 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 [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-311, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-270; THR-274; SER-311; RP SER-334; SER-351; SER-406; THR-425 AND SER-569, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [18] {ECO:0007744|PDB:5VYK} RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 27-172, FUNCTION, SUBUNIT, RP INTERACTION WITH BRAF; MAP2K1; MAP2K2; HSP90AA1; 14-3-3 AND CDC37, DOMAIN, RP AND MUTAGENESIS OF LEU-47; CYS-62; GLU-72; 602-TYR--GLN-604; ALA-637; RP ARG-639; ARG-665 AND TRP-831. RX PubMed=29433126; DOI=10.1038/nature25478; RA Lavoie H., Sahmi M., Maisonneuve P., Marullo S.A., Thevakumaran N., Jin T., RA Kurinov I., Sicheri F., Therrien M.; RT "MEK drives BRAF activation through allosteric control of KSR proteins."; RL Nature 554:549-553(2018). RN [19] RP VARIANTS [LARGE SCALE ANALYSIS] PRO-227; ALA-359 AND HIS-663. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Part of a multiprotein signaling complex which promotes CC phosphorylation of Raf family members and activation of downstream MAP CC kinases (By similarity). 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 (PubMed:29433126). Promotes activation of MAPK1 and/or CC MAPK3, both in response to EGF and to cAMP (By similarity). Its kinase CC activity is unsure (By similarity). Some protein kinase activity has CC been detected in vitro, however the physiological relevance of this CC activity is unknown (By similarity). {ECO:0000250|UniProtKB:Q61097, CC ECO:0000269|PubMed:29433126}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); 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:0000250|UniProtKB:Q61097}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000250|UniProtKB:Q61097}; CC -!- SUBUNIT: Homodimer (PubMed:29433126). Heterodimerizes (via N-terminus) CC with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent CC manner (PubMed:29433126). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 CC (PubMed:10409742, PubMed:29433126). Binding to MAP2K1/MEK1 releases the CC intramolecular inhibitory interaction between KSR1 N-terminus and CC kinase domains which is required for the subsequent RSK1 dimerization CC with BRAF (PubMed:29433126). Identified in a complex with AKAP13, CC MAP2K1 and BRAF (By similarity). Interacts with AKAP13 and BRAF CC (PubMed:21102438). Interacts with RAF and MAPK/ERK, in a Ras-dependent CC manner (By similarity). Interacts with 14-3-3 proteins including YWHAB CC (By similarity). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37 CC (PubMed:10409742, PubMed:29433126). The binding of 14-3-3 proteins to CC phosphorylated KSR1 prevents the membrane localization (By similarity). CC Interacts with MARK3/C-TAK1 (PubMed:12941695). Interacts with PPP2R1A CC and PPP2CA (By similarity). Interacts with isoform 1 of VRK2 CC (PubMed:20679487). {ECO:0000250|UniProtKB:Q61097, CC ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:12941695, CC ECO:0000269|PubMed:20679487, ECO:0000269|PubMed:21102438, CC ECO:0000269|PubMed:29433126}. CC -!- INTERACTION: CC Q8IVT5; P36507: MAP2K2; NbExp=10; IntAct=EBI-486984, EBI-1056930; CC Q8IVT5; P04049: RAF1; NbExp=5; IntAct=EBI-486984, EBI-365996; CC Q8IVT5; Q86Y07: VRK2; NbExp=4; IntAct=EBI-486984, EBI-1207615; CC Q8IVT5; P62258: YWHAE; NbExp=4; IntAct=EBI-486984, EBI-356498; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20679487}. Membrane CC {ECO:0000269|PubMed:20679487}; Peripheral membrane protein CC {ECO:0000269|PubMed:20679487}. Cell membrane CC {ECO:0000250|UniProtKB:Q61097}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q61097}. Cell projection, ruffle membrane CC {ECO:0000250|UniProtKB:Q61097}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:20679487}. 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:12007434}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q8IVT5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IVT5-2; Sequence=VSP_055656, VSP_055657; CC Name=3; CC IsoId=Q8IVT5-3; Sequence=VSP_055655; CC Name=4; CC IsoId=Q8IVT5-4; Sequence=VSP_055655, VSP_055657; 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:29433126). Also mediates membrane localization (By similarity). CC {ECO:0000250|UniProtKB:Q61097, ECO:0000269|PubMed:29433126}. CC -!- PTM: Phosphorylated on Ser-311 and, to a higher extent, on Ser-406 by CC MARK3. Dephosphorylated on Ser-406 by PPP2CA. In resting cells, CC phosphorylated KSR1 is cytoplasmic and in stimulated cells, CC dephosphorylated KSR1 is membrane-associated. Phosphorylated by PKA at CC Ser-888. Phosphorylation at Ser-888 is required for cAMP-dependent CC activation of MAPK1 and/or MAPK3 (By similarity). CC {ECO:0000250|UniProtKB:Q61097}. 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:29433126). CC Has protein kinase activity towards MAP2K1 in the presence of RAF1/c- CC RAF in vitro (By similarity). {ECO:0000250|UniProtKB:Q61097, CC ECO:0000269|PubMed:29433126, ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41107/KSR1"; 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; AC069366; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC015688; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC042106; AAH42106.1; -; mRNA. DR EMBL; U43586; AAC50354.1; -; mRNA. DR CCDS; CCDS58532.1; -. [Q8IVT5-4] DR RefSeq; NP_055053.1; NM_014238.2. [Q8IVT5-4] DR RefSeq; XP_011523731.1; XM_011525429.3. [Q8IVT5-1] DR RefSeq; XP_047292943.1; XM_047436987.1. [Q8IVT5-2] DR RefSeq; XP_054173640.1; XM_054317665.1. [Q8IVT5-1] DR RefSeq; XP_054173644.1; XM_054317669.1. [Q8IVT5-2] DR PDB; 5VYK; X-ray; 1.75 A; A/C=27-172. DR PDB; 7JUW; X-ray; 2.88 A; B=591-899. DR PDB; 7JUX; X-ray; 3.34 A; A=591-899. DR PDB; 7JUY; X-ray; 3.10 A; B=591-899. DR PDB; 7JUZ; X-ray; 3.21 A; A=591-899. DR PDB; 7JV0; X-ray; 3.63 A; A=591-899. DR PDB; 7JV1; X-ray; 3.62 A; D=591-899. DR PDB; 9AXH; X-ray; 2.81 A; C/D=601-882. DR AlphaFoldDB; Q8IVT5; -. DR SMR; Q8IVT5; -. DR BioGRID; 114371; 135. DR CORUM; Q8IVT5; -. DR DIP; DIP-32619N; -. DR FunCoup; Q8IVT5; 1648. DR IntAct; Q8IVT5; 385. DR MINT; Q8IVT5; -. DR NDEx; IQUERY-CP-KSR1; 10 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000381958; -. DR BindingDB; Q8IVT5; -. DR ChEMBL; CHEMBL1938215; -. DR GlyGen; Q8IVT5; 3 sites. DR iPTMnet; Q8IVT5; -. DR PhosphoSitePlus; Q8IVT5; -. DR BioMuta; KSR1; -. DR DMDM; 56749095; -. DR jPOST; Q8IVT5; -. DR MassIVE; Q8IVT5; -. DR PaxDb; 9606-ENSP00000381958; -. DR PeptideAtlas; Q8IVT5; -. DR ProteomicsDB; 31779; -. DR ProteomicsDB; 43732; -. DR ProteomicsDB; 70766; -. [Q8IVT5-1] DR ProteomicsDB; 70767; -. [Q8IVT5-2] DR ProteomicsDB; 70768; -. [Q8IVT5-3] DR Pumba; Q8IVT5; -. DR Antibodypedia; 2110; 437 antibodies from 36 providers. DR DNASU; 8844; -. DR Ensembl; ENST00000398988.7; ENSP00000381958.3; ENSG00000141068.17. [Q8IVT5-4] DR GeneID; 8844; -. DR UCSC; uc002gzo.2; human. [Q8IVT5-1] DR AGR; HGNC:6465; -. DR ClinPGx; PA30254; -. DR CTD; 8844; -. DR DisGeNET; 8844; -. DR GeneCards; KSR1; -. DR HGNC; HGNC:6465; KSR1. DR HPA; ENSG00000141068; Tissue enhanced (pancreas). DR MIM; 601132; gene. DR OpenTargets; ENSG00000141068; -. DR VEuPathDB; HostDB:ENSG00000141068; -. DR eggNOG; KOG0193; Eukaryota. DR GeneTree; ENSGT00940000156066; -. DR InParanoid; Q8IVT5; -. DR OrthoDB; 774951at2759; -. DR PAN-GO; Q8IVT5; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q8IVT5; -. DR PathwayCommons; Q8IVT5; -. DR Reactome; R-HSA-5673000; RAF activation. DR Reactome; R-HSA-5674135; MAP2K and MAPK activation. DR Reactome; R-HSA-5675221; Negative regulation of MAPK pathway. DR Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants. DR Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants. DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions. DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF. DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants. DR Reactome; R-HSA-9656223; Signaling by RAF1 mutants. DR SignaLink; Q8IVT5; -. DR SIGNOR; Q8IVT5; -. DR Agora; ENSG00000141068; -. DR BioGRID-ORCS; 8844; 18 hits in 1188 CRISPR screens. DR ChiTaRS; KSR1; human. DR GeneWiki; KSR1; -. DR GenomeRNAi; 8844; -. DR Pharos; Q8IVT5; Tbio. DR PRO; PR:Q8IVT5; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q8IVT5; protein. DR Bgee; ENSG00000141068; Expressed in body of pancreas and 171 other cell types or tissues. DR ExpressionAtlas; Q8IVT5; baseline and differential. DR GO; GO:0005737; C:cytoplasm; EXP:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI. DR GO; GO:0005789; C:endoplasmic reticulum membrane; EXP:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:MGI. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0071889; F:14-3-3 protein binding; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0005078; F:MAP kinase scaffold activity; ISS:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; ISS:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-EC. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB. DR GO; GO:0007265; P:Ras protein signal transduction; ISS:UniProtKB. DR GO; GO:0042127; P:regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:0043405; P:regulation of MAP kinase activity; ISS:UniProtKB. DR CDD; cd20872; C1_KSR1; 1. DR CDD; cd14152; STKc_KSR1; 1. DR FunFam; 3.30.200.20:FF:000034; Kinase suppressor of Ras 1; 1. DR FunFam; 1.10.510.10:FF:000107; kinase suppressor of Ras 1; 1. DR FunFam; 1.10.150.50:FF:000031; Kinase suppressor of Ras 2; 1. DR FunFam; 3.30.60.20:FF:000010; Putative kinase suppressor of Ras 1; 1. DR Gene3D; 3.30.60.20; -; 1. DR Gene3D; 6.10.140.1120; -; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 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; PKC_DAG/PE. 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 InterPro; IPR050167; Ser_Thr_protein_kinase. 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 PDBsum; 5VYK; -. DR PDBsum; 7JUW; -. DR PDBsum; 7JUX; -. DR PDBsum; 7JUY; -. DR PDBsum; 7JUZ; -. DR PDBsum; 7JV0; -. DR PDBsum; 7JV1; -. DR PDBsum; 9AXH; -. 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; KW Proteomics identification; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger. FT CHAIN 1..923 FT /note="Kinase suppressor of Ras 1" FT /id="PRO_0000086229" FT DOMAIN 613..883 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT ZN_FING 347..391 FT /note="Phorbol-ester/DAG-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226" FT REGION 1..172 FT /note="Mediates association with membranes" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT REGION 1..26 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 174..246 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 265..295 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 435..484 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 557..592 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 175..192 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 194..203 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 211..230 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 237..246 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 444..473 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 557..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 571..580 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 733 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 348 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 360 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 363 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 373 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 376 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 381 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 384 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 391 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT BINDING 619..627 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 735 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q6VAB6" FT BINDING 750 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q6VAB6" FT MOD_RES 270 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18088087, FT ECO:0007744|PubMed:18220336, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 274 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 311 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 334 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT MOD_RES 351 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 406 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 425 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 569 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 888 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q61097" FT VAR_SEQ 1..137 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_055655" FT VAR_SEQ 504..526 FT /note="VPSAGHCWKCLLIAESLKENAFN -> D (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8521512" FT /id="VSP_055656" FT VAR_SEQ 898..923 FT /note="DINSSKVVPRFERFGLGVLESSNPKM -> EL (in isoform 2 and FT isoform 4)" FT /evidence="ECO:0000303|PubMed:8521512" FT /id="VSP_055657" FT VARIANT 227 FT /note="S -> P" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040658" FT VARIANT 359 FT /note="V -> A" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_046048" FT VARIANT 663 FT /note="Q -> H" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_046049" FT MUTAGEN 47 FT /note="L->D: Reduces interaction with BRAF and MAP2K1 and FT thus phosphorylation of MAP2K1." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 62 FT /note="C->D: Reduces interaction with BRAF and MAP2K1 and FT thus phosphorylation of MAP2K1." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 72 FT /note="E->K: Loss of interaction with BRAF and MAP2K1 and FT severe decrease in MAP2K1 phosphorylation levels." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 602..604 FT /note="YLQ->DDE: No effect on MAP2K1- or FT MAP2K2-mediated-BRAF-KSR1 dimerization and BRAF FT activation." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 637 FT /note="A->F: No effect on MAP2K1 or MAP2K2 FT mediated-BRAF-KSR1 dimerization and BRAF activation." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 639 FT /note="R->M: No effect on MAP2K1 mediated-BRAF-KSR1 FT dimerization and BRAF activation." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 665 FT /note="R->H: Loss of MAP2K1 mediated-BRAF-KSR1 FT dimerization." FT /evidence="ECO:0000269|PubMed:29433126" FT MUTAGEN 831 FT /note="W->R: Loss of the interaction with MAP2K1 resulting FT in loss of BRAF-KSR1 dimerization and BRAF activation. No FT effect on ATP binding or interaction with HSP90AA1, 14-3-3 FT and CDC37." FT /evidence="ECO:0000269|PubMed:29433126" FT CONFLICT 243..265 FT /note="FSEGLSDTCIPLHASGRLTPRAL -> EFRHTSALTQHTAHTQHTSAHTQ FT (in Ref. 3; AAH42106)" FT /evidence="ECO:0000305" FT HELIX 34..61 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 67..93 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 101..104 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 109..115 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 120..124 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 132..137 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 140..149 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 154..170 FT /evidence="ECO:0007829|PDB:5VYK" FT HELIX 603..605 FT /evidence="ECO:0007829|PDB:7JUX" FT STRAND 606..608 FT /evidence="ECO:0007829|PDB:7JUW" FT STRAND 615..621 FT /evidence="ECO:0007829|PDB:9AXH" FT STRAND 623..642 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 649..662 FT /evidence="ECO:0007829|PDB:9AXH" FT STRAND 672..678 FT /evidence="ECO:0007829|PDB:9AXH" FT STRAND 681..687 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 688..690 FT /evidence="ECO:0007829|PDB:7JUX" FT STRAND 691..693 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 694..698 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 707..726 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 736..738 FT /evidence="ECO:0007829|PDB:9AXH" FT STRAND 739..742 FT /evidence="ECO:0007829|PDB:9AXH" FT STRAND 745..748 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 753..755 FT /evidence="ECO:0007829|PDB:7JUW" FT STRAND 767..770 FT /evidence="ECO:0007829|PDB:7JUW" FT HELIX 773..778 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 781..785 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 793..795 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 800..816 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 826..834 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 837..845 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 850..859 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 864..866 FT /evidence="ECO:0007829|PDB:9AXH" FT HELIX 870..878 FT /evidence="ECO:0007829|PDB:9AXH" SQ SEQUENCE 923 AA; 102160 MW; 61BF0F1598349540 CRC64; MDRAALRAAA MGEKKEGGGG GDAAAAEGGA GAAASRALQQ CGQLQKLIDI SIGSLRGLRT KCAVSNDLTQ QEIRTLEAKL VRYICKQRQC KLSVAPGERT PELNSYPRFS DWLYTFNVRP EVVQEIPRDL TLDALLEMNE AKVKETLRRC GASGDECGRL QYALTCLRKV TGLGGEHKED SSWSSLDARR ESGSGPSTDT LSAASLPWPP GSSQLGRAGN SAQGPRSISV SALPASDSPT PSFSEGLSDT CIPLHASGRL TPRALHSFIT PPTTPQLRRH TKLKPPRTPP PPSRKVFQLL PSFPTLTRSK SHESQLGNRI DDVSSMRFDL SHGSPQMVRR DIGLSVTHRF STKSWLSQVC HVCQKSMIFG VKCKHCRLKC HNKCTKEAPA CRISFLPLTR LRRTESVPSD INNPVDRAAE PHFGTLPKAL TKKEHPPAMN HLDSSSNPSS TTSSTPSSPA PFPTSSNPSS ATTPPNPSPG QRDSRFNFPA AYFIHHRQQF IFPVPSAGHC WKCLLIAESL KENAFNISAF AHAAPLPEAA DGTRLDDQPK ADVLEAHEAE AEEPEAGKSE AEDDEDEVDD LPSSRRPWRG PISRKASQTS VYLQEWDIPF EQVELGEPIG QGRWGRVHRG RWHGEVAIRL LEMDGHNQDH LKLFKKEVMN YRQTRHENVV LFMGACMNPP HLAIITSFCK GRTLHSFVRD PKTSLDINKT RQIAQEIIKG MGYLHAKGIV HKDLKSKNVF YDNGKVVITD FGLFGISGVV REGRRENQLK LSHDWLCYLA PEIVREMTPG KDEDQLPFSK AADVYAFGTV WYELQARDWP LKNQAAEASI WQIGSGEGMK RVLTSVSLGK EVSEILSACW AFDLQERPSF SLLMDMLEKL PKLNRRLSHP GHFWKSADIN SSKVVPRFER FGLGVLESSN PKM //