KSR1_HUMAN
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 03-AUG-2022, entry version 178.
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 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 [7]
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 [8]
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 [9]
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 [10]
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 [11]
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 [12]
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 [13]
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 [14]
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 [15]
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 [16]
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 [17] {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 [18]
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=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:0000250|UniProtKB:Q61097};
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: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 (By similarity). Interacts with PPP2R1A and PPP2CA
CC (By similarity). Interacts with isoform 1 of VRK2 (PubMed:20679487).
CC {ECO:0000250|UniProtKB:Q61097, ECO:0000269|PubMed:10409742,
CC ECO:0000269|PubMed:20679487, ECO:0000269|PubMed:21102438,
CC ECO:0000269|PubMed:29433126}.
CC -!- INTERACTION:
CC Q8IVT5; P36507: MAP2K2; NbExp=9; IntAct=EBI-486984, EBI-1056930;
CC Q8IVT5; Q86Y07: VRK2; NbExp=4; IntAct=EBI-486984, EBI-1207615;
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="http://atlasgeneticsoncology.org/Genes/KSR1ID41107ch17q11.html";
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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_014238.1. [Q8IVT5-4]
DR RefSeq; XP_011523731.1; XM_011525429.2. [Q8IVT5-1]
DR RefSeq; XP_016880760.1; XM_017025271.1. [Q8IVT5-3]
DR RefSeq; XP_016880761.1; XM_017025272.1. [Q8IVT5-3]
DR RefSeq; XP_016880762.1; XM_017025273.1. [Q8IVT5-3]
DR RefSeq; XP_016880763.1; XM_017025274.1. [Q8IVT5-3]
DR RefSeq; XP_016880764.1; XM_017025275.1. [Q8IVT5-3]
DR RefSeq; XP_016880765.1; XM_017025276.1. [Q8IVT5-3]
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 PDBsum; 5VYK; -.
DR PDBsum; 7JUW; -.
DR PDBsum; 7JUX; -.
DR PDBsum; 7JUY; -.
DR PDBsum; 7JUZ; -.
DR PDBsum; 7JV0; -.
DR PDBsum; 7JV1; -.
DR AlphaFoldDB; Q8IVT5; -.
DR SMR; Q8IVT5; -.
DR BioGRID; 114371; 122.
DR CORUM; Q8IVT5; -.
DR DIP; DIP-32619N; -.
DR IntAct; Q8IVT5; 359.
DR MINT; Q8IVT5; -.
DR STRING; 9606.ENSP00000381958; -.
DR BindingDB; Q8IVT5; -.
DR ChEMBL; CHEMBL1938215; -.
DR iPTMnet; Q8IVT5; -.
DR PhosphoSitePlus; Q8IVT5; -.
DR BioMuta; KSR1; -.
DR DMDM; 56749095; -.
DR EPD; Q8IVT5; -.
DR jPOST; Q8IVT5; -.
DR MassIVE; Q8IVT5; -.
DR MaxQB; Q8IVT5; -.
DR PaxDb; Q8IVT5; -.
DR PeptideAtlas; Q8IVT5; -.
DR PRIDE; Q8IVT5; -.
DR ProteomicsDB; 31779; -.
DR ProteomicsDB; 43732; -.
DR ProteomicsDB; 70766; -. [Q8IVT5-1]
DR ProteomicsDB; 70767; -. [Q8IVT5-2]
DR ProteomicsDB; 70768; -. [Q8IVT5-3]
DR Antibodypedia; 2110; 438 antibodies from 33 providers.
DR DNASU; 8844; -.
DR Ensembl; ENST00000398988.7; ENSP00000381958.3; ENSG00000141068.15. [Q8IVT5-4]
DR Ensembl; ENST00000509603.6; ENSP00000438795.2; ENSG00000141068.15. [Q8IVT5-4]
DR GeneID; 8844; -.
DR KEGG; hsa:8844; -.
DR UCSC; uc002gzo.2; human. [Q8IVT5-1]
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 neXtProt; NX_Q8IVT5; -.
DR OpenTargets; ENSG00000141068; -.
DR PharmGKB; PA30254; -.
DR VEuPathDB; HostDB:ENSG00000141068; -.
DR eggNOG; KOG0193; Eukaryota.
DR GeneTree; ENSGT00940000156066; -.
DR InParanoid; Q8IVT5; -.
DR OrthoDB; 281487at2759; -.
DR PhylomeDB; Q8IVT5; -.
DR TreeFam; TF317006; -.
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 BioGRID-ORCS; 8844; 16 hits in 1111 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 169 other tissues.
DR ExpressionAtlas; Q8IVT5; baseline and differential.
DR Genevisible; Q8IVT5; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
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; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; IDA:MGI.
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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008022; F:protein C-terminus binding; IDA:MGI.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
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:0019933; P:cAMP-mediated signaling; ISS:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
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 GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00029; C1; 1.
DR Gene3D; 1.10.150.50; -; 1.
DR InterPro; IPR046349; C1-like_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR025561; KSR_SAM-like_dom.
DR InterPro; IPR002219; PE/DAG-bd.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF13543; SAM_KSR1; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57889; SSF57889; 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.
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..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 187..246
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 440..467
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 565..579
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 MAP2K2-mediated-
FT BRAF-KSR1 dimerization and BRAF activation."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 637
FT /note="A->F: No effect on MAP2K1 or MAP2K2 mediated-BRAF-
FT 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 614..621
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 626..631
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 635..642
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 648..662
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 672..678
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 681..687
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 691..693
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 694..698
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 709..726
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 736..738
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 739..742
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 745..748
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 753..755
FT /evidence="ECO:0007829|PDB:7JUW"
FT STRAND 767..770
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 773..777
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 781..786
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 793..795
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 800..816
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 826..834
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 837..845
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 850..859
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 864..866
FT /evidence="ECO:0007829|PDB:7JUW"
FT HELIX 870..878
FT /evidence="ECO:0007829|PDB:7JUW"
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
