KSR2_MOUSE
ID KSR2_MOUSE Reviewed; 959 AA.
AC Q3UVC0;
DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 15-MAY-2007, sequence version 2.
DT 03-AUG-2022, entry version 116.
DE RecName: Full=Kinase suppressor of Ras 2;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q6VAB6};
GN Name=Ksr2 {ECO:0000312|MGI:MGI:3610315};
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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2] {ECO:0000305, ECO:0000312|EMBL:BAE23350.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-330.
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:BAE23350.1};
RC TISSUE=Cerebellum {ECO:0000312|EMBL:BAE23350.1};
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-273; THR-277 AND THR-507, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
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).
CC -!- FUNCTION: Location-regulated scaffold connecting MEK to RAF. Has very
CC low protein kinase activity and can phosphorylate MAP2K1 at several Ser
CC and Thr residues with very low efficiency (in vitro). Acts as
CC MAP2K1/MEK1-dependent allosteric activator of BRAF; upon binding to
CC MAP2K1/MEK1, dimerizes with BRAF and promotes BRAF-mediated
CC phosphorylation of MAP2K1/MEK1. Interaction with BRAF enhances KSR2-
CC mediated phosphorylation of MAP2K1 (in vitro). Blocks MAP3K8 kinase
CC activity and MAP3K8-mediated signaling. Acts as a negative regulator of
CC MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways,
CC inhibiting MAP3K3-mediated interleukin-8 production.
CC {ECO:0000250|UniProtKB:Q6VAB6}.
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:Q6VAB6};
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:Q6VAB6};
CC -!- SUBUNIT: Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in
CC a MAP2K1/MEK1-dependent manner. Interacts with BRAF; this increases the
CC low intrinsic protein kinase activity of KSR2. Interacts with MAP2K1,
CC forming a heterodimer that can dimerize to form a heterotetramer.
CC Interacts with MAP3K8, MAPK, RAS and RAF.
CC {ECO:0000250|UniProtKB:Q6VAB6}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q61097}.
CC Membrane {ECO:0000250|UniProtKB:Q61097}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q61097}.
CC -!- DOMAIN: The protein kinase domain is predicted to be catalytically
CC inactive and seems to have very low intrinsic kinase activity. This low
CC kinase activity can be increased by interaction with BRAF (By
CC similarity). {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- PTM: Phosphorylated on Ser-484 by MARK3.
CC {ECO:0000250|UniProtKB:Q61097}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
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DR EMBL; AC113299; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC113303; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC114617; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK137433; BAE23350.1; -; mRNA.
DR RefSeq; NP_001299843.1; NM_001312914.1.
DR AlphaFoldDB; Q3UVC0; -.
DR SMR; Q3UVC0; -.
DR IntAct; Q3UVC0; 1.
DR STRING; 10090.ENSMUSP00000137670; -.
DR iPTMnet; Q3UVC0; -.
DR PhosphoSitePlus; Q3UVC0; -.
DR MaxQB; Q3UVC0; -.
DR PaxDb; Q3UVC0; -.
DR PRIDE; Q3UVC0; -.
DR ProteomicsDB; 264956; -.
DR DNASU; 333050; -.
DR GeneID; 333050; -.
DR KEGG; mmu:333050; -.
DR UCSC; uc008zfw.2; mouse.
DR CTD; 283455; -.
DR MGI; MGI:3610315; Ksr2.
DR eggNOG; KOG0193; Eukaryota.
DR InParanoid; Q3UVC0; -.
DR OrthoDB; 281487at2759; -.
DR PhylomeDB; Q3UVC0; -.
DR Reactome; R-MMU-5674135; MAP2K and MAPK activation.
DR BioGRID-ORCS; 333050; 2 hits in 68 CRISPR screens.
DR ChiTaRS; Ksr2; mouse.
DR PRO; PR:Q3UVC0; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q3UVC0; protein.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
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; 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:0019722; P:calcium-mediated signaling; IGI:MGI.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; IMP:YuBioLab.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
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 ATP-binding; Cytoplasm; Kinase; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger.
FT CHAIN 1..959
FT /note="Kinase suppressor of Ras 2"
FT /id="PRO_0000286965"
FT DOMAIN 676..941
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ZN_FING 413..457
FT /note="Phorbol-ester/DAG-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT REGION 237..298
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 498..567
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 623..643
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 281..295
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 522..537
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 538..560
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 796
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 414
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 426
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 429
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 439
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 442
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 447
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 450
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 457
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q61097"
FT BINDING 682..690
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 798
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 813
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 273
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 277
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 484
FT /note="Phosphoserine; by MARK3"
FT /evidence="ECO:0000250"
FT MOD_RES 507
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
SQ SEQUENCE 959 AA; 108572 MW; 5A56146F4C6E8AA2 CRC64;
MDEENMTKSE EQQPLSLQKA LQQCELVQNM IDLSISNLEG LRTKCAASND LTQKEIRTLE
SKLVKYFSRQ LSCKKKVALQ ERNAELDGFP QLRHWFRIVD VRKEVLEEIS PDQLSLEDLL
EMTDEQVCET VEKYGANQEE CARLNASLSC LRNVHKSGGN LSKQDWIIQW PTTEPGQESN
PVCPPEPSPW IRTHLSQSPR VQTKCPQHFC PTSPTPGTPV YTQVDRLTVD AYPNLCPPPP
PLESGHRSLP PSPRQRHVVR TPPRTPNIVT TVTPPGTPPM RRKNKLKPPG TPPPSSRKLI
HLIPGFTALH RSKSHEFQLG NRVDEANTPK AKKKSKPLNL KIHSGVGSCE NIPAQQRSPL
LSERSLRSFF VGHGPFLPST PPVHTEANFS ANTLSVPRWS PQIPRRDLGN SIKHRFSTKY
WMSQTCTVCG KGMLFGLKCK NCKLKCHNKC TKEAPPCHLL IIHRGDSLCC FYPTDPARLV
RTESVPCDIN NPVRKPARYS DLHISQTLPK TNKINKDHIP VPYQPDSSSN PSSTTSSTPS
SPAPPLPPSA TPPSPLHPSP QCPRQKKNFN LPASHYYKYK QQFIFPDVVP VPETPTRAPQ
VILHPVTSNT ILEGNPLLQI EVEPTSENEE SHNEAEESED EFEEMNLSLL SARSFPRKAS
QTSIFLQEWD IPFEQLEIGE LIGKGRFGQV YHGRWHGEVA IRLIDIERDN EDQLKAFKRE
VMAYRQTRHE NVVLFMGACM SPPHLAIITS LCKGRTLYSV VRDAKIVLDV NKTRQIAQEI
VKGMGYLHAK GILHKDLKSK NVFYDNGKVV ITDFGLFSIS GVLQAGRRDD KLRIQNGWLC
HLAPEIIRQL SPDTEEDKLP FSKHSDVFAL GTIWYELHAR EWPFKTQPAE AIIWQMGTGM
KPNLSQIGMG KEISDILLFC WAFEQEERPT FTKLMDMLEK LPKRNRRLSH PGHFWKSAE
