M3K11_HUMAN
ID M3K11_HUMAN Reviewed; 847 AA.
AC Q16584; B4DS76; Q53H00; Q59F06; Q6P2G4;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 11;
DE EC=2.7.11.25;
DE AltName: Full=Mixed lineage kinase 3;
DE AltName: Full=Src-homology 3 domain-containing proline-rich kinase;
GN Name=MAP3K11 {ECO:0000312|HGNC:HGNC:6850};
GN Synonyms=MLK3 {ECO:0000303|PubMed:15258589}, PTK1,
GN SPRK {ECO:0000312|EMBL:AAA19647.1};
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] {ECO:0000305, ECO:0000312|EMBL:AAA19647.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP TISSUE SPECIFICITY, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF LYS-144 AND
RP GLU-164.
RC TISSUE=Megakaryocyte;
RX PubMed=8195146; DOI=10.1016/s0021-9258(17)36578-x;
RA Gallo K.A., Mark M.R., Scadden D.T., Wang Z., Gu Q., Godowski P.J.;
RT "Identification and characterization of SPRK, a novel src-homology 3
RT domain-containing proline-rich kinase with serine/threonine kinase
RT activity.";
RL J. Biol. Chem. 269:15092-15100(1994).
RN [2] {ECO:0000305, ECO:0000312|EMBL:AAA59859.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Thymus {ECO:0000312|EMBL:AAA59859.1};
RX PubMed=8183572;
RA Ing Y.L., Leung I.W.L., Heng H.H.Q., Tsui L.-C., Lassam N.J.;
RT "MLK-3: identification of a widely-expressed protein kinase bearing an SH3
RT domain and a leucine zipper-basic region domain.";
RL Oncogene 9:1745-1750(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Liver, and Spleen;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6] {ECO:0000305, ECO:0000312|EMBL:AAH64543.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT HIS-252.
RC TISSUE=Brain {ECO:0000312|EMBL:AAH11263.1}, and
RC Hippocampus {ECO:0000269|PubMed:15489334};
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 [7]
RP INTERACTION WITH MAP2K4/MKK4, AND FUNCTION IN PHOSPHORYLATION OF
RP MAP2K4/MKK4.
RX PubMed=9003778; DOI=10.1002/j.1460-2075.1996.tb01094.x;
RA Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R.,
RA Lassam N.J.;
RT "MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6.";
RL EMBO J. 15:7026-7035(1996).
RN [8] {ECO:0000305}
RP ACTIVITY REGULATION, AND HOMODIMERIZATION.
RX PubMed=9829970; DOI=10.1074/jbc.273.49.32408;
RA Leung I.W.L., Lassam N.J.;
RT "Dimerization via tandem leucine zippers is essential for the activation of
RT the mitogen-activated protein kinase kinase kinase, MLK-3.";
RL J. Biol. Chem. 273:32408-32415(1998).
RN [9] {ECO:0000305}
RP ACTIVITY REGULATION, PHOSPHORYLATION AT THR-277 AND SER-281, AND
RP MUTAGENESIS OF LYS-144; THR-277; THR-278 AND SER-281.
RX PubMed=11053428; DOI=10.1074/jbc.m004092200;
RA Leung I.W.L., Lassam N.J.;
RT "The kinase activation loop is the key to mixed lineage kinase-3 activation
RT via both autophosphorylation and hematopoietic progenitor kinase 1
RT phosphorylation.";
RL J. Biol. Chem. 276:1961-1967(2001).
RN [10] {ECO:0000305}
RP PHOSPHORYLATION AT SER-524; SER-555; SER-556; SER-654; SER-705; SER-724;
RP SER-727; SER-740; SER-758; SER-770 AND SER-793.
RX PubMed=11969422; DOI=10.1021/bi016075c;
RA Vacratsis P.O., Phinney B.S., Gage D.A., Gallo K.A.;
RT "Identification of in vivo phosphorylation sites of MLK3 by mass
RT spectrometry and phosphopeptide mapping.";
RL Biochemistry 41:5613-5624(2002).
RN [11] {ECO:0000305}
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12529434; DOI=10.1091/mbc.e02-02-0115;
RA Swenson K.I., Winkler K.E., Means A.R.;
RT "A new identity for MLK3 as an NIMA-related, cell cycle-regulated kinase
RT that is localized near centrosomes and influences microtubule
RT organization.";
RL Mol. Biol. Cell 14:156-172(2003).
RN [12] {ECO:0000305}
RP FUNCTION.
RX PubMed=15258589; DOI=10.1038/ncb1152;
RA Chadee D.N., Kyriakis J.M.;
RT "MLK3 is required for mitogen activation of B-Raf, ERK and cell
RT proliferation.";
RL Nat. Cell Biol. 6:770-776(2004).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-507, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-11; SER-507; SER-548;
RP SER-705; THR-708; SER-748; SER-758; SER-793 AND SER-815, AND IDENTIFICATION
RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-789 AND SER-793, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394; SER-507; SER-548;
RP SER-693; SER-705; SER-748; SER-758; SER-789 AND SER-793, AND IDENTIFICATION
RP 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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-789 AND SER-793, AND
RP IDENTIFICATION BY 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 [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-507; SER-524 AND SER-548, AND
RP IDENTIFICATION BY MASS 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 [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [20]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-151 AND GLY-282.
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: Activates the JUN N-terminal pathway. Required for serum-
CC stimulated cell proliferation and for mitogen and cytokine activation
CC of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation
CC and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-
CC stimulated phosphorylation and activation of BRAF, but does not
CC phosphorylate BRAF directly. Influences microtubule organization during
CC the cell cycle. {ECO:0000269|PubMed:12529434,
CC ECO:0000269|PubMed:15258589, ECO:0000269|PubMed:8195146,
CC ECO:0000269|PubMed:9003778}.
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=2.7.11.25;
CC Evidence={ECO:0000269|PubMed:8195146};
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=2.7.11.25; Evidence={ECO:0000269|PubMed:8195146};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P80192};
CC -!- ACTIVITY REGULATION: Homodimerization via the leucine zipper domains is
CC required for autophosphorylation and subsequent activation.
CC {ECO:0000269|PubMed:11053428, ECO:0000269|PubMed:9829970}.
CC -!- SUBUNIT: Homodimer; undergoes dimerization during activation
CC (PubMed:9829970). Interacts with MAP2K4/MKK4 (By similarity). Interacts
CC with MAP2K7/MKK7 (PubMed:9003778). Found in a complex with SH3RF1,
CC RAC1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity).
CC {ECO:0000250|UniProtKB:Q80XI6, ECO:0000269|PubMed:9003778,
CC ECO:0000269|PubMed:9829970}.
CC -!- INTERACTION:
CC Q16584; P60953: CDC42; NbExp=3; IntAct=EBI-49961, EBI-81752;
CC Q16584; P35240: NF2; NbExp=4; IntAct=EBI-49961, EBI-1014472;
CC Q16584; P70218: Map4k1; Xeno; NbExp=3; IntAct=EBI-49961, EBI-2906801;
CC Q16584; PRO_0000045602 [Q99IB8]; Xeno; NbExp=5; IntAct=EBI-49961, EBI-6927873;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule organizing
CC center, centrosome {ECO:0000269|PubMed:12529434}. Note=Location is cell
CC cycle dependent.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q16584-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q16584-2; Sequence=VSP_056183;
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of normal and
CC neoplastic tissues including fetal lung, liver, heart and kidney, and
CC adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas
CC and brain. {ECO:0000269|PubMed:8183572, ECO:0000269|PubMed:8195146}.
CC -!- PTM: Autophosphorylation on serine and threonine residues within the
CC activation loop plays a role in enzyme activation. Thr-277 is likely to
CC be the main autophosphorylation site. Phosphorylation of Ser-555 and
CC Ser-556 is induced by CDC42. {ECO:0000269|PubMed:11053428,
CC ECO:0000269|PubMed:11969422, ECO:0000269|PubMed:8195146}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92892.1; Type=Erroneous initiation; Evidence={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; U07747; AAA19647.1; -; mRNA.
DR EMBL; L32976; AAA59859.1; -; mRNA.
DR EMBL; AB209655; BAD92892.1; ALT_INIT; mRNA.
DR EMBL; AK299609; BAG61538.1; -; mRNA.
DR EMBL; AK316032; BAH14403.1; -; mRNA.
DR EMBL; AK222781; BAD96501.1; -; mRNA.
DR EMBL; AP001362; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC011263; AAH11263.1; -; mRNA.
DR EMBL; BC064543; AAH64543.1; -; mRNA.
DR CCDS; CCDS8107.1; -. [Q16584-1]
DR PIR; A53800; A53800.
DR RefSeq; NP_002410.1; NM_002419.3. [Q16584-1]
DR PDB; 5K26; X-ray; 1.20 A; A/B=41-105.
DR PDB; 5K28; X-ray; 1.50 A; A/B=44-105.
DR PDB; 6AQB; X-ray; 1.50 A; A/B=41-108.
DR PDB; 6CQ7; X-ray; 2.00 A; A=41-108.
DR PDBsum; 5K26; -.
DR PDBsum; 5K28; -.
DR PDBsum; 6AQB; -.
DR PDBsum; 6CQ7; -.
DR AlphaFoldDB; Q16584; -.
DR SMR; Q16584; -.
DR BioGRID; 110442; 49.
DR CORUM; Q16584; -.
DR IntAct; Q16584; 19.
DR MINT; Q16584; -.
DR STRING; 9606.ENSP00000309597; -.
DR BindingDB; Q16584; -.
DR ChEMBL; CHEMBL2708; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q16584; -.
DR GuidetoPHARMACOLOGY; 2071; -.
DR iPTMnet; Q16584; -.
DR PhosphoSitePlus; Q16584; -.
DR BioMuta; MAP3K11; -.
DR DMDM; 71153819; -.
DR CPTAC; CPTAC-1047; -.
DR CPTAC; CPTAC-833; -.
DR CPTAC; CPTAC-835; -.
DR CPTAC; CPTAC-836; -.
DR CPTAC; CPTAC-837; -.
DR CPTAC; CPTAC-838; -.
DR CPTAC; CPTAC-839; -.
DR CPTAC; CPTAC-840; -.
DR EPD; Q16584; -.
DR jPOST; Q16584; -.
DR MassIVE; Q16584; -.
DR MaxQB; Q16584; -.
DR PaxDb; Q16584; -.
DR PeptideAtlas; Q16584; -.
DR PRIDE; Q16584; -.
DR ProteomicsDB; 5004; -.
DR ProteomicsDB; 60929; -. [Q16584-1]
DR ABCD; Q16584; 1 sequenced antibody.
DR Antibodypedia; 29871; 317 antibodies from 34 providers.
DR DNASU; 4296; -.
DR Ensembl; ENST00000309100.8; ENSP00000309597.3; ENSG00000173327.8. [Q16584-1]
DR Ensembl; ENST00000530153.5; ENSP00000433886.1; ENSG00000173327.8. [Q16584-2]
DR GeneID; 4296; -.
DR KEGG; hsa:4296; -.
DR MANE-Select; ENST00000309100.8; ENSP00000309597.3; NM_002419.4; NP_002410.1.
DR UCSC; uc001oew.4; human. [Q16584-1]
DR CTD; 4296; -.
DR DisGeNET; 4296; -.
DR GeneCards; MAP3K11; -.
DR HGNC; HGNC:6850; MAP3K11.
DR HPA; ENSG00000173327; Low tissue specificity.
DR MIM; 600050; gene.
DR neXtProt; NX_Q16584; -.
DR OpenTargets; ENSG00000173327; -.
DR PharmGKB; PA30594; -.
DR VEuPathDB; HostDB:ENSG00000173327; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000161064; -.
DR HOGENOM; CLU_000288_7_14_1; -.
DR InParanoid; Q16584; -.
DR OMA; WKREIQD; -.
DR OrthoDB; 100698at2759; -.
DR PhylomeDB; Q16584; -.
DR TreeFam; TF105118; -.
DR PathwayCommons; Q16584; -.
DR Reactome; R-HSA-5673000; RAF activation.
DR Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants.
DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF.
DR Reactome; R-HSA-9013148; CDC42 GTPase cycle.
DR Reactome; R-HSA-9013408; RHOG GTPase cycle.
DR Reactome; R-HSA-9013424; RHOV GTPase cycle.
DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants.
DR SABIO-RK; Q16584; -.
DR SignaLink; Q16584; -.
DR SIGNOR; Q16584; -.
DR BioGRID-ORCS; 4296; 63 hits in 1110 CRISPR screens.
DR ChiTaRS; MAP3K11; human.
DR GeneWiki; MAP3K11; -.
DR GenomeRNAi; 4296; -.
DR Pharos; Q16584; Tchem.
DR PRO; PR:Q16584; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q16584; protein.
DR Bgee; ENSG00000173327; Expressed in sural nerve and 187 other tissues.
DR ExpressionAtlas; Q16584; baseline and differential.
DR Genevisible; Q16584; HS.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IMP:UniProtKB.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IMP:UniProtKB.
DR GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; IEA:Ensembl.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; IEA:Ensembl.
DR GO; GO:0044843; P:cell cycle G1/S phase transition; IMP:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:Ensembl.
DR GO; GO:0007254; P:JNK cascade; IMP:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR GO; GO:0007017; P:microtubule-based process; IMP:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IMP:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR CDD; cd12059; SH3_MLK1-3; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR035779; MLK1-3_SH3.
DR InterPro; IPR016231; MLK1-4.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF14604; SH3_9; 1.
DR PIRSF; PIRSF000556; MAPKKK9_11; 1.
DR PRINTS; PR00452; SH3DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasm; Cytoskeleton;
KW Kinase; Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; SH3 domain; Transferase.
FT CHAIN 1..847
FT /note="Mitogen-activated protein kinase kinase kinase 11"
FT /id="PRO_0000086260"
FT DOMAIN 41..105
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 117..379
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 11..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 403..424
FT /note="Leucine-zipper 1"
FT REGION 438..459
FT /note="Leucine-zipper 2"
FT REGION 537..643
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 655..847
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 577..591
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 674..697
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 746..766
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 785..801
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 241
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q02779,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 123..131
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q02779,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 144
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:11053428, ECO:0000269|PubMed:8195146"
FT MOD_RES 11
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 35
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80XI6"
FT MOD_RES 277
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11053428"
FT MOD_RES 281
FT /note="Phosphoserine; by autocatalysis and MAP4K1"
FT /evidence="ECO:0000269|PubMed:11053428"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 507
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 524
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 548
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT MOD_RES 555
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 556
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 654
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 693
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 705
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195"
FT MOD_RES 708
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 724
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 727
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 740
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 748
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195"
FT MOD_RES 758
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195"
FT MOD_RES 770
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422"
FT MOD_RES 789
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332"
FT MOD_RES 793
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11969422,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332"
FT MOD_RES 815
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT VAR_SEQ 1..257
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056183"
FT VARIANT 151
FT /note="D -> V (in dbSNP:rs34178129)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040703"
FT VARIANT 252
FT /note="P -> H (in dbSNP:rs17855912)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_030604"
FT VARIANT 282
FT /note="A -> G (in dbSNP:rs34594252)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040704"
FT MUTAGEN 144
FT /note="K->A: Greatly reduced autophosphorylation activity."
FT /evidence="ECO:0000269|PubMed:11053428,
FT ECO:0000269|PubMed:8195146"
FT MUTAGEN 144
FT /note="K->R: Loss of kinase activity. Prevents activation
FT of SAPK and MAPK14."
FT /evidence="ECO:0000269|PubMed:11053428,
FT ECO:0000269|PubMed:8195146"
FT MUTAGEN 164
FT /note="E->A: Greatly reduced autophosphorylation activity."
FT /evidence="ECO:0000269|PubMed:8195146"
FT MUTAGEN 277
FT /note="T->A: Severely reduced autophosphorylation activity.
FT Prevents phosphorylation of SAPK and MAPK14."
FT /evidence="ECO:0000269|PubMed:11053428"
FT MUTAGEN 277
FT /note="T->E: No effect on SAPK activation."
FT /evidence="ECO:0000269|PubMed:11053428"
FT MUTAGEN 278
FT /note="T->A: No effect on autophosphorylation activity or
FT activation of SAPK and MAPK14."
FT /evidence="ECO:0000269|PubMed:11053428"
FT MUTAGEN 281
FT /note="S->A: Reduced autophosphorylation activity. Reduced
FT activation of SAPK and MAPK14."
FT /evidence="ECO:0000269|PubMed:11053428"
FT MUTAGEN 281
FT /note="S->E: No effect on SAPK activation."
FT /evidence="ECO:0000269|PubMed:11053428"
FT CONFLICT 247..272
FT /note="ILLLQPIESDDMEHKTLKITDFGLAR -> SEFLGAWLGVAWLWYTPAPNLP
FT LSLA (in Ref. 4; BAD92892)"
FT /evidence="ECO:0000305"
FT CONFLICT 791
FT /note="L -> P (in Ref. 4; BAD96501)"
FT /evidence="ECO:0000305"
FT STRAND 45..50
FT /evidence="ECO:0007829|PDB:5K26"
FT STRAND 67..73
FT /evidence="ECO:0007829|PDB:5K26"
FT HELIX 78..80
FT /evidence="ECO:0007829|PDB:5K26"
FT STRAND 83..88
FT /evidence="ECO:0007829|PDB:5K26"
FT STRAND 91..96
FT /evidence="ECO:0007829|PDB:5K26"
FT HELIX 97..99
FT /evidence="ECO:0007829|PDB:5K26"
FT STRAND 100..105
FT /evidence="ECO:0007829|PDB:5K26"
SQ SEQUENCE 847 AA; 92688 MW; AFB6E930EA281C15 CRC64;
MEPLKSLFLK SPLGSWNGSG SGGGGGGGGG RPEGSPKAAG YANPVWTALF DYEPSGQDEL
ALRKGDRVEV LSRDAAISGD EGWWAGQVGG QVGIFPSNYV SRGGGPPPCE VASFQELRLE
EVIGIGGFGK VYRGSWRGEL VAVKAARQDP DEDISVTAES VRQEARLFAM LAHPNIIALK
AVCLEEPNLC LVMEYAAGGP LSRALAGRRV PPHVLVNWAV QIARGMHYLH CEALVPVIHR
DLKSNNILLL QPIESDDMEH KTLKITDFGL AREWHKTTQM SAAGTYAWMA PEVIKASTFS
KGSDVWSFGV LLWELLTGEV PYRGIDCLAV AYGVAVNKLT LPIPSTCPEP FAQLMADCWA
QDPHRRPDFA SILQQLEALE AQVLREMPRD SFHSMQEGWK REIQGLFDEL RAKEKELLSR
EEELTRAARE QRSQAEQLRR REHLLAQWEL EVFERELTLL LQQVDRERPH VRRRRGTFKR
SKLRARDGGE RISMPLDFKH RITVQASPGL DRRRNVFEVG PGDSPTFPRF RAIQLEPAEP
GQAWGRQSPR RLEDSSNGER RACWAWGPSS PKPGEAQNGR RRSRMDEATW YLDSDDSSPL
GSPSTPPALN GNPPRPSLEP EEPKRPVPAE RGSSSGTPKL IQRALLRGTA LLASLGLGRD
LQPPGGPGRE RGESPTTPPT PTPAPCPTEP PPSPLICFSL KTPDSPPTPA PLLLDLGIPV
GQRSAKSPRR EEEPRGGTVS PPPGTSRSAP GTPGTPRSPP LGLISRPRPS PLRSRIDPWS
FVSAGPRPSP LPSPQPAPRR APWTLFPDSD PFWDSPPANP FQGGPQDCRA QTKDMGAQAP
WVPEAGP
