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 27-MAR-2024, entry version 209. 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, SPRK GN {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 Hippocampus RC {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; 58. DR CORUM; Q16584; -. DR IntAct; Q16584; 21. 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; 9606-ENSP00000309597; -. DR PeptideAtlas; Q16584; -. DR ProteomicsDB; 5004; -. DR ProteomicsDB; 60929; -. [Q16584-1] DR ABCD; Q16584; 1 sequenced antibody. DR Antibodypedia; 29871; 411 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 AGR; HGNC:6850; -. 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; HLSPKMP; -. DR OrthoDB; 876955at2759; -. 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; 83 hits in 1189 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 189 other cell types or tissues. DR ExpressionAtlas; Q16584; baseline and differential. 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: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 CDD; cd14147; STKc_MLK3; 1. DR Gene3D; 2.30.30.40; SH3 Domains; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 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 PANTHER; PTHR23257:SF757; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. 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; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF50044; SH3-domain; 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. DR Genevisible; Q16584; HS. 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 //