ID MARK3_HUMAN Reviewed; 753 AA. AC P27448; A0A0A0MQR8; A0A0A0MST9; A0A0A0MT23; O60219; Q86TT8; Q8TB41; Q8WX83; AC Q96RG1; Q9UMY9; Q9UN34; DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot. DT 28-MAR-2018, sequence version 5. DT 27-MAR-2024, entry version 223. DE RecName: Full=MAP/microtubule affinity-regulating kinase 3; DE EC=2.7.11.1 {ECO:0000269|PubMed:12941695, ECO:0000269|PubMed:16822840, ECO:0000269|PubMed:16980613}; DE AltName: Full=C-TAK1; DE Short=cTAK1; DE AltName: Full=Cdc25C-associated protein kinase 1; DE AltName: Full=ELKL motif kinase 2; DE Short=EMK-2; DE AltName: Full=Protein kinase STK10; DE AltName: Full=Ser/Thr protein kinase PAR-1; DE Short=Par-1a; DE AltName: Full=Serine/threonine-protein kinase p78; GN Name=MARK3; Synonyms=CTAK1, EMK2; 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 [MRNA] (ISOFORM 3), AND VARIANT GLY-443. RC TISSUE=Cervix carcinoma; RX PubMed=9543386; RA Peng C.Y., Graves P.R., Ogg S., Thoma R.S., Byrnes M.J. III, Wu Z., RA Stephenson M.T., Piwnica-Worms H.; RT "C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and RT promotes 14-3-3 protein binding."; RL Cell Growth Differ. 9:197-208(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT GLY-443. RC TISSUE=Monocyte; RA Waggoner S.N., Stephen R., Farrar W.L., Howard O.M.Z.; RT "Human serine/threonine protein kinase cTAK1/Kp78/Mark3: Identification of RT a novel splice variant and a larger 5'UTR."; RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RX PubMed=11433294; DOI=10.1038/35083016; RA Sun T.-Q., Lu B., Feng J.-J., Reinhard C., Jan Y.N., Fantl W.J., RA Williams L.T.; RT "PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt RT signalling."; RL Nat. Cell Biol. 3:628-636(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Drewes G.; RT "Characterization of an alternatively spliced form of MARK3 from human RT brain."; RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RC TISSUE=Pancreas; RA Maheshwari K.K., Som S., Parsa I.; RL Submitted (JAN-1992) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7), AND VARIANT PHE-410. RC TISSUE=Neuroblastoma; RA Li W.B., Gruber C., Jessee J., Polayes D.; RT "Full-length cDNA libraries and normalization."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Cervix; 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 [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 300-752 (ISOFORM 6). RC TISSUE=Urinary bladder; RA Reynolds C.H., Patel U.A., Anderton B.H.; RT "Homo sapiens mRNA partial sequence for a protein kinase, STK10, similar to RT p78/C-TAK1."; RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases. RN [11] RP FUNCTION, AND INTERACTION WITH PKP2; KSR1 AND CDC25C. RX PubMed=12941695; DOI=10.1093/emboj/cdg426; RA Mueller J., Ritt D.A., Copeland T.D., Morrison D.K.; RT "Functional analysis of C-TAK1 substrate binding and identification of PKP2 RT as a new C-TAK1 substrate."; RL EMBO J. 22:4431-4442(2003). RN [12] RP PHOSPHORYLATION AT THR-564. RX PubMed=15084291; DOI=10.1016/j.cub.2004.04.007; RA Hurov J.B., Watkins J.L., Piwnica-Worms H.; RT "Atypical PKC phosphorylates PAR-1 kinases to regulate localization and RT activity."; RL Curr. Biol. 14:736-741(2004). RN [13] RP ACTIVITY REGULATION, PHOSPHORYLATION AT THR-211, AND MUTAGENESIS OF RP THR-211. RX PubMed=14976552; DOI=10.1038/sj.emboj.7600110; RA Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A., Boudeau J., RA Hawley S.A., Udd L., Maekelae T.P., Hardie D.G., Alessi D.R.; RT "LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, RT including MARK/PAR-1."; RL EMBO J. 23:833-843(2004). RN [14] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16822840; DOI=10.1091/mbc.e06-05-0470; RA Bronisz A., Sharma S.M., Hu R., Godlewski J., Tzivion G., Mansky K.C., RA Ostrowski M.C.; RT "Microphthalmia-associated transcription factor interactions with 14-3-3 RT modulate differentiation of committed myeloid precursors."; RL Mol. Biol. Cell 17:3897-3906(2006). RN [15] RP FUNCTION. RX PubMed=16980613; DOI=10.1128/mcb.00231-06; RA Dequiedt F., Martin M., Von Blume J., Vertommen D., Lecomte E., Mari N., RA Heinen M.F., Bachmann M., Twizere J.C., Huang M.C., Rider M.H., RA Piwnica-Worms H., Seufferlein T., Kettmann R.; RT "New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and RT activity of class IIa histone deacetylases."; RL Mol. Cell. Biol. 26:7086-7102(2006). RN [16] RP INTERACTION WITH YWHAB; YWHAG; YWHAQ AND YWHAZ. RX PubMed=16959763; DOI=10.1074/mcp.m600147-mcp200; RA Angrand P.O., Segura I., Voelkel P., Ghidelli S., Terry R., Brajenovic M., RA Vintersten K., Klein R., Superti-Furga G., Drewes G., Kuster B., RA Bouwmeester T., Acker-Palmer A.; RT "Transgenic mouse proteomics identifies new 14-3-3-associated proteins RT involved in cytoskeletal rearrangements and cell signaling."; RL Mol. Cell. Proteomics 5:2211-2227(2006). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-549, AND IDENTIFICATION BY RP 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 [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383; SER-400; SER-469; RP THR-549; SER-598 AND SER-643, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT RP SER-384 (ISOFORM 5), PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-407 RP (ISOFORM 6), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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 [19] 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 [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-42; SER-383; SER-469 AND RP SER-643, AND 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 [22] 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 [23] RP SUBCELLULAR LOCATION. RX PubMed=21145462; DOI=10.1016/j.cell.2010.11.028; RA Moravcevic K., Mendrola J.M., Schmitz K.R., Wang Y.H., Slochower D., RA Janmey P.A., Lemmon M.A.; RT "Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by RT binding acidic phospholipids."; RL Cell 143:966-977(2010). RN [24] 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 [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-469, 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 [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-376; SER-380; SER-419; RP SER-469; SER-540; THR-549; SER-583 AND SER-601, 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 [27] RP FUNCTION, INTERACTION WITH MAPT, AND SUBCELLULAR LOCATION. RX PubMed=23666762; DOI=10.1007/s12017-013-8232-3; RA Gu G.J., Lund H., Wu D., Blokzijl A., Classon C., von Euler G., RA Landegren U., Sunnemark D., Kamali-Moghaddam M.; RT "Role of individual MARK isoforms in phosphorylation of tau at Ser262 in RT Alzheimer's disease."; RL NeuroMolecular Med. 15:458-469(2013). RN [28] RP FUNCTION, AND INTERACTION WITH STK3; STK4 AND DLG5. RX PubMed=28087714; DOI=10.1101/gad.284539.116; RA Kwan J., Sczaniecka A., Arash E.H., Nguyen L., Chen C.C., Ratkovic S., RA Klezovitch O., Attisano L., McNeill H., Emili A., Vasioukhin V.; RT "DLG5 connects cell polarity and Hippo signaling protein networks by RT linking PAR-1 with MST1/2."; RL Genes Dev. 30:2696-2709(2016). RN [29] RP VARIANTS [LARGE SCALE ANALYSIS] ALA-429 AND GLY-443. 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). RN [30] RP VARIANT VIPB GLY-570, AND INVOLVEMENT IN VIPB. RX PubMed=29771303; DOI=10.1093/hmg/ddy180; RA Ansar M., Chung H., Waryah Y.M., Makrythanasis P., Falconnet E., Rao A.R., RA Guipponi M., Narsani A.K., Fingerhut R., Santoni F.A., Ranza E., RA Waryah A.M., Bellen H.J., Antonarakis S.E.; RT "Visual impairment and progressive phthisis bulbi caused by recessive RT pathogenic variant in MARK3."; RL Hum. Mol. Genet. 27:2703-2711(2018). CC -!- FUNCTION: Serine/threonine-protein kinase (PubMed:16822840, CC PubMed:16980613, PubMed:23666762). Involved in the specific CC phosphorylation of microtubule-associated proteins for MAP2 and MAP4. CC Phosphorylates the microtubule-associated protein MAPT/TAU CC (PubMed:23666762). Phosphorylates CDC25C on 'Ser-216' CC (PubMed:12941695). Regulates localization and activity of some histone CC deacetylases by mediating phosphorylation of HDAC7, promoting CC subsequent interaction between HDAC7 and 14-3-3 and export from the CC nucleus (PubMed:16980613). Regulates localization and activity of MITF CC by mediating its phosphorylation, promoting subsequent interaction CC between MITF and 14-3-3 and retention in the cytosol (PubMed:16822840). CC Negatively regulates the Hippo signaling pathway and antagonizes the CC phosphorylation of LATS1. Cooperates with DLG5 to inhibit the kinase CC activity of STK3/MST2 toward LATS1 (PubMed:28087714). Phosphorylates CC PKP2 and KSR1 (PubMed:12941695). {ECO:0000269|PubMed:12941695, CC ECO:0000269|PubMed:16822840, ECO:0000269|PubMed:16980613, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:28087714}. 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:0000269|PubMed:12941695, ECO:0000269|PubMed:16822840, CC ECO:0000269|PubMed:16980613}; 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:0000269|PubMed:12941695, CC ECO:0000269|PubMed:16980613}; CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-211. Inhibited CC by phosphorylation on Thr-564. {ECO:0000269|PubMed:14976552}. CC -!- SUBUNIT: Interacts with MAPT/TAU (PubMed:23666762). Interacts with DLG5 CC (via coiled-coil domain). Interacts with STK3/MST2 and STK4/MST1 in the CC presence of DLG5 (PubMed:28087714). Interacts with YWHAB, YWHAG, YWHAQ CC and YWHAZ (PubMed:16959763). Interacts with PKP2 (via N-terminus) CC (PubMed:12941695). Interacts with CDC25C (PubMed:12941695). Interacts CC with KSR1 (PubMed:12941695). {ECO:0000269|PubMed:12941695, CC ECO:0000269|PubMed:16959763, ECO:0000269|PubMed:23666762, CC ECO:0000269|PubMed:28087714}. CC -!- INTERACTION: CC P27448; Q8WXK3: ASB13; NbExp=2; IntAct=EBI-707595, EBI-707573; CC P27448; P31947: SFN; NbExp=5; IntAct=EBI-707595, EBI-476295; CC P27448; Q15560: TCEA2; NbExp=2; IntAct=EBI-707595, EBI-710310; CC P27448; P31946: YWHAB; NbExp=8; IntAct=EBI-707595, EBI-359815; CC P27448; P62258: YWHAE; NbExp=7; IntAct=EBI-707595, EBI-356498; CC P27448; P61981: YWHAG; NbExp=8; IntAct=EBI-707595, EBI-359832; CC P27448; Q04917: YWHAH; NbExp=10; IntAct=EBI-707595, EBI-306940; CC P27448; P63104: YWHAZ; NbExp=14; IntAct=EBI-707595, EBI-347088; CC P27448; Q6S8E0: ORF9b; Xeno; NbExp=2; IntAct=EBI-707595, EBI-25489144; CC P27448; Q8BHN0: Ppm1l; Xeno; NbExp=3; IntAct=EBI-707595, EBI-7970002; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21145462}; CC Peripheral membrane protein {ECO:0000269|PubMed:21145462}. Cell CC projection, dendrite {ECO:0000269|PubMed:23666762}. Cytoplasm CC {ECO:0000269|PubMed:23666762}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; CC IsoId=P27448-5; Sequence=Displayed; CC Name=2; Synonyms=CTAK75a; CC IsoId=P27448-2; Sequence=VSP_041582, VSP_004944; CC Name=3; CC IsoId=P27448-3; Sequence=VSP_004944; CC Name=4; CC IsoId=P27448-4; Sequence=VSP_004945; CC Name=5; Synonyms=p58; CC IsoId=P27448-6; Sequence=VSP_004943, VSP_004944; CC Name=6; CC IsoId=P27448-7; Sequence=VSP_041582, VSP_004943; CC Name=7; CC IsoId=P27448-8; Sequence=VSP_043197, VSP_043198; CC -!- TISSUE SPECIFICITY: Ubiquitous. CC -!- PTM: Phosphorylated at Thr-211 by STK11/LKB1 in complex with STE20- CC related adapter-alpha (STRADA) pseudo kinase and CAB39 CC (PubMed:14976552). Phosphorylation at Thr-564 by PRKCZ/aPKC inhibits CC the kinase activity (PubMed:15084291). {ECO:0000269|PubMed:14976552, CC ECO:0000269|PubMed:15084291}. CC -!- DISEASE: Visual impairment and progressive phthisis bulbi (VIPB) CC [MIM:618283]: An autosomal recessive, progressive disease characterized CC by poor vision at birth and development of bilateral phthisis bulbi by CC adulthood. {ECO:0000269|PubMed:29771303}. Note=The disease may be CC caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr CC protein kinase family. SNF1 subfamily. {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; U64205; AAC15093.1; -; mRNA. DR EMBL; AF159295; AAD48007.1; -; mRNA. DR EMBL; AF387637; AAK82367.1; -; mRNA. DR EMBL; AF465413; AAL69982.1; -; mRNA. DR EMBL; M80359; AAA59991.1; -; mRNA. DR EMBL; BX161395; CAD61882.1; -; mRNA. DR EMBL; AL133367; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF456011; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471061; EAW81813.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81815.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81817.1; -; Genomic_DNA. DR EMBL; BC024773; AAH24773.1; -; mRNA. DR EMBL; AF170723; AAD51631.1; -; mRNA. DR CCDS; CCDS41993.1; -. [P27448-3] DR CCDS; CCDS45165.1; -. [P27448-5] DR CCDS; CCDS45166.1; -. [P27448-4] DR CCDS; CCDS45167.1; -. [P27448-8] DR CCDS; CCDS55947.1; -. [P27448-6] DR PIR; S27966; S27966. DR RefSeq; NP_001122390.2; NM_001128918.2. [P27448-5] DR RefSeq; NP_001122391.2; NM_001128919.2. [P27448-4] DR RefSeq; NP_001122392.2; NM_001128920.2. [P27448-6] DR RefSeq; NP_001122393.2; NM_001128921.2. [P27448-8] DR RefSeq; NP_002367.5; NM_002376.6. [P27448-3] DR PDB; 2QNJ; X-ray; 2.70 A; A/B=48-370. DR PDB; 3FE3; X-ray; 1.90 A; A/B=41-367. DR PDB; 7P1L; X-ray; 1.95 A; A/B=48-366. DR PDBsum; 2QNJ; -. DR PDBsum; 3FE3; -. DR PDBsum; 7P1L; -. DR AlphaFoldDB; P27448; -. DR BMRB; P27448; -. DR SMR; P27448; -. DR BioGRID; 110310; 247. DR DIP; DIP-34637N; -. DR IntAct; P27448; 117. DR MINT; P27448; -. DR STRING; 9606.ENSP00000411397; -. DR BindingDB; P27448; -. DR ChEMBL; CHEMBL5600; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; P27448; -. DR GuidetoPHARMACOLOGY; 2099; -. DR GlyGen; P27448; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P27448; -. DR MetOSite; P27448; -. DR PhosphoSitePlus; P27448; -. DR BioMuta; MARK3; -. DR DMDM; 341941142; -. DR CPTAC; non-CPTAC-3196; -. DR CPTAC; non-CPTAC-3197; -. DR EPD; P27448; -. DR jPOST; P27448; -. DR MassIVE; P27448; -. DR MaxQB; P27448; -. DR PaxDb; 9606-ENSP00000411397; -. DR PeptideAtlas; P27448; -. DR ProteomicsDB; 54386; -. [P27448-5] DR ProteomicsDB; 54387; -. [P27448-2] DR ProteomicsDB; 54388; -. [P27448-3] DR ProteomicsDB; 54389; -. [P27448-4] DR ProteomicsDB; 54390; -. [P27448-6] DR ProteomicsDB; 54391; -. [P27448-7] DR ProteomicsDB; 54392; -. [P27448-8] DR Pumba; P27448; -. DR Antibodypedia; 6515; 575 antibodies from 37 providers. DR DNASU; 4140; -. DR Ensembl; ENST00000216288.11; ENSP00000216288.7; ENSG00000075413.19. [P27448-6] DR Ensembl; ENST00000303622.13; ENSP00000303698.9; ENSG00000075413.19. [P27448-3] DR Ensembl; ENST00000416682.6; ENSP00000408092.2; ENSG00000075413.19. [P27448-2] DR Ensembl; ENST00000429436.7; ENSP00000411397.2; ENSG00000075413.19. [P27448-5] DR Ensembl; ENST00000440884.7; ENSP00000402104.3; ENSG00000075413.19. [P27448-8] DR Ensembl; ENST00000553942.5; ENSP00000450772.1; ENSG00000075413.19. [P27448-4] DR GeneID; 4140; -. DR KEGG; hsa:4140; -. DR MANE-Select; ENST00000429436.7; ENSP00000411397.2; NM_001128918.3; NP_001122390.2. DR UCSC; uc001ymw.5; human. [P27448-5] DR UCSC; uc001ymy.5; human. DR UCSC; uc001ymz.5; human. DR UCSC; uc001yna.5; human. DR AGR; HGNC:6897; -. DR CTD; 4140; -. DR DisGeNET; 4140; -. DR GeneCards; MARK3; -. DR HGNC; HGNC:6897; MARK3. DR HPA; ENSG00000075413; Low tissue specificity. DR MalaCards; MARK3; -. DR MIM; 602678; gene. DR MIM; 618283; phenotype. DR neXtProt; NX_P27448; -. DR OpenTargets; ENSG00000075413; -. DR PharmGKB; PA30640; -. DR VEuPathDB; HostDB:ENSG00000075413; -. DR eggNOG; KOG0586; Eukaryota. DR GeneTree; ENSGT00940000154862; -. DR InParanoid; P27448; -. DR OMA; AKFRQGC; -. DR OrthoDB; 5475340at2759; -. DR TreeFam; TF315213; -. DR PathwayCommons; P27448; -. 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; P27448; -. DR SIGNOR; P27448; -. DR BioGRID-ORCS; 4140; 30 hits in 1203 CRISPR screens. DR ChiTaRS; MARK3; human. DR EvolutionaryTrace; P27448; -. DR GeneWiki; MARK3; -. DR GenomeRNAi; 4140; -. DR Pharos; P27448; Tchem. DR PRO; PR:P27448; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P27448; Protein. DR Bgee; ENSG00000075413; Expressed in cerebellar hemisphere and 205 other cell types or tissues. DR ExpressionAtlas; P27448; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. 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:0048156; F:tau protein binding; NAS:ARUK-UCL. DR GO; GO:0050321; F:tau-protein kinase activity; IMP:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0035331; P:negative regulation of hippo signaling; IDA:UniProtKB. DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; IDA:UniProtKB. DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:ARUK-UCL. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:ARUK-UCL. DR GO; GO:0032092; P:positive regulation of protein binding; IDA:ARUK-UCL. DR GO; GO:0006468; P:protein phosphorylation; IMP:UniProtKB. DR CDD; cd12196; MARK1-3_C; 1. DR CDD; cd14072; STKc_MARK; 1. DR CDD; cd14407; UBA_MARK3_4; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.30.310.80; Kinase associated domain 1, KA1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR028375; KA1/Ssp2_C. DR InterPro; IPR001772; KA1_dom. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR049508; MARK1-4_cat. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR015940; UBA. DR PANTHER; PTHR24346; MAP/MICROTUBULE AFFINITY-REGULATING KINASE; 1. DR PANTHER; PTHR24346:SF1; MAP_MICROTUBULE AFFINITY-REGULATING KINASE 3; 1. DR Pfam; PF02149; KA1; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF00627; UBA; 1. DR SMART; SM00220; S_TKc; 1. DR SMART; SM00165; UBA; 1. DR SUPFAM; SSF103243; KA1-like; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50032; KA1; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS50030; UBA; 1. DR Genevisible; P27448; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; KW Cell projection; Cytoplasm; Disease variant; Kinase; Membrane; KW Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase. FT CHAIN 1..753 FT /note="MAP/microtubule affinity-regulating kinase 3" FT /id="PRO_0000086304" FT DOMAIN 56..307 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 326..365 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT DOMAIN 704..753 FT /note="KA1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00565" FT REGION 1..36 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 370..600 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 632..655 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 14..28 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 370..418 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 488..548 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 578..600 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 178 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 62..70 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 85 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 42 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 211 FT /note="Phosphothreonine; by LKB1" FT /evidence="ECO:0000269|PubMed:14976552" FT MOD_RES 368 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q03141" FT MOD_RES 374 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q03141" FT MOD_RES 376 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 380 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 383 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195" FT MOD_RES 400 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 419 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 469 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 540 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 543 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q03141" FT MOD_RES 549 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 564 FT /note="Phosphothreonine; by PKC/PRKCZ" FT /evidence="ECO:0000269|PubMed:15084291" FT MOD_RES 583 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 598 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 601 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 643 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195" FT VAR_SEQ 161 FT /note="Q -> QGCQAGQTIKVQVSFDLLSLMFTF (in isoform 2 and FT isoform 6)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_041582" FT VAR_SEQ 179..257 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|Ref.6" FT /id="VSP_043197" FT VAR_SEQ 371..386 FT /note="Missing (in isoform 5 and isoform 6)" FT /evidence="ECO:0000303|Ref.10, ECO:0000303|Ref.5" FT /id="VSP_004943" FT VAR_SEQ 615..638 FT /note="Missing (in isoform 2, isoform 3 and isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9543386, ECO:0000303|Ref.2, FT ECO:0000303|Ref.5" FT /id="VSP_004944" FT VAR_SEQ 615..623 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:11433294" FT /id="VSP_004945" FT VAR_SEQ 624..638 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|Ref.6" FT /id="VSP_043198" FT VARIANT 410 FT /note="S -> F (in dbSNP:rs10137161)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_080189" FT VARIANT 429 FT /note="V -> A" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040765" FT VARIANT 443 FT /note="S -> G (in dbSNP:rs56305318)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:9543386, ECO:0000269|Ref.2" FT /id="VAR_046763" FT VARIANT 570 FT /note="R -> G (in VIPB; dbSNP:rs376395495)" FT /evidence="ECO:0000269|PubMed:29771303" FT /id="VAR_080778" FT MUTAGEN 211 FT /note="T->A: Prevents phosphorylation and activation by FT STK11/LKB1 complex." FT /evidence="ECO:0000269|PubMed:14976552" FT CONFLICT 125 FT /note="E -> Q (in Ref. 5; AAA59991)" FT /evidence="ECO:0000305" FT CONFLICT 139 FT /note="E -> K (in Ref. 4; AAL69982 and 5; AAA59991)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="R -> K (in Ref. 2; AAD48007)" FT /evidence="ECO:0000305" FT CONFLICT 425 FT /note="A -> G (in Ref. 5; AAA59991)" FT /evidence="ECO:0000305" FT CONFLICT 456 FT /note="S -> T (in Ref. 5; AAA59991)" FT /evidence="ECO:0000305" FT CONFLICT 516 FT /note="A -> D (in Ref. 5; AAA59991)" FT /evidence="ECO:0000305" FT CONFLICT 603 FT /note="N -> T (in Ref. 5; AAA59991)" FT /evidence="ECO:0000305" FT CONFLICT 645 FT /note="E -> K (in Ref. 5; AAA59991)" FT /evidence="ECO:0000305" FT STRAND 56..64 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 66..75 FT /evidence="ECO:0007829|PDB:3FE3" FT TURN 76..78 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 81..88 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 89..91 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 94..109 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 118..123 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 125..132 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 140..147 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 152..171 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 181..183 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 184..186 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 192..194 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 201..203 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 204..206 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 208..210 FT /evidence="ECO:0007829|PDB:3FE3" FT STRAND 213..215 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 216..218 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 221..225 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 232..248 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 258..267 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 278..287 FT /evidence="ECO:0007829|PDB:3FE3" FT TURN 292..294 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 298..301 FT /evidence="ECO:0007829|PDB:3FE3" FT TURN 305..310 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 329..337 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 342..350 FT /evidence="ECO:0007829|PDB:3FE3" FT HELIX 356..364 FT /evidence="ECO:0007829|PDB:3FE3" FT MOD_RES P27448-6:384 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES P27448-7:407 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" SQ SEQUENCE 753 AA; 84429 MW; B50B3C145E896B0B CRC64; MSTRTPLPTV NERDTENHTS HGDGRQEVTS RTSRSGARCR NSIASCADEQ PHIGNYRLLK TIGKGNFAKV KLARHILTGR EVAIKIIDKT QLNPTSLQKL FREVRIMKIL NHPNIVKLFE VIETEKTLYL IMEYASGGEV FDYLVAHGRM KEKEARSKFR QIVSAVQYCH QKRIVHRDLK AENLLLDADM NIKIADFGFS NEFTVGGKLD TFCGSPPYAA PELFQGKKYD GPEVDVWSLG VILYTLVSGS LPFDGQNLKE LRERVLRGKY RIPFYMSTDC ENLLKRFLVL NPIKRGTLEQ IMKDRWINAG HEEDELKPFV EPELDISDQK RIDIMVGMGY SQEEIQESLS KMKYDEITAT YLLLGRKSSE LDASDSSSSS NLSLAKVRPS SDLNNSTGQS PHHKVQRSVS SSQKQRRYSD HAGPAIPSVV AYPKRSQTST ADSDLKEDGI SSRKSSGSAV GGKGIAPASP MLGNASNPNK ADIPERKKSS TVPSSNTASG GMTRRNTYVC SERTTADRHS VIQNGKENST IPDQRTPVAS THSISSAATP DRIRFPRGTA SRSTFHGQPR ERRTATYNGP PASPSLSHEA TPLSQTRSRG STNLFSKLTS KLTRRNMSFR FIKRLPTEYE RNGRYEGSSR NVSAEQKDEN KEAKPRSLRF TWSMKTTSSM DPGDMMREIR KVLDANNCDY EQRERFLLFC VHGDGHAENL VQWEMEVCKL PRLSLNGVRF KRISGTSIAF KNIASKIANE LKL //