ID STK4_HUMAN Reviewed; 487 AA. AC Q13043; B2RCR8; Q15802; Q4G156; Q5H982; Q6PD60; Q9BR32; Q9NTZ4; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 21-FEB-2001, sequence version 2. DT 27-MAR-2024, entry version 229. DE RecName: Full=Serine/threonine-protein kinase 4; DE EC=2.7.11.1; DE AltName: Full=Mammalian STE20-like protein kinase 1; DE Short=MST-1; DE AltName: Full=STE20-like kinase MST1; DE AltName: Full=Serine/threonine-protein kinase Krs-2; DE Contains: DE RecName: Full=Serine/threonine-protein kinase 4 37kDa subunit; DE Short=MST1/N; DE Contains: DE RecName: Full=Serine/threonine-protein kinase 4 18kDa subunit; DE Short=MST1/C; GN Name=STK4; Synonyms=KRS2, MST1; 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 1), AND VARIANT MET-312. RX PubMed=7665586; DOI=10.1074/jbc.270.37.21695; RA Creasy C.L., Chernoff J.; RT "Cloning and characterization of a human protein kinase with homology to RT Ste20."; RL J. Biol. Chem. 270:21695-21700(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=8816758; DOI=10.1073/pnas.93.19.10099; RA Taylor L.K., Wang H.C., Erikson R.L.; RT "Newly identified stress-responsive protein kinases, Krs-1 and Krs-2."; RL Proc. Natl. Acad. Sci. U.S.A. 93:10099-10104(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [5] 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Bone, Brain, and Liver; 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 PROTEIN SEQUENCE OF 1-7; 16-94; 118-144; 152-181; 232-259; 270-282; RP 292-301; 333-342; 384-402; 405-413; 421-465 AND 470-481, ACETYLATION AT RP MET-1, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Mammary carcinoma; RA Bienvenut W.V., Matallanas D., Cooper W.N., Kolch W.; RL Submitted (JUL-2007) to UniProtKB. RN [8] RP FUNCTION, HOMODIMERIZATION, AND ACTIVITY REGULATION. RX PubMed=8702870; DOI=10.1074/jbc.271.35.21049; RA Creasy C.L., Ambrose D.M., Chernoff J.; RT "The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory RT domain."; RL J. Biol. Chem. 271:21049-21053(1996). RN [9] RP FUNCTION, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASP-326 AND ASP-349. RX PubMed=11278283; DOI=10.1074/jbc.m005109200; RA Lee K.-K., Ohyama T., Yajima N., Tsubuki S., Yonehara S.; RT "MST, a physiological caspase substrate, highly sensitizes apoptosis both RT upstream and downstream of caspase activation."; RL J. Biol. Chem. 276:19276-19285(2001). RN [10] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=11517310; DOI=10.1073/pnas.181161698; RA Ura S., Masuyama N., Graves J.D., Gotoh Y.; RT "Caspase cleavage of MST1 promotes nuclear translocation and chromatin RT condensation."; RL Proc. Natl. Acad. Sci. U.S.A. 98:10148-10153(2001). RN [11] RP FUNCTION IN PHOSPHORYLATION OF HISTONE H2B. RX PubMed=12757711; DOI=10.1016/s0092-8674(03)00355-6; RA Cheung W.L., Ajiro K., Samejima K., Kloc M., Cheung P., Mizzen C.A., RA Beeser A., Etkin L.D., Chernoff J., Earnshaw W.C., Allis C.D.; RT "Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile RT twenty kinase."; RL Cell 113:507-517(2003). RN [12] RP FUNCTION, ACTIVITY REGULATION, HOMODIMERIZATION, PHOSPHORYLATION AT RP THR-183, MUTAGENESIS OF LYS-59; THR-175; THR-177; THR-183 AND LEU-444, AND RP INTERACTION WITH RASSF1 AND NORE1. RX PubMed=15109305; DOI=10.1042/bj20040025; RA Praskova M., Khoklatchev A., Ortiz-Vega S., Avruch J.; RT "Regulation of the MST1 kinase by autophosphorylation, by the growth RT inhibitory proteins, RASSF1 and NORE1, and by Ras."; RL Biochem. J. 381:453-462(2004). RN [13] RP FUNCTION, AND INTERACTION WITH RASSF1. RX PubMed=16510573; DOI=10.1158/0008-5472.can-05-2951; RA Oh H.J., Lee K.-K., Song S.J., Jin M.S., Song M.S., Lee J.H., Im C.R., RA Lee J.-O., Yonehara S., Lim D.-S.; RT "Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis."; RL Cancer Res. 66:2562-2569(2006). RN [14] RP FUNCTION, AND INTERACTION WITH FOXO3. RX PubMed=16751106; DOI=10.1016/j.cell.2006.03.046; RA Lehtinen M.K., Yuan Z., Boag P.R., Yang Y., Villen J., Becker E.B.E., RA DiBacco S., de la Iglesia N., Gygi S.P., Blackwell T.K., Bonni A.; RT "A conserved MST-FOXO signaling pathway mediates oxidative-stress responses RT and extends life span."; RL Cell 125:987-1001(2006). RN [15] RP INTERACTION WITH SAV1, FUNCTION, AND MUTAGENESIS OF LYS-59. RX PubMed=16930133; DOI=10.1111/j.1742-4658.2006.05427.x; RA Callus B.A., Verhagen A.M., Vaux D.L.; RT "Association of mammalian sterile twenty kinases, Mst1 and Mst2, with RT hSalvador via C-terminal coiled-coil domains, leads to its stabilization RT and phosphorylation."; RL FEBS J. 273:4264-4276(2006). RN [16] RP FUNCTION, INTERACTION WITH PKB/AKT1, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=17932490; DOI=10.1038/sj.emboj.7601872; RA Cinar B., Fang P.K., Lutchman M., Di Vizio D., Adam R.M., Pavlova N., RA Rubin M.A., Yelick P.C., Freeman M.R.; RT "The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct RT inhibitors of Akt1."; RL EMBO J. 26:4523-4534(2007). RN [17] RP PHOSPHORYLATION AT THR-387, AND INTERACTION WITH PKB/AKT1. RX PubMed=17726016; DOI=10.1074/jbc.m704542200; RA Jang S.W., Yang S.J., Srinivasan S., Ye K.; RT "Akt phosphorylates MstI and prevents its proteolytic activation, blocking RT FOXO3 phosphorylation and nuclear translocation."; RL J. Biol. Chem. 282:30836-30844(2007). RN [18] RP FUNCTION. RX PubMed=18328708; DOI=10.1016/j.cub.2008.02.006; RA Praskova M., Xia F., Avruch J.; RT "MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell RT proliferation."; RL Curr. Biol. 18:311-321(2008). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-265; SER-320 AND THR-340, AND RP IDENTIFICATION 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 [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY RP 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 [21] RP REVIEW. RX PubMed=19484742; DOI=10.1002/biof.47; RA Hergovich A., Hemmings B.A.; RT "Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling."; RL BioFactors 35:338-345(2009). RN [22] RP FUNCTION, AND INTERACTION WITH TNNI3. RX PubMed=18986304; DOI=10.1042/bj20081340; RA You B., Yan G., Zhang Z., Yan L., Li J., Ge Q., Jin J.P., Sun J.; RT "Phosphorylation of cardiac troponin I by mammalian sterile 20-like kinase RT 1."; RL Biochem. J. 418:93-101(2009). RN [23] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT THR-3; SER-320; THR-340; THR-367; SER-410 AND SER-414, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [24] RP FUNCTION, INTERACTION WITH RASSF2, AND SUBCELLULAR LOCATION. RX PubMed=19525978; DOI=10.1038/onc.2009.152; RA Cooper W.N., Hesson L.B., Matallanas D., Dallol A., von Kriegsheim A., RA Ward R., Kolch W., Latif F.; RT "RASSF2 associates with and stabilizes the proapoptotic kinase MST2."; RL Oncogene 28:2988-2998(2009). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [26] RP RETRACTED PAPER. RX PubMed=19940129; DOI=10.1074/jbc.m109.059675; RA Yuan Z., Kim D., Shu S., Wu J., Guo J., Xiao L., Kaneko S., Coppola D., RA Cheng J.Q.; RT "Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic RT signaling through phosphorylation of threonine 120."; RL J. Biol. Chem. 285:3815-3824(2010). RN [27] RP CAUTION, AND RETRACTION NOTICE OF PUBMED:19940129. RX PubMed=27825096; DOI=10.1074/jbc.a109.059675; RA Yuan Z., Kim D., Shu S., Wu J., Guo J., Xiao L., Kaneko S., Coppola D., RA Cheng J.Q.; RL J. Biol. Chem. 291:22858-22858(2016). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [29] 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 [30] RP FUNCTION. RX PubMed=21245099; DOI=10.1158/0008-5472.can-10-2203; RA Valis K., Prochazka L., Boura E., Chladova J., Obsil T., Rohlena J., RA Truksa J., Dong L.F., Ralph S.J., Neuzil J.; RT "Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a RT FoxO1-dependent manner."; RL Cancer Res. 71:946-954(2011). RN [31] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH AR. RX PubMed=21512132; DOI=10.1158/0008-5472.can-10-4532; RA Cinar B., Collak F.K., Lopez D., Akgul S., Mukhopadhyay N.K., RA Kilicarslan M., Gioeli D.G., Freeman M.R.; RT "MST1 is a multifunctional caspase-independent inhibitor of androgenic RT signaling."; RL Cancer Res. 71:4303-4313(2011). RN [32] RP INTERACTION WITH RASSF1, AND ACTIVITY REGULATION. RX PubMed=21199877; DOI=10.1074/jbc.m110.178210; RA Guo C., Zhang X., Pfeifer G.P.; RT "The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian RT STE20-like kinases MST1 and MST2."; RL J. Biol. Chem. 286:6253-6261(2011). RN [33] RP FUNCTION, AND INTERACTION WITH SIRT1. RX PubMed=21212262; DOI=10.1074/jbc.m110.182543; RA Yuan F., Xie Q., Wu J., Bai Y., Mao B., Dong Y., Bi W., Ji G., Tao W., RA Wang Y., Yuan Z.; RT "MST1 promotes apoptosis through regulating Sirt1-dependent p53 RT deacetylation."; RL J. Biol. Chem. 286:6940-6945(2011). RN [34] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, 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 [35] RP INVOLVEMENT IN IMD110. RX PubMed=22294732; DOI=10.1182/blood-2011-09-378158; RA Abdollahpour H., Appaswamy G., Kotlarz D., Diestelhorst J., Beier R., RA Schaffer A.A., Gertz E.M., Schambach A., Kreipe H.H., Pfeifer D., RA Engelhardt K.R., Rezaei N., Grimbacher B., Lohrmann S., Sherkat R., RA Klein C.; RT "The phenotype of human STK4 deficiency."; RL Blood 119:3450-3457(2012). RN [36] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [37] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-340; THR-387; SER-410 AND RP SER-414, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=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 [39] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY RP 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 [40] RP INTERACTION WITH MARK3 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 [41] RP INTERACTION WITH SCRIB. RX PubMed=28169360; DOI=10.1038/srep42125; RA Liu J., Li J., Li P., Wang Y., Liang Z., Jiang Y., Li J., Feng C., Wang R., RA Chen H., Zhou C., Zhang J., Yang J., Liu P.; RT "Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo RT signaling pathway."; RL Sci. Rep. 7:42125-42125(2017). RN [42] RP VARIANTS [LARGE SCALE ANALYSIS] ASN-162; GLN-310; MET-312; THR-355 AND RP LEU-416. 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: Stress-activated, pro-apoptotic kinase which, following CC caspase-cleavage, enters the nucleus and induces chromatin condensation CC followed by internucleosomal DNA fragmentation. Key component of the CC Hippo signaling pathway which plays a pivotal role in organ size CC control and tumor suppression by restricting proliferation and CC promoting apoptosis. The core of this pathway is composed of a kinase CC cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory CC protein SAV1, phosphorylates and activates LATS1/2 in complex with its CC regulatory protein MOB1, which in turn phosphorylates and inactivates CC YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 CC inhibits its translocation into the nucleus to regulate cellular genes CC important for cell proliferation, cell death, and cell migration. CC STK3/MST2 and STK4/MST1 are required to repress proliferation of mature CC hepatocytes, to prevent activation of facultative adult liver stem CC cells (oval cells), and to inhibit tumor formation (By similarity). CC Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. CC Phosphorylates FOXO3 upon oxidative stress, which results in its CC nuclear translocation and cell death initiation. Phosphorylates CC MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and CC alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac CC Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation CC and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. CC Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 CC deacetylation, thereby promoting p53/TP53 dependent transcription and CC apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. CC Phosphorylates AR on 'Ser-650' and suppresses its activity by CC intersecting with PKB/AKT1 signaling and antagonizing formation of AR- CC chromatin complexes. {ECO:0000250|UniProtKB:Q9JI11, CC ECO:0000269|PubMed:11278283, ECO:0000269|PubMed:11517310, CC ECO:0000269|PubMed:12757711, ECO:0000269|PubMed:15109305, CC ECO:0000269|PubMed:16510573, ECO:0000269|PubMed:16751106, CC ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:17932490, CC ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18986304, CC ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:21212262, CC ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:21512132, CC ECO:0000269|PubMed:8702870, ECO:0000269|PubMed:8816758}. 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 -!- 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; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC -!- ACTIVITY REGULATION: Inhibited by the C-terminal non-catalytic region. CC Activated by caspase-cleavage. Full activation also requires CC homodimerization and autophosphorylation of Thr-183. Activated by CC RASSF1 which acts by preventing its dephosphorylation. CC {ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:21199877, CC ECO:0000269|PubMed:8702870}. CC -!- SUBUNIT: Homodimer; mediated via the coiled-coil region. Interacts with CC NORE1, which inhibits autoactivation. Interacts with and stabilizes CC SAV1. Interacts with RASSF1. Interacts with FOXO3. Interacts with CC RASSF2 (via SARAH domain). Interacts with AR, PKB/AKT1, TNNI3 and CC SIRT1. Interacts with DLG5 (via PDZ domain 3). Interacts with MARK3 in CC the presence of DLG5 (PubMed:28087714). Interacts with SCRIB in the CC presence of DLG5 (PubMed:28169360). {ECO:0000250|UniProtKB:Q13188, CC ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:16510573, CC ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:16930133, CC ECO:0000269|PubMed:17726016, ECO:0000269|PubMed:17932490, CC ECO:0000269|PubMed:18986304, ECO:0000269|PubMed:19525978, CC ECO:0000269|PubMed:21199877, ECO:0000269|PubMed:21212262, CC ECO:0000269|PubMed:21512132, ECO:0000269|PubMed:28087714, CC ECO:0000269|PubMed:28169360}. CC -!- INTERACTION: CC Q13043; P31749: AKT1; NbExp=13; IntAct=EBI-367376, EBI-296087; CC Q13043; O95166: GABARAP; NbExp=2; IntAct=EBI-367376, EBI-712001; CC Q13043; Q9H0R8: GABARAPL1; NbExp=2; IntAct=EBI-367376, EBI-746969; CC Q13043; P60520: GABARAPL2; NbExp=2; IntAct=EBI-367376, EBI-720116; CC Q13043; Q9GZQ8: MAP1LC3B; NbExp=7; IntAct=EBI-367376, EBI-373144; CC Q13043; Q9H8S9: MOB1A; NbExp=9; IntAct=EBI-367376, EBI-748229; CC Q13043; Q7L9L4: MOB1B; NbExp=4; IntAct=EBI-367376, EBI-2558745; CC Q13043; Q06830: PRDX1; NbExp=11; IntAct=EBI-367376, EBI-353193; CC Q13043; Q9NS23-2: RASSF1; NbExp=4; IntAct=EBI-367376, EBI-438698; CC Q13043; P50749: RASSF2; NbExp=16; IntAct=EBI-367376, EBI-960081; CC Q13043; Q86WH2: RASSF3; NbExp=6; IntAct=EBI-367376, EBI-2845202; CC Q13043; Q9H2L5: RASSF4; NbExp=6; IntAct=EBI-367376, EBI-2933362; CC Q13043; Q8WWW0: RASSF5; NbExp=8; IntAct=EBI-367376, EBI-367390; CC Q13043; Q8WWW0-2: RASSF5; NbExp=4; IntAct=EBI-367376, EBI-960502; CC Q13043; Q8WWW0-3: RASSF5; NbExp=2; IntAct=EBI-367376, EBI-960507; CC Q13043; Q6ZTQ3: RASSF6; NbExp=4; IntAct=EBI-367376, EBI-2933412; CC Q13043; Q9H4B6: SAV1; NbExp=19; IntAct=EBI-367376, EBI-1017775; CC Q13043; Q14BN4: SLMAP; NbExp=7; IntAct=EBI-367376, EBI-1043216; CC Q13043; Q13188: STK3; NbExp=19; IntAct=EBI-367376, EBI-992580; CC Q13043; Q13043: STK4; NbExp=4; IntAct=EBI-367376, EBI-367376; CC Q13043; P35700: Prdx1; Xeno; NbExp=3; IntAct=EBI-367376, EBI-444948; CC Q13043; Q91VJ4: Stk38; Xeno; NbExp=2; IntAct=EBI-367376, EBI-2527046; CC Q13043-1; Q8WWW0-1: RASSF5; NbExp=3; IntAct=EBI-15638366, EBI-960496; CC Q13043-1; Q9H4B6: SAV1; NbExp=2; IntAct=EBI-15638366, EBI-1017775; CC Q13043-1; Q13043-1: STK4; NbExp=4; IntAct=EBI-15638366, EBI-15638366; CC Q13043-2; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-14280485, EBI-742054; CC Q13043-2; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-14280485, EBI-79165; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=The caspase-cleaved form CC cycles between the nucleus and cytoplasm. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13043-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13043-2; Sequence=VSP_019851, VSP_019852; CC -!- TISSUE SPECIFICITY: Expressed in prostate cancer and levels increase CC from the normal to the malignant state (at protein level). Ubiquitously CC expressed. {ECO:0000269|PubMed:17932490}. CC -!- INDUCTION: Activity increases during mitosis. CC -!- PTM: Autophosphorylated on serine and threonine residues. CC Phosphorylation at Thr-387 by PKB/AKT1, leads to inhibition of its: CC kinase activity, nuclear translocation and autophosphorylation at Thr- CC 183. It also diminishes its cleavage by caspases and its ability to CC phosphorylate FOXO3. {ECO:0000269|PubMed:11278283, CC ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:17726016, CC ECO:0000269|PubMed:19940129}. CC -!- PTM: Proteolytically cleaved by caspase-3 during apoptosis at Asp-326 CC and Asp-349 resulting in a 37 kDa or a 39 kDa subunit respectively. The CC 39 kDa subunit is further cleaved into the 37 kDa form. Proteolytic CC cleavage results in kinase activation and nuclear translocation of the CC truncated form (MST1/N). It is less likely that cleavage at Asp-349 is CC a prerequisite for activation as this site is not conserved in the CC murine ortholog. {ECO:0000269|PubMed:11278283}. CC -!- DISEASE: Immunodeficiency 110 with lymphoproliferation (IMD110) CC [MIM:614868]: An autosomal recessive, primary T-cell immunodeficiency CC syndrome characterized by progressive loss of naive T-cells, recurrent CC bacterial, viral, and fungal infections, warts, and abscesses, CC autoimmune manifestations, and cardiac malformations, including atrial CC septal defect. Patients are at risk for developing lymphoproliferative CC disorders or lymphoma. {ECO:0000269|PubMed:22294732}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr CC protein kinase family. STE20 subfamily. {ECO:0000305}. CC -!- CAUTION: Was originally thought to be phosphorylated at Thr-120 CC (PubMed:19940129). However, this work has been retracted CC (PubMed:27825096). {ECO:0000269|PubMed:19940129, CC ECO:0000305|PubMed:27825096}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH29511.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=AAH58916.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/42440/STK4"; 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; U18297; AAA83254.1; -; mRNA. DR EMBL; U60207; AAB17262.1; -; mRNA. DR EMBL; AK315238; BAG37665.1; -; mRNA. DR EMBL; Z93016; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL109839; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471077; EAW75882.1; -; Genomic_DNA. DR EMBL; BC029511; AAH29511.1; ALT_SEQ; mRNA. DR EMBL; BC058916; AAH58916.1; ALT_SEQ; mRNA. DR EMBL; BC093768; AAH93768.1; -; mRNA. DR CCDS; CCDS13341.1; -. [Q13043-1] DR CCDS; CCDS86957.1; -. [Q13043-2] DR RefSeq; NP_006273.1; NM_006282.3. [Q13043-1] DR RefSeq; XP_005260590.1; XM_005260533.2. DR PDB; 2JO8; NMR; -; A/B=432-480. DR PDB; 3COM; X-ray; 2.20 A; A/B=2-311. DR PDB; 4NR2; X-ray; 2.00 A; A/B/C/D/E/F/G/H=432-480. DR PDB; 4OH8; X-ray; 2.28 A; A=432-480. DR PDB; 5TWG; X-ray; 2.30 A; E=343-356. DR PDB; 5TWH; X-ray; 2.50 A; E=358-374. DR PDB; 6YAT; X-ray; 2.58 A; A/B=1-311. DR PDB; 8A5J; X-ray; 2.12 A; A/B=28-309. DR PDBsum; 2JO8; -. DR PDBsum; 3COM; -. DR PDBsum; 4NR2; -. DR PDBsum; 4OH8; -. DR PDBsum; 5TWG; -. DR PDBsum; 5TWH; -. DR PDBsum; 6YAT; -. DR PDBsum; 8A5J; -. DR AlphaFoldDB; Q13043; -. DR SMR; Q13043; -. DR BioGRID; 112665; 159. DR CORUM; Q13043; -. DR DIP; DIP-32491N; -. DR ELM; Q13043; -. DR IntAct; Q13043; 189. DR MINT; Q13043; -. DR STRING; 9606.ENSP00000361892; -. DR BindingDB; Q13043; -. DR ChEMBL; CHEMBL4598; -. DR DrugCentral; Q13043; -. DR GuidetoPHARMACOLOGY; 2225; -. DR iPTMnet; Q13043; -. DR MetOSite; Q13043; -. DR PhosphoSitePlus; Q13043; -. DR BioMuta; STK4; -. DR DMDM; 13124559; -. DR EPD; Q13043; -. DR jPOST; Q13043; -. DR MassIVE; Q13043; -. DR MaxQB; Q13043; -. DR PaxDb; 9606-ENSP00000361892; -. DR PeptideAtlas; Q13043; -. DR ProteomicsDB; 59119; -. [Q13043-1] DR ProteomicsDB; 59120; -. [Q13043-2] DR Pumba; Q13043; -. DR Antibodypedia; 3325; 607 antibodies from 42 providers. DR DNASU; 6789; -. DR Ensembl; ENST00000372801.5; ENSP00000361887.1; ENSG00000101109.13. [Q13043-2] DR Ensembl; ENST00000372806.8; ENSP00000361892.3; ENSG00000101109.13. [Q13043-1] DR GeneID; 6789; -. DR KEGG; hsa:6789; -. DR MANE-Select; ENST00000372806.8; ENSP00000361892.3; NM_006282.5; NP_006273.1. DR UCSC; uc002xnb.4; human. [Q13043-1] DR AGR; HGNC:11408; -. DR CTD; 6789; -. DR DisGeNET; 6789; -. DR GeneCards; STK4; -. DR HGNC; HGNC:11408; STK4. DR HPA; ENSG00000101109; Tissue enhanced (bone marrow, lymphoid tissue). DR MalaCards; STK4; -. DR MIM; 604965; gene. DR MIM; 614868; phenotype. DR neXtProt; NX_Q13043; -. DR OpenTargets; ENSG00000101109; -. DR Orphanet; 314689; Combined immunodeficiency due to STK4 deficiency. DR PharmGKB; PA36215; -. DR VEuPathDB; HostDB:ENSG00000101109; -. DR eggNOG; KOG0574; Eukaryota. DR GeneTree; ENSGT00940000159787; -. DR InParanoid; Q13043; -. DR OMA; INFMKQC; -. DR OrthoDB; 152877at2759; -. DR PhylomeDB; Q13043; -. DR TreeFam; TF354217; -. DR BRENDA; 2.7.11.1; 2681. DR PathwayCommons; Q13043; -. DR Reactome; R-HSA-2028269; Signaling by Hippo. DR SignaLink; Q13043; -. DR SIGNOR; Q13043; -. DR BioGRID-ORCS; 6789; 14 hits in 1192 CRISPR screens. DR ChiTaRS; STK4; human. DR EvolutionaryTrace; Q13043; -. DR GeneWiki; STK4; -. DR GenomeRNAi; 6789; -. DR Pharos; Q13043; Tchem. DR PRO; PR:Q13043; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; Q13043; Protein. DR Bgee; ENSG00000101109; Expressed in colonic epithelium and 190 other cell types or tissues. DR ExpressionAtlas; Q13043; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IDA:MGI. DR GO; GO:0004672; F:protein kinase activity; IGI:MGI. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; TAS:BHF-UCL. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IDA:UniProtKB. DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; IEA:Ensembl. DR GO; GO:0060070; P:canonical Wnt signaling pathway; IEA:Ensembl. DR GO; GO:0060706; P:cell differentiation involved in embryonic placenta development; IEA:Ensembl. DR GO; GO:0000902; P:cell morphogenesis; IDA:MGI. DR GO; GO:0007417; P:central nervous system development; IEA:Ensembl. DR GO; GO:0003157; P:endocardium development; IEA:Ensembl. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl. DR GO; GO:0097284; P:hepatocyte apoptotic process; IEA:Ensembl. DR GO; GO:0035329; P:hippo signaling; IDA:BHF-UCL. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:BHF-UCL. DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0046621; P:negative regulation of organ growth; IEA:Ensembl. DR GO; GO:0001841; P:neural tube formation; IEA:Ensembl. DR GO; GO:0035265; P:organ growth; IEA:Ensembl. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:1902043; P:positive regulation of extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl. DR GO; GO:0045600; P:positive regulation of fat cell differentiation; IEA:Ensembl. DR GO; GO:1903945; P:positive regulation of hepatocyte apoptotic process; IEA:Ensembl. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:MGI. DR GO; GO:0032092; P:positive regulation of protein binding; IDA:MGI. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:MGI. DR GO; GO:1904237; P:positive regulation of substrate-dependent cell migration, cell attachment to substrate; IEA:Ensembl. DR GO; GO:0060215; P:primitive hemopoiesis; IEA:Ensembl. DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI. DR GO; GO:0006606; P:protein import into nucleus; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IDA:MGI. DR GO; GO:0051262; P:protein tetramerization; IEA:InterPro. DR GO; GO:0060800; P:regulation of cell differentiation involved in embryonic placenta development; IEA:Ensembl. DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd21887; SARAH_MST1; 1. DR CDD; cd06612; STKc_MST1_2; 1. DR Gene3D; 1.10.287.4270; -; 1. DR Gene3D; 4.10.170.10; p53-like tetramerisation domain; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00168; -. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR024205; Mst1_2_SARAH_domain. DR InterPro; IPR036674; p53_tetramer_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR011524; SARAH_dom. DR PANTHER; PTHR48015; SERINE/THREONINE-PROTEIN KINASE TAO; 1. DR PANTHER; PTHR48015:SF32; SERINE_THREONINE-PROTEIN KINASE 4; 1. DR Pfam; PF11629; Mst1_SARAH; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS50951; SARAH; 1. DR Genevisible; Q13043; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; KW Coiled coil; Cytoplasm; Direct protein sequencing; Kinase; Magnesium; KW Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein; KW Reference proteome; Serine/threonine-protein kinase; Transferase. FT CHAIN 1..487 FT /note="Serine/threonine-protein kinase 4" FT /id="PRO_0000086691" FT CHAIN 1..326 FT /note="Serine/threonine-protein kinase 4 37kDa subunit" FT /id="PRO_0000413735" FT CHAIN 327..487 FT /note="Serine/threonine-protein kinase 4 18kDa subunit" FT /id="PRO_0000413736" FT DOMAIN 30..281 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 433..480 FT /note="SARAH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00310" FT REGION 303..332 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 290..310 FT /evidence="ECO:0000255" FT ACT_SITE 149 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 36..44 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 59 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT SITE 326..327 FT /note="Cleavage; by caspase-3" FT SITE 349..350 FT /note="Cleavage; by caspase-3" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|Ref.7, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378" FT MOD_RES 3 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 183 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:15109305" FT MOD_RES 265 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 320 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:24275569" FT MOD_RES 340 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163" FT MOD_RES 367 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 387 FT /note="Phosphothreonine; by PKB/AKT1" FT /evidence="ECO:0000269|PubMed:17726016, FT ECO:0007744|PubMed:23186163" FT MOD_RES 410 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:23186163" FT MOD_RES 414 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:23186163" FT MOD_RES 433 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q9JI11" FT VAR_SEQ 436..462 FT /note="LKSWTVEDLQKRLLALDPMMEQEIEEI -> KTSQEQQSGKDICIQNCQGNL FT LCRYAF (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_019851" FT VAR_SEQ 463..487 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_019852" FT VARIANT 162 FT /note="H -> N (in dbSNP:rs55850759)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041123" FT VARIANT 310 FT /note="R -> Q (in dbSNP:rs35447878)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041124" FT VARIANT 312 FT /note="V -> M (in dbSNP:rs17420378)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:7665586" FT /id="VAR_027040" FT VARIANT 355 FT /note="I -> T (in dbSNP:rs35944046)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041125" FT VARIANT 416 FT /note="P -> L (in dbSNP:rs33963346)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041126" FT MUTAGEN 59 FT /note="K->R: Loss of activity." FT /evidence="ECO:0000269|PubMed:15109305, FT ECO:0000269|PubMed:16930133" FT MUTAGEN 175 FT /note="T->A: No effect on activity." FT /evidence="ECO:0000269|PubMed:15109305" FT MUTAGEN 177 FT /note="T->A: No effect on activity." FT /evidence="ECO:0000269|PubMed:15109305" FT MUTAGEN 183 FT /note="T->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:15109305" FT MUTAGEN 326 FT /note="D->N: Resistant to proteolytic cleavage by caspase FT during apoptosis; when associated with N-349." FT /evidence="ECO:0000269|PubMed:11278283" FT MUTAGEN 349 FT /note="D->N: Resistant to proteolytic cleavage by caspase FT during apoptosis; when associated with N-326." FT /evidence="ECO:0000269|PubMed:11278283" FT MUTAGEN 444 FT /note="L->P: Loss of homodimerization, activation, and FT autophosphorylation." FT /evidence="ECO:0000269|PubMed:15109305" FT CONFLICT 222 FT /note="P -> R (in Ref. 1; AAA83254)" FT /evidence="ECO:0000305" FT HELIX 19..22 FT /evidence="ECO:0007829|PDB:3COM" FT HELIX 26..29 FT /evidence="ECO:0007829|PDB:6YAT" FT STRAND 30..35 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 44..49 FT /evidence="ECO:0007829|PDB:8A5J" FT TURN 50..52 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 55..61 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 67..78 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 88..94 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 97..103 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 110..117 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 123..142 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 152..154 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 155..157 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 163..165 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 188..190 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 193..196 FT /evidence="ECO:0007829|PDB:8A5J" FT STRAND 197..199 FT /evidence="ECO:0007829|PDB:3COM" FT HELIX 205..219 FT /evidence="ECO:0007829|PDB:8A5J" FT TURN 223..226 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 229..235 FT /evidence="ECO:0007829|PDB:8A5J" FT TURN 236..238 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 247..249 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 252..261 FT /evidence="ECO:0007829|PDB:8A5J" FT TURN 266..268 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 272..275 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 279..282 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 287..290 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 291..307 FT /evidence="ECO:0007829|PDB:8A5J" FT HELIX 433..436 FT /evidence="ECO:0007829|PDB:4NR2" FT HELIX 441..478 FT /evidence="ECO:0007829|PDB:4NR2" SQ SEQUENCE 487 AA; 55630 MW; 150758EBC5F77D5C CRC64; METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK ETGQIVAIKQ VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI VMEYCGAGSV SDIIRLRNKT LTEDEIATIL QSTLKGLEYL HFMRKIHRDI KAGNILLNTE GHAKLADFGV AGQLTDTMAK RNTVIGTPFW MAPEVIQEIG YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP PPTFRKPELW SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VRSAKGVSIL RDLINEAMDV KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT LPSQLGTMVI NAEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK NSSDWKIPQD GDYEFLKSWT VEDLQKRLLA LDPMMEQEIE EIRQKYQSKR QPILDAIEAK KRRQQNF //