ID KS6A4_HUMAN Reviewed; 772 AA. AC O75676; A8K7Z8; O75585; Q53ES8; DT 24-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 27-MAR-2024, entry version 211. DE RecName: Full=Ribosomal protein S6 kinase alpha-4; DE Short=S6K-alpha-4; DE EC=2.7.11.1; DE AltName: Full=90 kDa ribosomal protein S6 kinase 4; DE AltName: Full=Nuclear mitogen- and stress-activated protein kinase 2; DE AltName: Full=Ribosomal protein kinase B; DE Short=RSKB; GN Name=RPS6KA4; Synonyms=MSK2; 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 {ECO:0000312|EMBL:CAA09009.1}; RN [1] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, ACTIVITY REGULATION, RP INTERACTION WITH MAPK14; MAPK1 AND MAPK3, AND SUBCELLULAR LOCATION. RC TISSUE=Placenta {ECO:0000312|EMBL:CAA09009.1}; RX PubMed=9792677; DOI=10.1074/jbc.273.45.29661; RA Pierrat B., Correia J.D.S., Mary J.L., Tomas-Zuber M., Lesslauer W.; RT "RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under RT dominant control of p38alpha mitogen-activated protein kinase RT (p38alphaMAPK)."; RL J. Biol. Chem. 273:29661-29671(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Synovium; 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ALA-758. RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [4] 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 [5] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] OF 17-727 (ISOFORM 2). RX PubMed=9687510; DOI=10.1093/emboj/17.15.4426; RA Deak M., Clifton A.D., Lucocq J.M., Alessi D.R.; RT "Mitogen- and stress-activated protein kinase-1 (MSK1) is directly RT activated by MAPK and SAPK2/p38, and may mediate activation of CREB."; RL EMBO J. 17:4426-4441(1998). RN [6] RP FUNCTION, INTERACTION WITH MAPK14, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP PHE-709. RX PubMed=11035004; DOI=10.1074/jbc.m005822200; RA Tomas-Zuber M., Mary J.L., Lamour F., Bur D., Lesslauer W.; RT "C-terminal elements control location, activation threshold, and p38 RT docking of ribosomal S6 kinase B (RSKB)."; RL J. Biol. Chem. 276:5892-5899(2001). RN [7] RP FUNCTION IN PHOSPHORYLATION OF HISTONE H3 AND HMGN1/HMG14. RX PubMed=12773393; DOI=10.1093/emboj/cdg273; RA Soloaga A., Thomson S., Wiggin G.R., Rampersaud N., Dyson M.H., RA Hazzalin C.A., Mahadevan L.C., Arthur J.S.; RT "MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of RT histone H3 and HMG-14."; RL EMBO J. 22:2788-2797(2003). RN [8] RP REVIEW ON FUNCTION. RX PubMed=18508628; DOI=10.2741/3122; RA Arthur J.S.; RT "MSK activation and physiological roles."; RL Front. Biosci. 13:5866-5879(2008). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-347; SER-634; SER-678; RP THR-687 AND SER-745, 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 [10] 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 [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-347; THR-542 AND THR-687, 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 [12] RP REVIEW ON FUNCTION. RX PubMed=19464896; DOI=10.1016/j.tibs.2009.02.007; RA Vermeulen L., Vanden Berghe W., Beck I.M., De Bosscher K., Haegeman G.; RT "The versatile role of MSKs in transcriptional regulation."; RL Trends Biochem. Sci. 34:311-318(2009). RN [13] RP IDENTIFICATION BY 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 [14] RP IDENTIFICATION BY MASS 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 [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-347; THR-542 AND THR-687, 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 [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-678 AND SER-745, AND 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 [17] RP VARIANTS [LARGE SCALE ANALYSIS] LEU-236 AND ALA-758. 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: Serine/threonine-protein kinase that is required for the CC mitogen or stress-induced phosphorylation of the transcription factors CC CREB1 and ATF1 and for the regulation of the transcription factor RELA, CC and that contributes to gene activation by histone phosphorylation and CC functions in the regulation of inflammatory genes. Phosphorylates CREB1 CC and ATF1 in response to mitogenic or stress stimuli such as UV-C CC irradiation, epidermal growth factor (EGF) and anisomycin. Plays an CC essential role in the control of RELA transcriptional activity in CC response to TNF. Phosphorylates 'Ser-10' of histone H3 in response to CC mitogenics, stress stimuli and EGF, which results in the CC transcriptional activation of several immediate early genes, including CC proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser- CC 28' of histone H3. Mediates the mitogen- and stress-induced CC phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In CC lipopolysaccharide-stimulated primary macrophages, acts downstream of CC the Toll-like receptor TLR4 to limit the production of pro-inflammatory CC cytokines. Functions probably by inducing transcription of the MAP CC kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin CC 10 (IL10), via CREB1 and ATF1 transcription factors. CC {ECO:0000269|PubMed:11035004, ECO:0000269|PubMed:12773393, CC ECO:0000269|PubMed:9792677}. 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:9792677}; 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:9792677}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:9792677}; CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Ser-343, Thr-568 CC and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by CC further autophosphorylation of Ser-196, Ser-360 and Ser-365 by the CC activated C-terminal kinase domain. {ECO:0000250}. CC -!- SUBUNIT: Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in CC quiescent cells which transiently dissociates following mitogenic CC stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA4 CC associates with and phosphorylates the NF-kappa-B p65 subunit RELA. CC -!- INTERACTION: CC O75676; Q16539: MAPK14; NbExp=6; IntAct=EBI-73933, EBI-73946; CC O75676-2; O14901: KLF11; NbExp=3; IntAct=EBI-21622593, EBI-948266; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11035004, CC ECO:0000269|PubMed:9792677}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O75676-1; Sequence=Displayed; CC Name=2; CC IsoId=O75676-2; Sequence=VSP_017733; CC -!- PTM: Ser-343 and Thr-568 phosphorylation is required for kinase CC activity. Ser-343 and Ser-196 are autophosphorylated by the C-terminal CC kinase domain, and their phosphorylation is essential for the catalytic CC activity of the N-terminal kinase domain. Phosphorylated at Ser-343, CC Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. CC Autophosphorylated at Ser-737 and Ser-745 by the N-terminal kinase CC domain (By similarity). {ECO:0000250}. CC -!- MISCELLANEOUS: Enzyme activity requires the presence of both kinase CC domains. {ECO:0000250|UniProtKB:O75582}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr CC protein kinase family. S6 kinase 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; AJ010119; CAA09009.1; -; mRNA. DR EMBL; AK223561; BAD97281.1; -; mRNA. DR EMBL; AK292163; BAF84852.1; -; mRNA. DR EMBL; CH471076; EAW74260.1; -; Genomic_DNA. DR EMBL; AF074715; AAC67395.1; -; mRNA. DR CCDS; CCDS8073.1; -. [O75676-1] DR RefSeq; NP_001006945.1; NM_001006944.1. [O75676-2] DR RefSeq; NP_001287731.1; NM_001300802.1. DR RefSeq; NP_001305290.1; NM_001318361.1. DR RefSeq; NP_003933.1; NM_003942.2. [O75676-1] DR AlphaFoldDB; O75676; -. DR SMR; O75676; -. DR BioGRID; 114468; 128. DR ELM; O75676; -. DR IntAct; O75676; 25. DR MINT; O75676; -. DR STRING; 9606.ENSP00000333896; -. DR BindingDB; O75676; -. DR ChEMBL; CHEMBL3125; -. DR DrugBank; DB03247; Flavin mononucleotide. DR DrugCentral; O75676; -. DR GuidetoPHARMACOLOGY; 1524; -. DR GlyGen; O75676; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O75676; -. DR PhosphoSitePlus; O75676; -. DR BioMuta; RPS6KA4; -. DR CPTAC; CPTAC-3104; -. DR EPD; O75676; -. DR jPOST; O75676; -. DR MassIVE; O75676; -. DR MaxQB; O75676; -. DR PaxDb; 9606-ENSP00000333896; -. DR PeptideAtlas; O75676; -. DR ProteomicsDB; 50149; -. [O75676-1] DR ProteomicsDB; 50150; -. [O75676-2] DR Pumba; O75676; -. DR Antibodypedia; 3272; 324 antibodies from 32 providers. DR DNASU; 8986; -. DR Ensembl; ENST00000334205.9; ENSP00000333896.4; ENSG00000162302.13. [O75676-1] DR GeneID; 8986; -. DR KEGG; hsa:8986; -. DR MANE-Select; ENST00000334205.9; ENSP00000333896.4; NM_003942.3; NP_003933.1. DR UCSC; uc001oae.4; human. [O75676-1] DR AGR; HGNC:10433; -. DR CTD; 8986; -. DR DisGeNET; 8986; -. DR GeneCards; RPS6KA4; -. DR HGNC; HGNC:10433; RPS6KA4. DR HPA; ENSG00000162302; Tissue enhanced (brain). DR MIM; 603606; gene. DR neXtProt; NX_O75676; -. DR OpenTargets; ENSG00000162302; -. DR PharmGKB; PA34848; -. DR VEuPathDB; HostDB:ENSG00000162302; -. DR eggNOG; KOG0603; Eukaryota. DR GeneTree; ENSGT00940000161083; -. DR InParanoid; O75676; -. DR OMA; CKDPRKR; -. DR OrthoDB; 5489497at2759; -. DR PhylomeDB; O75676; -. DR TreeFam; TF313438; -. DR PathwayCommons; O75676; -. DR Reactome; R-HSA-437239; Recycling pathway of L1. DR SignaLink; O75676; -. DR SIGNOR; O75676; -. DR BioGRID-ORCS; 8986; 23 hits in 1197 CRISPR screens. DR ChiTaRS; RPS6KA4; human. DR GeneWiki; RPS6KA4; -. DR GenomeRNAi; 8986; -. DR Pharos; O75676; Tchem. DR PRO; PR:O75676; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; O75676; Protein. DR Bgee; ENSG00000162302; Expressed in right hemisphere of cerebellum and 144 other cell types or tissues. DR ExpressionAtlas; O75676; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0045202; C:synapse; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0035175; F:histone H3S10 kinase activity; IMP:UniProtKB. DR GO; GO:0044022; F:histone H3S28 kinase activity; IMP:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro. 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:0004711; F:ribosomal protein S6 kinase activity; NAS:UniProtKB. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:BHF-UCL. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0001818; P:negative regulation of cytokine production; TAS:UniProtKB. DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; TAS:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:BHF-UCL. DR GO; GO:0043687; P:post-translational protein modification; IMP:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR CDD; cd05614; STKc_MSK2_N; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 2. DR InterPro; IPR000961; AGC-kinase_C. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR037714; MSK2_N_dom. DR InterPro; IPR017892; Pkinase_C. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR016239; Ribosomal_S6_kinase_II. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24351; RIBOSOMAL PROTEIN S6 KINASE; 1. DR PANTHER; PTHR24351:SF41; RIBOSOMAL PROTEIN S6 KINASE ALPHA-4; 1. DR Pfam; PF00069; Pkinase; 2. DR Pfam; PF00433; Pkinase_C; 1. DR PIRSF; PIRSF000606; Ribsml_S6_kin_2; 1. DR SMART; SM00133; S_TK_X; 1. DR SMART; SM00220; S_TKc; 2. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 2. DR PROSITE; PS51285; AGC_KINASE_CTER; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 2. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 2. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 2. DR Genevisible; O75676; HS. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Inflammatory response; Kinase; KW Magnesium; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein; KW Reference proteome; Repeat; Serine/threonine-protein kinase; KW Stress response; Transferase. FT CHAIN 1..772 FT /note="Ribosomal protein S6 kinase alpha-4" FT /id="PRO_0000086205" FT DOMAIN 33..301 FT /note="Protein kinase 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 302..371 FT /note="AGC-kinase C-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618" FT DOMAIN 411..674 FT /note="Protein kinase 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 673..696 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 725..772 FT /note="Required for nuclear targeting and association with FT MAPK14" FT REGION 728..772 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 161 FT /note="Proton acceptor" FT /evidence="ECO:0000250" FT ACT_SITE 530 FT /note="Proton acceptor" FT /evidence="ECO:0000250" FT BINDING 39..47 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 65 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 417..425 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 440 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 196 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250" FT MOD_RES 343 FT /note="Phosphoserine; by MAPK1, MAPK3 and MAPK14" FT /evidence="ECO:0000305" FT MOD_RES 347 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163" FT MOD_RES 360 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250" FT MOD_RES 365 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250" FT MOD_RES 542 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:23186163" FT MOD_RES 568 FT /note="Phosphothreonine; by MAPK1, MAPK3 and MAPK14" FT /evidence="ECO:0000250" FT MOD_RES 634 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 678 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:24275569" FT MOD_RES 687 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163" FT MOD_RES 737 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000305" FT MOD_RES 745 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:24275569" FT VAR_SEQ 401..406 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9687510, ECO:0000303|Ref.3" FT /id="VSP_017733" FT VARIANT 236 FT /note="S -> L (in a breast infiltrating ductal carcinoma FT sample; somatic mutation; dbSNP:rs746466314)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040632" FT VARIANT 758 FT /note="S -> A (in dbSNP:rs17857342)" FT /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.3" FT /id="VAR_040633" FT MUTAGEN 709 FT /note="F->A: Strongly elevates basal activity." FT /evidence="ECO:0000269|PubMed:11035004" FT CONFLICT 477 FT /note="L -> P (in Ref. 3; BAD97281)" FT /evidence="ECO:0000305" FT CONFLICT O75676-2:400..401 FT /note="QQ -> Q (in Ref. 3; BAD97281)" FT /evidence="ECO:0000305" SQ SEQUENCE 772 AA; 85606 MW; 3606209693D0B5F3 CRC64; MGDEDDDESC AVELRITEAN LTGHEEKVSV ENFELLKVLG TGAYGKVFLV RKAGGHDAGK LYAMKVLRKA ALVQRAKTQE HTRTERSVLE LVRQAPFLVT LHYAFQTDAK LHLILDYVSG GEMFTHLYQR QYFKEAEVRV YGGEIVLALE HLHKLGIIYR DLKLENVLLD SEGHIVLTDF GLSKEFLTEE KERTFSFCGT IEYMAPEIIR SKTGHGKAVD WWSLGILLFE LLTGASPFTL EGERNTQAEV SRRILKCSPP FPPRIGPVAQ DLLQRLLCKD PKKRLGAGPQ GAQEVRNHPF FQGLDWVALA ARKIPAPFRP QIRSELDVGN FAEEFTRLEP VYSPPGSPPP GDPRIFQGYS FVAPSILFDH NNAVMTDGLE APGAGDRPGR AAVARSAMMQ DSPFFQQYEL DLREPALGQG SFSVCRRCRQ RQSGQEFAVK ILSRRLEANT QREVAALRLC QSHPNVVNLH EVHHDQLHTY LVLELLRGGE LLEHIRKKRH FSESEASQIL RSLVSAVSFM HEEAGVVHRD LKPENILYAD DTPGAPVKII DFGFARLRPQ SPGVPMQTPC FTLQYAAPEL LAQQGYDESC DLWSLGVILY MMLSGQVPFQ GASGQGGQSQ AAEIMCKIRE GRFSLDGEAW QGVSEEAKEL VRGLLTVDPA KRLKLEGLRG SSWLQDGSAR SSPPLRTPDV LESSGPAVRS GLNATFMAFN RGKREGFFLK SVENAPLAKR RKQKLRSATA SRRGSPAPAN PGRAPVASKG APRRANGPLP PS //