ID KS6A4_MOUSE Reviewed; 773 AA. AC Q9Z2B9; Q3U3M8; Q91X18; DT 24-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 24-JAN-2024, entry version 192. 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=RSK-like protein kinase; DE Short=RLSK; GN Name=Rps6ka4; Synonyms=Msk2; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090 {ECO:0000312|EMBL:AAC67394.1}; RN [1] {ECO:0000312|EMBL:AAC67394.1} RP NUCLEOTIDE SEQUENCE [MRNA]. 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=NOD; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Liver {ECO:0000312|EMBL:AAH12964.1}; 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 [4] RP FUNCTION IN PHOSPHORYLATION OF CREB1 AND ATF1. RX PubMed=11909979; DOI=10.1128/mcb.22.8.2871-2881.2002; RA Wiggin G.R., Soloaga A., Foster J.M., Murray-Tait V., Cohen P., RA Arthur J.S.; RT "MSK1 and MSK2 are required for the mitogen- and stress-induced RT phosphorylation of CREB and ATF1 in fibroblasts."; RL Mol. Cell. Biol. 22:2871-2881(2002). RN [5] RP FUNCTION IN PHOSPHORYLATION OF HISTONE H3. RX PubMed=16517600; DOI=10.1074/jbc.m513333200; RA Duncan E.A., Anest V., Cogswell P., Baldwin A.S.; RT "The kinases MSK1 and MSK2 are required for epidermal growth factor- RT induced, but not tumor necrosis factor-induced, histone H3 Ser10 RT phosphorylation."; RL J. Biol. Chem. 281:12521-12525(2006). RN [6] RP FUNCTION IN PHOSPHORYLATION OF CREB1; ATF1 AND HISTONE H3. RX PubMed=18690222; DOI=10.1038/ni.1644; RA Ananieva O., Darragh J., Johansen C., Carr J.M., McIlrath J., Park J.M., RA Wingate A., Monk C.E., Toth R., Santos S.G., Iversen L., Arthur J.S.; RT "The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor RT signaling."; RL Nat. Immunol. 9:1028-1036(2008). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-687, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brown adipose tissue, Heart, Kidney, Liver, Lung, and Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). 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 (By similarity). CC {ECO:0000250, ECO:0000269|PubMed:11909979, ECO:0000269|PubMed:16517600, CC ECO:0000269|PubMed:18690222}. 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:0000250|UniProtKB:O75582}; 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:0000250|UniProtKB:O75582}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:O75582}; 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 (By CC similarity). {ECO:0000250}. CC -!- INTERACTION: CC Q9Z2B9; P63085: Mapk1; NbExp=3; IntAct=EBI-412887, EBI-397697; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. 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; AF074714; AAC67394.1; -; mRNA. DR EMBL; AK154674; BAE32757.1; -; mRNA. DR EMBL; BC012964; AAH12964.1; -; mRNA. DR CCDS; CCDS37899.1; -. DR RefSeq; NP_064308.2; NM_019924.2. DR AlphaFoldDB; Q9Z2B9; -. DR SMR; Q9Z2B9; -. DR BioGRID; 208103; 1. DR IntAct; Q9Z2B9; 2. DR STRING; 10090.ENSMUSP00000025903; -. DR iPTMnet; Q9Z2B9; -. DR PhosphoSitePlus; Q9Z2B9; -. DR SwissPalm; Q9Z2B9; -. DR EPD; Q9Z2B9; -. DR jPOST; Q9Z2B9; -. DR MaxQB; Q9Z2B9; -. DR PaxDb; 10090-ENSMUSP00000025903; -. DR PeptideAtlas; Q9Z2B9; -. DR ProteomicsDB; 263567; -. DR Pumba; Q9Z2B9; -. DR Antibodypedia; 3272; 324 antibodies from 32 providers. DR DNASU; 56613; -. DR Ensembl; ENSMUST00000239527.1; ENSMUSP00000159422.2; ENSMUSG00000118668.1. DR GeneID; 56613; -. DR KEGG; mmu:56613; -. DR UCSC; uc008gja.2; mouse. DR AGR; MGI:1930076; -. DR CTD; 8986; -. DR MGI; MGI:1930076; Rps6ka4. DR VEuPathDB; HostDB:ENSMUSG00000024952; -. DR eggNOG; KOG0603; Eukaryota. DR GeneTree; ENSGT00940000161083; -. DR HOGENOM; CLU_000288_58_0_1; -. DR InParanoid; Q9Z2B9; -. DR OMA; CKDPRKR; -. DR OrthoDB; 5489497at2759; -. DR PhylomeDB; Q9Z2B9; -. DR TreeFam; TF313438; -. DR BioGRID-ORCS; 56613; 4 hits in 82 CRISPR screens. DR PRO; PR:Q9Z2B9; -. DR Proteomes; UP000000589; Chromosome 19. DR RNAct; Q9Z2B9; Protein. DR ExpressionAtlas; Q9Z2B9; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0045202; C:synapse; IDA:SynGO. DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB. DR GO; GO:0035175; F:histone H3S10 kinase activity; ISS:UniProtKB. DR GO; GO:0044022; F:histone H3S28 kinase activity; ISS: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; ISS:UniProtKB. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; ISO:MGI. DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI. DR GO; GO:0043687; P:post-translational protein modification; ISS:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB. DR CDD; cd14180; STKc_MSK2_C; 1. 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; Q9Z2B9; MM. PE 1: Evidence at protein level; KW ATP-binding; Inflammatory response; Kinase; Nucleotide-binding; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; KW Serine/threonine-protein kinase; Stress response; Transferase. FT CHAIN 1..773 FT /note="Ribosomal protein S6 kinase alpha-4" FT /id="PRO_0000086206" 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 417..674 FT /note="Protein kinase 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 674..696 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 728..773 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:0000250|UniProtKB:O75676" 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:0000250|UniProtKB:O75676" 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:0000250|UniProtKB:O75676" FT MOD_RES 678 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O75676" FT MOD_RES 687 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 737 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250" FT MOD_RES 745 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:O75676, ECO:0000305" FT CONFLICT 307 FT /note="V -> W (in Ref. 1; AAC67394)" FT /evidence="ECO:0000305" FT CONFLICT 343 FT /note="S -> P (in Ref. 3; AAH12964)" FT /evidence="ECO:0000305" SQ SEQUENCE 773 AA; 85652 MW; 298DA76E00A9937F CRC64; MGDEDEDEGC AVELQITEAN LTGHEEKVSV ENFALLKVLG TGAYGKVFLV RKTGGHDAGK LYAMKVLRKA ALVQRAKTQE HTRTERSVLE LVRQAPFLVT LHYAFQTDAK LHLILDYVSG GEMFTHLYQR QYFKEAEVRV YGGEIVLALE HLHKLGIIYR DLKLENVLLD SEGHIVLTDF GLSKEFLTEE KERTFSFCGT IEYMAPEIIR SKAGHGKAVD WWSLGILLFE LLTGASPFTL EGERNTQAEV SRRILKCSPP FPLRIGPVAQ DLLQRLLCKD PKKRLGAGPQ GAQEVKSHPF FQGLDWVALA ARKIPAPFRP QIRSELDVGN FAEEFTRLEP VYSPAGSPPP GDPRIFQGYS FVAPSILFDH NNAVMADVLQ APGAGYRPGR AAVARSAMMQ DSPFFQQYEL DLREPALGQG SFSVCRRCRQ RQSGQEFAVK ILSRRLEENT QREVAALRLC QSHPNVVNLH EVLHDQLHTY LVLELLRGGE LLEHIRKKRL FSESEASQIL RSLVSAVSFM HEEAGVVHRD LKPENILYAD DTPGAPVKII DFGFARLRPQ SPAEPMQTPC FTLQYAAPEL LAQQGYDESC DLWSLGVILY MMLSGQVPFQ GASGQGGQSQ AAEIMCKIRE GRFSLDGEAW QGVSEEAKEL VRGLLTVDPA KRLKLEGLRS SSWLQDGSAR SSPPLRTPDV LESSGPAVRS GLNATFMAFN RGKREGFFLK SVENAPLAKR RKQKLRSAAA SRRGSPVPAS SGRLPASAAK GTTRRANGPL SPS //