KS6A4_MOUSE
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 03-AUG-2022, entry version 184.
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}.
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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 EPD; Q9Z2B9; -.
DR jPOST; Q9Z2B9; -.
DR MaxQB; Q9Z2B9; -.
DR PaxDb; Q9Z2B9; -.
DR PeptideAtlas; Q9Z2B9; -.
DR PRIDE; Q9Z2B9; -.
DR ProteomicsDB; 263567; -.
DR Antibodypedia; 3272; 286 antibodies from 32 providers.
DR DNASU; 56613; -.
DR Ensembl; ENSMUST00000239527; ENSMUSP00000159422; ENSMUSG00000118668.
DR GeneID; 56613; -.
DR KEGG; mmu:56613; -.
DR UCSC; uc008gja.2; mouse.
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; HDVHHDQ; -.
DR OrthoDB; 1132245at2759; -.
DR PhylomeDB; Q9Z2B9; -.
DR TreeFam; TF313438; -.
DR BioGRID-ORCS; 56613; 4 hits in 76 CRISPR screens.
DR PRO; PR:Q9Z2B9; -.
DR Proteomes; UP000000589; Chromosome 19.
DR RNAct; Q9Z2B9; protein.
DR ExpressionAtlas; Q9Z2B9; baseline and differential.
DR Genevisible; Q9Z2B9; MM.
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:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0035175; F:histone kinase activity (H3-S10 specific); ISS:UniProtKB.
DR GO; GO:0044022; F:histone kinase activity (H3-S28 specific); 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:0043987; P:histone H3-S10 phosphorylation; ISO:MGI.
DR GO; GO:0043988; P:histone H3-S28 phosphorylation; ISO:MGI.
DR GO; GO:0016572; P:histone phosphorylation; IBA:GO_Central.
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:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0035066; P:positive regulation of histone acetylation; ISO:MGI.
DR GO; GO:0033129; P:positive regulation of histone phosphorylation; ISO:MGI.
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 transcription, DNA-templated; ISS:UniProtKB.
DR CDD; cd05614; STKc_MSK2_N; 1.
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 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; SSF56112; 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.
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
