ID   KS6A1_MOUSE             Reviewed;         724 AA.
AC   P18653;
DT   01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1990, sequence version 1.
DT   27-MAR-2024, entry version 197.
DE   RecName: Full=Ribosomal protein S6 kinase alpha-1;
DE            Short=S6K-alpha-1;
DE            EC=2.7.11.1;
DE   AltName: Full=90 kDa ribosomal protein S6 kinase 1;
DE            Short=p90-RSK 1;
DE            Short=p90RSK1;
DE            Short=p90S6K;
DE   AltName: Full=MAP kinase-activated protein kinase 1a;
DE            Short=MAPK-activated protein kinase 1a;
DE            Short=MAPKAP kinase 1a;
DE            Short=MAPKAPK-1a;
DE   AltName: Full=Ribosomal S6 kinase 1;
DE            Short=RSK-1;
GN   Name=Rps6ka1; Synonyms=Mapkapk1a, Rsk1;
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;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=2779569; DOI=10.1128/mcb.9.9.3850-3859.1989;
RA   Alcorta D.A., Crews C.M., Sweet L.J., Bankston L., Jones S.W.,
RA   Erikson R.L.;
RT   "Sequence and expression of chicken and mouse rsk: homologs of Xenopus
RT   laevis ribosomal S6 kinase.";
RL   Mol. Cell. Biol. 9:3850-3859(1989).
RN   [2]
RP   FUNCTION.
RX   PubMed=10635333; DOI=10.1016/s1097-2765(00)80237-3;
RA   Buck M., Poli V., van der Geer P., Chojkier M., Hunter T.;
RT   "Phosphorylation of rat serine 105 or mouse threonine 217 in C/EBP beta is
RT   required for hepatocyte proliferation induced by TGF alpha.";
RL   Mol. Cell 4:1087-1092(1999).
RN   [3]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-369, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA   Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT   "Large-scale phosphorylation analysis of mouse liver.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-369, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA   Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA   Thibault P.;
RT   "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL   Immunity 30:143-154(2009).
RN   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-369, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Lung, Spleen, and
RC   Testis;
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 acts downstream of ERK
CC       (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and
CC       stress-induced activation of the transcription factors CREB1, ETV1/ER81
CC       and NR4A1/NUR77, regulates translation through RPS6 and EIF4B
CC       phosphorylation, and mediates cellular proliferation, survival, and
CC       differentiation by modulating mTOR signaling and repressing pro-
CC       apoptotic function of BAD and DAPK1 (By similarity). In fibroblast, is
CC       required for EGF-stimulated phosphorylation of CREB1, which results in
CC       the subsequent transcriptional activation of several immediate-early
CC       genes (By similarity). In response to mitogenic stimulation (EGF and
CC       PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81
CC       transcription factors and the cofactor CREBBP (By similarity). Upon
CC       insulin-derived signal, acts indirectly on the transcription regulation
CC       of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its
CC       activity (By similarity). Phosphorylates RPS6 in response to serum or
CC       EGF via an mTOR-independent mechanism and promotes translation
CC       initiation by facilitating assembly of the pre-initiation complex (By
CC       similarity). In response to insulin, phosphorylates EIF4B, enhancing
CC       EIF4B affinity for the EIF3 complex and stimulating cap-dependent
CC       translation (By similarity). Is involved in the mTOR nutrient-sensing
CC       pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently
CC       inhibits TSC2 ability to suppress mTOR signaling, and mediates
CC       phosphorylation of RPTOR, which regulates mTORC1 activity and may
CC       promote rapamycin-sensitive signaling independently of the PI3K/AKT
CC       pathway (By similarity). Also involved in feedback regulation of mTORC1
CC       and mTORC2 by phosphorylating DEPTOR (By similarity). Mediates cell
CC       survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1
CC       and suppressing their pro-apoptotic function (By similarity). Promotes
CC       the survival of hepatic stellate cells by phosphorylating CEBPB in
CC       response to the hepatotoxin carbon tetrachloride (CCl4)
CC       (PubMed:10635333). Mediates induction of hepatocyte prolifration by
CC       TGFA through phosphorylation of CEBPB (By similarity). Is involved in
CC       cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B,
CC       which promotes CDKN1B association with 14-3-3 proteins and prevents its
CC       translocation to the nucleus and inhibition of G1 progression (By
CC       similarity). Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2
CC       signaling pathway controls cell migration (By similarity). In response
CC       to mTORC1 activation, phosphorylates EIF4B at 'Ser-406' and 'Ser-422'
CC       which stimulates bicarbonate cotransporter SLC4A7 mRNA translation,
CC       increasing SLC4A7 protein abundance and function (By similarity).
CC       {ECO:0000250|UniProtKB:Q15418, ECO:0000269|PubMed:10635333}.
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; Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: Upon extracellular signal or mitogen stimulation,
CC       phosphorylated at Thr-562 in the C-terminal kinase domain (CTKD) by
CC       MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates
CC       Ser-369, allowing binding of PDPK1, which in turn phosphorylates Ser-
CC       221 in the N-terminal kinase domain (NTDK) leading to the full
CC       activation of the protein and subsequent phosphorylation of the
CC       substrates by the NTKD (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in
CC       quiescent cells. Transiently dissociates following mitogenic
CC       stimulation. Interacts with ETV1/ER81 and FGFR1 (By similarity).
CC       {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Intestine, thymus, and lung.
CC   -!- PTM: Activated by phosphorylation at Ser-221 by PDPK1.
CC       Autophosphorylated on Ser-369, as part of the activation process. May
CC       be phosphorylated at Thr-348 and Ser-352 by MAPK1/ERK2 and MAPK3/ERK1
CC       (By similarity). {ECO:0000250}.
CC   -!- PTM: N-terminal myristoylation results in an activated kinase in the
CC       absence of added growth factors. {ECO:0000250}.
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; M28489; AAA50300.1; -; mRNA.
DR   CCDS; CCDS71488.1; -.
DR   PIR; B32571; B32571.
DR   RefSeq; NP_001272434.1; NM_001285505.1.
DR   AlphaFoldDB; P18653; -.
DR   SMR; P18653; -.
DR   BioGRID; 203014; 23.
DR   IntAct; P18653; 8.
DR   MINT; P18653; -.
DR   STRING; 10090.ENSMUSP00000101514; -.
DR   ChEMBL; CHEMBL3309057; -.
DR   GlyGen; P18653; 2 sites, 1 O-linked glycan (2 sites).
DR   iPTMnet; P18653; -.
DR   PhosphoSitePlus; P18653; -.
DR   SwissPalm; P18653; -.
DR   EPD; P18653; -.
DR   jPOST; P18653; -.
DR   MaxQB; P18653; -.
DR   PaxDb; 10090-ENSMUSP00000101514; -.
DR   ProteomicsDB; 264874; -.
DR   Antibodypedia; 2073; 2020 antibodies from 45 providers.
DR   DNASU; 20111; -.
DR   Ensembl; ENSMUST00000003741.16; ENSMUSP00000003741.10; ENSMUSG00000003644.18.
DR   GeneID; 20111; -.
DR   KEGG; mmu:20111; -.
DR   UCSC; uc012dmp.3; mouse.
DR   AGR; MGI:104558; -.
DR   CTD; 6195; -.
DR   MGI; MGI:104558; Rps6ka1.
DR   VEuPathDB; HostDB:ENSMUSG00000003644; -.
DR   eggNOG; KOG0603; Eukaryota.
DR   GeneTree; ENSGT00940000159314; -.
DR   InParanoid; P18653; -.
DR   OrthoDB; 5489497at2759; -.
DR   BRENDA; 2.7.11.1; 3474.
DR   Reactome; R-MMU-198753; ERK/MAPK targets.
DR   Reactome; R-MMU-199920; CREB phosphorylation.
DR   Reactome; R-MMU-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR   Reactome; R-MMU-442742; CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling.
DR   Reactome; R-MMU-444257; RSK activation.
DR   Reactome; R-MMU-881907; Gastrin-CREB signalling pathway via PKC and MAPK.
DR   BioGRID-ORCS; 20111; 7 hits in 81 CRISPR screens.
DR   ChiTaRS; Rps6ka1; mouse.
DR   PRO; PR:P18653; -.
DR   Proteomes; UP000000589; Chromosome 4.
DR   RNAct; P18653; Protein.
DR   Bgee; ENSMUSG00000003644; Expressed in granulocyte and 225 other cell types or tissues.
DR   ExpressionAtlas; P18653; 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:0005819; C:spindle; IDA:MGI.
DR   GO; GO:0045202; C:synapse; IDA:SynGO.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; ISO:MGI.
DR   GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB.
DR   GO; GO:0016301; F:kinase activity; IDA: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:0004712; F:protein serine/threonine/tyrosine kinase activity; ISO:MGI.
DR   GO; GO:0004711; F:ribosomal protein S6 kinase activity; IBA:GO_Central.
DR   GO; GO:0072574; P:hepatocyte proliferation; IDA:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; ISO:MGI.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:MGI.
DR   GO; GO:2000491; P:positive regulation of hepatic stellate cell activation; ISS:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI.
DR   CDD; cd14175; STKc_RSK1_C; 1.
DR   CDD; cd05582; STKc_RSK_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; 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; IPR041906; RSK_N.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR24351; RIBOSOMAL PROTEIN S6 KINASE; 1.
DR   PANTHER; PTHR24351:SF43; RIBOSOMAL PROTEIN S6 KINASE ALPHA-1; 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; P18653; MM.
PE   1: Evidence at protein level;
KW   ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Reference proteome; Repeat;
KW   Serine/threonine-protein kinase; Transferase.
FT   CHAIN           1..724
FT                   /note="Ribosomal protein S6 kinase alpha-1"
FT                   /id="PRO_0000086199"
FT   DOMAIN          62..310
FT                   /note="Protein kinase 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          311..380
FT                   /note="AGC-kinase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT   DOMAIN          407..664
FT                   /note="Protein kinase 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   ACT_SITE        187
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        524
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   BINDING         68..76
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         94
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         413..421
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         436
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         54
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         221
FT                   /note="Phosphoserine; by PDPK1"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         296
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         348
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         352
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         358
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         369
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17242355,
FT                   ECO:0007744|PubMed:19144319, ECO:0007744|PubMed:21183079"
FT   MOD_RES         562
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
FT   MOD_RES         721
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q15418"
SQ   SEQUENCE   724 AA;  81595 MW;  A5D8E5E5FDBCE4BF CRC64;
     MPLAQLKEPW PLMELVPLDP ENGQTSGEEA GLQPSKDEAI LKEISITHHV KAGSEKADPS
     QFELLKVLGQ GSFGKVFLVR KVTRPDSGHL YAMKVLKKAT LKVRDRVRTK MERDILADVN
     HPFVVKLHYA FQTEGKLYLI LDFLRGGDLF TRLSKEVMFT EEDVKFYLAE LALGLDHLHS
     LGIIYRDLKP ENILLDEEGH IKLTDFGLSK EAIDHEKKAY SFCGTVEYMA PEVVNRQGHT
     HSADWWSYGV LMGKDRKETM TLILKAKLGM PQFLSTEAQS LLRALFKRNP ANRLGSGPDG
     AEEIKRHIFY STIDWNKLYR REIKPPFKPA VAQPDDTFYF DTEFTSRTPR DSPGIPPSAG
     AHQLFRGFSF VATGLMEDDG KPRTTQAPLH SVVQQLHGKN LVFSDGYVVK ETIGVGSYSV
     CKRCVHKATN MEYAVKVIDK SKRDPSEEIE ILLRYGQHPN IITLKDVYDD GKHVYLVTEL
     MRGGELLDKI LRQKFFSERE ASFVLHTISK TVEYLHSQGV VHRDLKPSNI LYVDESGNPE
     CLRICDFGFA KQLRAENGLL MTPCYTANFV APEVLKRQGY DEGCDIWSLG ILLYTMLAGY
     TPFANGPSDT PEEILTRIGS GKFTLSGGNW NTVSETAKDL VSKMLHVDPH QRLTAKQVLQ
     HPWITQKDKL PQSQLSHQDL QLVKGAMAAT YSALNSSKPT PQLKPIESSI LAQRRVRKLP
     STTL
//