KS6A1_MOUSE
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 03-AUG-2022, entry version 188.
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. In fibroblast, is required for
CC EGF-stimulated phosphorylation of CREB1, which results in the
CC subsequent transcriptional activation of several immediate-early genes.
CC In response to mitogenic stimulation (EGF and PMA), phosphorylates and
CC activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the
CC cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the
CC transcription regulation of several genes by phosphorylating GSK3B at
CC 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to
CC serum or EGF via an mTOR-independent mechanism and promotes translation
CC initiation by facilitating assembly of the pre-initiation complex. In
CC response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for
CC the EIF3 complex and stimulating cap-dependent translation. Is involved
CC in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2
CC at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR
CC signaling, and mediates phosphorylation of RPTOR, which regulates
CC mTORC1 activity and may promote rapamycin-sensitive signaling
CC independently of the PI3K/AKT pathway. Mediates cell survival by
CC phosphorylating the pro-apoptotic proteins BAD and DAPK1 and
CC suppressing their pro-apoptotic function. Promotes the survival of
CC hepatic stellate cells by phosphorylating CEBPB in response to the
CC hepatotoxin carbon tetrachloride (CCl4). Mediates induction of
CC hepatocyte prolifration by TGFA through phosphorylation of CEBPB
CC (PubMed:10635333). Is involved in cell cycle regulation by
CC phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B
CC association with 14-3-3 proteins and prevents its translocation to the
CC nucleus and inhibition of G1 progression (By similarity).
CC Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway
CC controls cell migration (By similarity). {ECO:0000250|UniProtKB:Q15418,
CC ECO:0000250|UniProtKB:Q63531, 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 iPTMnet; P18653; -.
DR PhosphoSitePlus; P18653; -.
DR SwissPalm; P18653; -.
DR EPD; P18653; -.
DR jPOST; P18653; -.
DR MaxQB; P18653; -.
DR PaxDb; P18653; -.
DR PRIDE; P18653; -.
DR ProteomicsDB; 264874; -.
DR Antibodypedia; 2073; 1701 antibodies from 45 providers.
DR DNASU; 20111; -.
DR Ensembl; ENSMUST00000003741; ENSMUSP00000003741; ENSMUSG00000003644.
DR GeneID; 20111; -.
DR KEGG; mmu:20111; -.
DR UCSC; uc012dmp.3; mouse.
DR CTD; 6195; -.
DR MGI; MGI:104558; Rps6ka1.
DR VEuPathDB; HostDB:ENSMUSG00000003644; -.
DR eggNOG; KOG0603; Eukaryota.
DR GeneTree; ENSGT00940000159314; -.
DR InParanoid; P18653; -.
DR BRENDA; 2.7.11.1; 3474.
DR BioGRID-ORCS; 20111; 7 hits in 76 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 222 other tissues.
DR ExpressionAtlas; P18653; baseline and differential.
DR Genevisible; P18653; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0005819; C:spindle; IDA:MGI.
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:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
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 GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR CDD; cd05582; STKc_RSK_N; 1.
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 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; 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
