KS6A1_RAT
ID KS6A1_RAT Reviewed; 735 AA.
AC Q63531;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 158.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7688567; DOI=10.1021/bi00081a018;
RA Grove J.R., Price D.J., Banerjee P., Balasubramanyam A., Ahmad M.F.,
RA Avruch J.;
RT "Regulation of an epitope-tagged recombinant Rsk-1 S6 kinase by phorbol
RT ester and erk/MAP kinase.";
RL Biochemistry 32:7727-7738(1993).
RN [2]
RP ACTIVITY REGULATION, AND PHOSPHORYLATION AT SER-221.
RX PubMed=10480933; DOI=10.1074/jbc.274.38.27168;
RA Jensen C.J., Buch M.-B., Krag T.O., Hemmings B.A., Gammeltoft S.,
RA Froedin M.;
RT "90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-
RT phosphoinositide-dependent protein kinase-1.";
RL J. Biol. Chem. 274:27168-27176(1999).
RN [3]
RP FUNCTION IN CELL CYCLE REGULATION, AND FUNCTION IN PHOSPHORYLATION OF
RP CDKN1B.
RX PubMed=14504289; DOI=10.1074/jbc.m306614200;
RA Fujita N., Sato S., Tsuruo T.;
RT "Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6
RT kinases promotes its binding to 14-3-3 and cytoplasmic localization.";
RL J. Biol. Chem. 278:49254-49260(2003).
RN [4]
RP FUNCTION, INTERACTION WITH FGFR1, ACTIVITY REGULATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=15117958; DOI=10.1074/jbc.m311144200;
RA Hu Y., Fang X., Dunham S.M., Prada C., Stachowiak E.K., Stachowiak M.K.;
RT "90-kDa ribosomal S6 kinase is a direct target for the nuclear fibroblast
RT growth factor receptor 1 (FGFR1): role in FGFR1 signaling.";
RL J. Biol. Chem. 279:29325-29335(2004).
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) (By similarity). Mediates
CC induction of hepatocyte prolifration by TGFA through phosphorylation of
CC CEBPB (By similarity). 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. Phosphorylates EPHA2 at 'Ser-
CC 897', the RPS6KA-EPHA2 signaling pathway controls cell migration (By
CC similarity). {ECO:0000250|UniProtKB:P18653,
CC ECO:0000250|UniProtKB:Q15418, ECO:0000269|PubMed:14504289,
CC ECO:0000269|PubMed:15117958}.
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-573 in the C-terminal kinase domain (CTKD) by
CC MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates
CC Ser-380, 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. {ECO:0000269|PubMed:10480933,
CC ECO:0000269|PubMed:15117958}.
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:0000269|PubMed:15117958}. Cytoplasm
CC {ECO:0000269|PubMed:15117958}.
CC -!- PTM: Activated by phosphorylation at Ser-221 by PDPK1.
CC Autophosphorylated on Ser-380, as part of the activation process. May
CC be phosphorylated at Thr-359 and Ser-363 by MAPK1/ERK2 and MAPK3/ERK1.
CC {ECO:0000269|PubMed:10480933}.
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; M99169; AAA02872.1; -; mRNA.
DR PIR; A53300; A53300.
DR RefSeq; NP_112369.1; NM_031107.1.
DR AlphaFoldDB; Q63531; -.
DR SMR; Q63531; -.
DR BioGRID; 249643; 6.
DR IntAct; Q63531; 1.
DR MINT; Q63531; -.
DR STRING; 10116.ENSRNOP00000060054; -.
DR ChEMBL; CHEMBL5528; -.
DR iPTMnet; Q63531; -.
DR PhosphoSitePlus; Q63531; -.
DR jPOST; Q63531; -.
DR PaxDb; Q63531; -.
DR PRIDE; Q63531; -.
DR GeneID; 81771; -.
DR KEGG; rno:81771; -.
DR UCSC; RGD:620675; rat.
DR CTD; 6195; -.
DR RGD; 620675; Rps6ka1.
DR eggNOG; KOG0603; Eukaryota.
DR InParanoid; Q63531; -.
DR OrthoDB; 1132245at2759; -.
DR PhylomeDB; Q63531; -.
DR BRENDA; 2.7.11.1; 5301.
DR PRO; PR:Q63531; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005819; C:spindle; ISO:RGD.
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:RGD.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0016301; F: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:0004712; F:protein serine/threonine/tyrosine kinase activity; ISO:RGD.
DR GO; GO:0004711; F:ribosomal protein S6 kinase activity; IBA:GO_Central.
DR GO; GO:0072574; P:hepatocyte proliferation; ISS: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:RGD.
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:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
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..735
FT /note="Ribosomal protein S6 kinase alpha-1"
FT /id="PRO_0000086200"
FT DOMAIN 62..321
FT /note="Protein kinase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 322..391
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT DOMAIN 418..675
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 535
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 424..432
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 447
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:0000269|PubMed:10480933"
FT MOD_RES 307
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
FT MOD_RES 359
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
FT MOD_RES 363
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
FT MOD_RES 369
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
FT MOD_RES 380
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
FT MOD_RES 573
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
FT MOD_RES 732
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15418"
SQ SEQUENCE 735 AA; 82883 MW; 12DEAD1E07140FDE CRC64;
MPLAQLKEPW PLMELVPLDP ENGQASGEEA GLQPSKDEGI LKEISITHHV KAGSEKADPS
HFELLKVLGQ GSFGKVFLVR KVTRPDNGHL YAMKVLKKAT LKVRDRVRTK MERDILADVN
HPFVVKLHYA FQTEGKLYLI LDFLRGGDLF TRLSKEVMFT EEDVKFYLAE LALGLDHLHS
LGIIYRDLKP ENILLDEEGH IKLTDFGLSK EAIDHEKKAY SFCGTVEYMA PEVVNRQGHT
HSADWWSYGV LMFEMLTGSL PFQGKDRKET MTLILKAKLG MPQFLSTEAQ SLLRALFKRN
PANRLGSGPD GAEEIKRHIF YSTIDWNKLY RREIKPPFKP AVAQPDDTFY FDTEFTSRTP
RDSPGIPPSA GAHQLFRGFS FVATGLMEDD SKPRATQAPL HSVVQQLHGK NLVFSDGYIV
KETIGVGSYS VCKRCVHKAT NMEYAVKVID KSKRDPSEEI EILLRYGQHP NIITLKDVYD
DSKHVYLVTE LMRGGELLDK ILRQKFFSER EASFVLYTIS KTVEYLHSQG VVHRDLKPSN
ILYVDESGNP ECLRICDFGF AKQLRAENGL LMTPCYTANF VAPEVLKRQG YDEGCDIWSL
GVLLYTMLAG YTPFANGPSD TPEEILTRIS SGKFTLSGGN WNTVSETAKD LVSKMLHVDP
HQRLTAKQVL QHPWITQKDK LPQSQLSHQD LQLVKGGMAA TYSALSSSKP TPQLKPIESS
ILAQRRVRKL PSTTL
