ID   KS6A2_MOUSE             Reviewed;         733 AA.
AC   Q9WUT3; Q9D2C0;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1999, sequence version 1.
DT   27-MAR-2024, entry version 206.
DE   RecName: Full=Ribosomal protein S6 kinase alpha-2;
DE            Short=S6K-alpha-2;
DE            EC=2.7.11.1;
DE   AltName: Full=90 kDa ribosomal protein S6 kinase 2;
DE            Short=p90-RSK 2;
DE            Short=p90RSK2;
DE   AltName: Full=MAP kinase-activated protein kinase 1c;
DE            Short=MAPK-activated protein kinase 1c;
DE            Short=MAPKAP kinase 1c;
DE            Short=MAPKAPK-1c;
DE   AltName: Full=Protein-tyrosine kinase Mpk-9;
DE   AltName: Full=Ribosomal S6 kinase 3;
DE            Short=RSK-3;
DE   AltName: Full=pp90RSK3;
GN   Name=Rps6ka2; Synonyms=Mapkapk1c, Rsk3;
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].
RC   TISSUE=Brain;
RX   PubMed=10430666; DOI=10.1007/s003359901094;
RA   Kispert A., Stoeger R.J., Caparros M., Herrmann B.G.;
RT   "The mouse Rsk3 gene maps to the Leh66 elements carrying the T-complex
RT   responder Tcr.";
RL   Mamm. Genome 10:794-802(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Ovary, and Uterus;
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]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Brain, and Retina;
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   NUCLEOTIDE SEQUENCE [MRNA] OF 534-592.
RC   STRAIN=C57BL/6J; TISSUE=Embryonic brain;
RX   PubMed=1281307;
RA   Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A.,
RA   Wilkinson D.G., Charnay P.;
RT   "An Eph-related receptor protein tyrosine kinase gene segmentally expressed
RT   in the developing mouse hindbrain.";
RL   Oncogene 7:2499-2506(1992).
RN   [5]
RP   INTERACTION WITH FBXO5.
RX   PubMed=15526037; DOI=10.1038/sj.emboj.7600448;
RA   Paronetto M.P., Giorda E., Carsetti R., Rossi P., Geremia R., Sette C.;
RT   "Functional interaction between p90Rsk2 and Emi1 contributes to the
RT   metaphase arrest of mouse oocytes.";
RL   EMBO J. 23:4649-4659(2004).
RN   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Embryonic brain;
RX   PubMed=15345747; DOI=10.1074/mcp.m400085-mcp200;
RA   Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.;
RT   "Phosphoproteomic analysis of the developing mouse brain.";
RL   Mol. Cell. Proteomics 3:1093-1101(2004).
RN   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Kidney, and Lung;
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 transcription factors, regulates
CC       translation, and mediates cellular proliferation, survival, and
CC       differentiation. May function as tumor suppressor in epithelial ovarian
CC       cancer cells (By similarity). {ECO:0000250}.
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-570 in the C-terminal kinase domain (CTKD) by
CC       MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates
CC       Ser-377, allowing binding of PDPK1, which in turn phosphorylates Ser-
CC       218 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.
CC   -!- SUBUNIT: Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in
CC       quiescent cells. Transiently dissociates following mitogenic
CC       stimulation (By similarity). Interacts with FBXO5; cooperate to induce
CC       the metaphase arrest of early blastomeres; increases and stabilizes
CC       interaction of FBXO5 with CDC20 (PubMed:15526037). {ECO:0000250,
CC       ECO:0000269|PubMed:15526037}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC   -!- PTM: Activated by phosphorylation at Ser-218 by PDPK1.
CC       Autophosphorylated on Ser-377, as part of the activation process. May
CC       be phosphorylated at Thr-356 and Ser-360 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}.
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; AJ131021; CAB44492.1; -; mRNA.
DR   EMBL; AK019881; BAB31901.1; -; mRNA.
DR   EMBL; BC043064; AAH43064.1; -; mRNA.
DR   EMBL; BC051079; AAH51079.1; -; mRNA.
DR   EMBL; BC056946; AAH56946.1; -; mRNA.
DR   EMBL; X57237; CAA40513.1; -; mRNA.
DR   CCDS; CCDS28376.1; -.
DR   RefSeq; NP_035429.1; NM_011299.4.
DR   AlphaFoldDB; Q9WUT3; -.
DR   SMR; Q9WUT3; -.
DR   BioGRID; 203015; 11.
DR   IntAct; Q9WUT3; 5.
DR   MINT; Q9WUT3; -.
DR   STRING; 10090.ENSMUSP00000024575; -.
DR   ChEMBL; CHEMBL3351220; -.
DR   iPTMnet; Q9WUT3; -.
DR   PhosphoSitePlus; Q9WUT3; -.
DR   jPOST; Q9WUT3; -.
DR   MaxQB; Q9WUT3; -.
DR   PaxDb; 10090-ENSMUSP00000024575; -.
DR   ProteomicsDB; 264875; -.
DR   Antibodypedia; 33522; 658 antibodies from 42 providers.
DR   DNASU; 20112; -.
DR   Ensembl; ENSMUST00000024575.8; ENSMUSP00000024575.7; ENSMUSG00000023809.11.
DR   GeneID; 20112; -.
DR   KEGG; mmu:20112; -.
DR   UCSC; uc008aih.2; mouse.
DR   AGR; MGI:1342290; -.
DR   CTD; 6196; -.
DR   MGI; MGI:1342290; Rps6ka2.
DR   VEuPathDB; HostDB:ENSMUSG00000023809; -.
DR   eggNOG; KOG0603; Eukaryota.
DR   GeneTree; ENSGT00940000159956; -.
DR   HOGENOM; CLU_000288_58_3_1; -.
DR   InParanoid; Q9WUT3; -.
DR   OMA; MREINIT; -.
DR   OrthoDB; 5489497at2759; -.
DR   PhylomeDB; Q9WUT3; -.
DR   TreeFam; TF313438; -.
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; 20112; 2 hits in 80 CRISPR screens.
DR   PRO; PR:Q9WUT3; -.
DR   Proteomes; UP000000589; Chromosome 17.
DR   RNAct; Q9WUT3; Protein.
DR   Bgee; ENSMUSG00000023809; Expressed in granulocyte and 137 other cell types or tissues.
DR   ExpressionAtlas; Q9WUT3; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR   GO; GO:0072687; C:meiotic spindle; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0005819; C:spindle; IDA:MGI.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR   GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:MGI.
DR   GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; ISO:MGI.
DR   GO; GO:0004711; F:ribosomal protein S6 kinase activity; IDA:MGI.
DR   GO; GO:0002035; P:brain renin-angiotensin system; IDA:MGI.
DR   GO; GO:0010659; P:cardiac muscle cell apoptotic process; IDA:MGI.
DR   GO; GO:0071322; P:cellular response to carbohydrate stimulus; IDA:MGI.
DR   GO; GO:0060047; P:heart contraction; IDA:MGI.
DR   GO; GO:0007507; P:heart development; IDA:MGI.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR   GO; GO:0045786; P:negative regulation of cell cycle; ISS:UniProtKB.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0045835; P:negative regulation of meiotic nuclear division; IDA:MGI.
DR   GO; GO:0001556; P:oocyte maturation; IDA:MGI.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; IDA:MGI.
DR   GO; GO:0070613; P:regulation of protein processing; IMP:MGI.
DR   CDD; cd14178; STKc_RSK3_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; IPR042766; RSK3_STKc.
DR   InterPro; IPR041906; RSK_N.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR24351; RIBOSOMAL PROTEIN S6 KINASE; 1.
DR   PANTHER; PTHR24351:SF213; RIBOSOMAL PROTEIN S6 KINASE ALPHA-2; 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; Q9WUT3; 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; Tumor suppressor.
FT   CHAIN           1..733
FT                   /note="Ribosomal protein S6 kinase alpha-2"
FT                   /id="PRO_0000086202"
FT   DOMAIN          59..318
FT                   /note="Protein kinase 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          319..388
FT                   /note="AGC-kinase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT   DOMAIN          415..672
FT                   /note="Protein kinase 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   ACT_SITE        184
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        532
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   BINDING         65..73
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         91
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         421..429
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         444
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         218
FT                   /note="Phosphoserine; by PDPK1"
FT                   /evidence="ECO:0000250|UniProtKB:Q15349"
FT   MOD_RES         377
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:15345747,
FT                   ECO:0007744|PubMed:21183079"
FT   CONFLICT        72
FT                   /note="K -> E (in Ref. 2; BAB31901)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   733 AA;  83157 MW;  49C1390316CFCE91 CRC64;
     MELSMKKFTV RRFFSVYLRK KSRSKSSSLS RLEEEGIVKE IDISNHVKEG FEKADPSQFE
     LLKVLGQGSY GKVFLVRKVT GSDAGQLYAM KVLKKATLKV RDRVRSKMER DILAEVNHPF
     IVKLHYAFQT EGKLYLILDF LRGGDLFTRL SKEVMFTEED VKFYLAELAL ALDHLHGLGI
     IYRDLKPENI LLDEEGHIKI TDFGLSKEAT DHDKRAYSFC GTIEYMAPEV VNRRGHTQSA
     DWWSFGVLMF EMLTGSLPFQ GKDRKETMAL ILKAKLGMPQ FLSAEAQSLL RALFKRNPCN
     RLGAGVDGVE EIKRHPFFVT IDWNKLYRKE IKPPFKPAVG RPEDTFHFDP EFTARTPTDS
     PGVPPSANAH HLFRGFSFVA SSLVQEPSQQ DVPKAPIHPI VQQLHGNNIH FTDGYEIKED
     IGVGSYSVCK RCVHKATDAE YAVKIIDKSK RDPSEEIEIL LRYGQHPNII TLKDVYDDGK
     YVYLVMELMR GGELLDRILR QRCFSEREAS DVLYTIARTM DYLHSQGVVH RDLKPSNILY
     MDESGNPESI RICDFGFAKQ LRAENGLLMT PCYTANFVAP EVLKRQGYDA ACDVWSLGIL
     LYTMLAGFTP FANGPDDTPE EILARIGSGK YALSGGNWDS ISDAAKDVVS KMLHVDPQQR
     LTAVQVLKHP WIVNREYLSQ NQLSRQDVHL VKGAMAATYF ALNRTPQAPR LEPVLSSSLA
     QRRGMKRLTS TRL
//