CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-008432
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Ribosomal protein S6 kinase alpha-3 
Protein Synonyms/Alias
 S6K-alpha-3; 90 kDa ribosomal protein S6 kinase 3; p90-RSK 3; p90RSK3; Insulin-stimulated protein kinase 1; ISPK-1; MAP kinase-activated protein kinase 1b; MAPK-activated protein kinase 1b; MAPKAP kinase 1b; MAPKAPK-1b; Ribosomal S6 kinase 2; RSK-2; pp90RSK2 
Gene Name
 RPS6KA3 
Gene Synonyms/Alias
 ISPK1; MAPKAPK1B; RSK2 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
72PSQFELLKVLGQGSFubiquitination[1]
81LGQGSFGKVFLVKKIubiquitination[1, 2]
274PFQGKDRKETMTMILubiquitination[2]
322PDGVEEIKRHSFFSTubiquitination[2]
509LDKILRQKFFSEREAubiquitination[2]
566ICDFGFAKQLRAENGubiquitination[2]
591FVAPEVLKRQGYDAAubiquitination[2]
658TAKDLVSKMLHVDPHubiquitination[2]
Reference
 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961] 
Functional Description
 Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR- independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro- apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Phosphorylates DAPK1. 
Sequence Annotation
 DOMAIN 68 327 Protein kinase 1.
 DOMAIN 328 397 AGC-kinase C-terminal.
 DOMAIN 422 679 Protein kinase 2.
 NP_BIND 74 82 ATP (By similarity).
 NP_BIND 428 436 ATP (By similarity).
 ACT_SITE 193 193 Proton acceptor (By similarity).
 ACT_SITE 539 539 Proton acceptor (By similarity).
 BINDING 100 100 ATP (By similarity).
 BINDING 451 451 ATP (By similarity).
 MOD_RES 227 227 Phosphoserine; by PDPK1 (Probable).
 MOD_RES 365 365 Phosphothreonine.
 MOD_RES 369 369 Phosphoserine.
 MOD_RES 375 375 Phosphoserine.
 MOD_RES 386 386 Phosphoserine; by autocatalysis and
 MOD_RES 415 415 Phosphoserine.
 MOD_RES 529 529 Phosphotyrosine; by FGFR3 (By
 MOD_RES 556 556 Phosphoserine.
 MOD_RES 715 715 Phosphoserine.  
Keyword
 3D-structure; ATP-binding; Cell cycle; Complete proteome; Cytoplasm; Disease mutation; Kinase; Magnesium; Mental retardation; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat; Serine/threonine-protein kinase; Stress response; Transferase. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 740 AA 
Protein Sequence
MPLAQLADPW QKMAVESPSD SAENGQQIMD EPMGEEEINP QTEEVSIKEI AITHHVKEGH 60
EKADPSQFEL LKVLGQGSFG KVFLVKKISG SDARQLYAMK VLKKATLKVR DRVRTKMERD 120
ILVEVNHPFI VKLHYAFQTE GKLYLILDFL RGGDLFTRLS KEVMFTEEDV KFYLAELALA 180
LDHLHSLGII YRDLKPENIL LDEEGHIKLT DFGLSKESID HEKKAYSFCG TVEYMAPEVV 240
NRRGHTQSAD WWSFGVLMFE MLTGTLPFQG KDRKETMTMI LKAKLGMPQF LSPEAQSLLR 300
MLFKRNPANR LGAGPDGVEE IKRHSFFSTI DWNKLYRREI HPPFKPATGR PEDTFYFDPE 360
FTAKTPKDSP GIPPSANAHQ LFRGFSFVAI TSDDESQAMQ TVGVHSIVQQ LHRNSIQFTD 420
GYEVKEDIGV GSYSVCKRCI HKATNMEFAV KIIDKSKRDP TEEIEILLRY GQHPNIITLK 480
DVYDDGKYVY VVTELMKGGE LLDKILRQKF FSEREASAVL FTITKTVEYL HAQGVVHRDL 540
KPSNILYVDE SGNPESIRIC DFGFAKQLRA ENGLLMTPCY TANFVAPEVL KRQGYDAACD 600
IWSLGVLLYT MLTGYTPFAN GPDDTPEEIL ARIGSGKFSL SGGYWNSVSD TAKDLVSKML 660
HVDPHQRLTA ALVLRHPWIV HWDQLPQYQL NRQDAPHLVK GAMAATYSAL NRNQSPVLEP 720
VGRSTLAQRR GIKKITSTAL 740 
Gene Ontology
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005654; C:nucleoplasm; TAS:Reactome.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:UniProtKB.
 GO:0000287; F:magnesium ion binding; IEA:InterPro.
 GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
 GO:0007411; P:axon guidance; TAS:Reactome.
 GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
 GO:0007417; P:central nervous system development; TAS:ProtInc.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0045597; P:positive regulation of cell differentiation; TAS:UniProtKB.
 GO:0030307; P:positive regulation of cell growth; TAS:UniProtKB.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IMP:BHF-UCL.
 GO:0043620; P:regulation of DNA-dependent transcription in response to stress; TAS:UniProtKB.
 GO:0043555; P:regulation of translation in response to stress; TAS:UniProtKB.
 GO:0032496; P:response to lipopolysaccharide; ISS:UniProtKB.
 GO:0001501; P:skeletal system development; TAS:ProtInc.
 GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
 GO:0007268; P:synaptic transmission; TAS:Reactome.
 GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
 GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
 GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
 GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. 
Interpro
 IPR000961; AGC-kinase_C.
 IPR011009; Kinase-like_dom.
 IPR017892; Pkinase_C.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR016239; Ribosomal_S6_kinase_II.
 IPR002290; Ser/Thr_dual-sp_kinase_dom.
 IPR008271; Ser/Thr_kinase_AS. 
Pfam
 PF00069; Pkinase
 PF00433; Pkinase_C 
SMART
 SM00133; S_TK_X
 SM00220; S_TKc 
PROSITE
 PS51285; AGC_KINASE_CTER
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 
PRINTS