ID:KS6A3_HUMAN DESCRIPTION: RecName: Full=Ribosomal protein S6 kinase alpha-3; Short=S6K-alpha-3; EC=2.7.11.1; AltName: Full=90 kDa ribosomal protein S6 kinase 3; Short=p90-RSK 3; Short=p90RSK3; AltName: Full=Insulin-stimulated protein kinase 1; Short=ISPK-1; AltName: Full=MAP kinase-activated protein kinase 1b; Short=MAPK-activated protein kinase 1b; Short=MAPKAP kinase 1b; Short=MAPKAPK-1b; AltName: Full=Ribosomal S6 kinase 2; Short=RSK-2; AltName: Full=pp90RSK2; FUNCTION: 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. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Magnesium (By similarity). ENZYME REGULATION: Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-577 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-386, allowing binding of PDPK1, which in turn phosphorylates Ser-227 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD. SUBUNIT: Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation (By similarity). Interacts with NFATC4, ETV1/ER81 and FGFR1. SUBCELLULAR LOCATION: Nucleus (By similarity). Cytoplasm (By similarity). TISSUE SPECIFICITY: Expressed in many tissues, highest levels in skeletal muscle. PTM: Activated by phosphorylation at Ser-227 by PDPK1. Autophosphorylated on Ser-386, as part of the activation process. May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386 by MAPKAPK2. PTM: N-terminal myristoylation results in an activated kinase in the absence of added growth factors. DISEASE: Defects in RPS6KA3 are the cause of Coffin-Lowry syndrome (CLS) [MIM:303600]. A X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. DISEASE: Defects in RPS6KA3 are the cause of mental retardation X- linked type 19 (MRX19) [MIM:300844]. MRX19 is a non-syndromic form of mild to moderate mental retardation. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation. SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily. SIMILARITY: Contains 1 AGC-kinase C-terminal domain. SIMILARITY: Contains 2 protein kinase domains. SEQUENCE CAUTION: Sequence=BAD92170.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RPS6KA3";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF00433 - Protein kinase C terminal domain PF06293 - Lipopolysaccharide kinase (Kdo/WaaP) family PF07714 - Protein tyrosine and serine/threonine kinase PF14531 - Kinase-like
SCOP Domains: 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on P51812
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001501 skeletal system development GO:0002224 toll-like receptor signaling pathway GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0007049 cell cycle GO:0007165 signal transduction GO:0007417 central nervous system development GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0030307 positive regulation of cell growth GO:0032496 response to lipopolysaccharide GO:0035556 intracellular signal transduction GO:0043066 negative regulation of apoptotic process GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043555 regulation of translation in response to stress GO:0043620 regulation of DNA-templated transcription in response to stress GO:0045597 positive regulation of cell differentiation GO:0045944 positive regulation of transcription from RNA polymerase II promoter
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
