MGP Database

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MGP002702

UniProt Annotations

Entry Information
Gene Nameribosomal protein S6 kinase, 90kDa, polypeptide 3
Protein EntryKS6A3_HUMAN
UniProt IDP51812
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
CofactorName=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
DiseaseCoffin-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. {ECO:0000269|PubMed:10094187, ECO:0000269|PubMed:10528858, ECO:0000269|PubMed:14986828, ECO:0000269|PubMed:15214012, ECO:0000269|PubMed:8955270, ECO:0000269|PubMed:9837815}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseMental retardation, X-linked 19 (MRX19) [MIM:300844]: 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 adaptive 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. {ECO:0000269|PubMed:10319851, ECO:0000269|PubMed:17100996}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Enzyme RegulationUpon 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.
FunctionSerine/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. {ECO:0000269|PubMed:10436156, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:8250835, ECO:0000269|PubMed:9770464}.
InteractionP28482:MAPK1; NbExp=3; IntAct=EBI-1046616, EBI-959949;
PtmActivated 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. {ECO:0000269|PubMed:16964243, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:19369195, ECO:0000269|PubMed:19690332, ECO:0000269|PubMed:20068231, ECO:0000269|PubMed:21406692}.
PtmN-terminal myristoylation results in an activated kinase in the absence of added growth factors.
Sequence CautionSequence=BAD92170.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
SimilarityBelongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily. {ECO:0000305}.
SimilarityContains 1 AGC-kinase C-terminal domain. {ECO:0000305}.
SimilarityContains 2 protein kinase domains. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationNucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
SubunitForms 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. {ECO:0000250, ECO:0000269|PubMed:17213202}.
Tissue SpecificityExpressed in many tissues, highest levels in skeletal muscle.
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