InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: RPS6KA3

Summary

InnateDB Protein

IDBP-50814.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

RPS6KA3

Protein Name

ribosomal protein S6 kinase, 90kDa, polypeptide 3

Synonyms

CLS; HU-3; ISPK-1; MAPKAPK1B; MRX19; p90-RSK2; pp90RSK2; RSK; RSK2; S6K-alpha3;

Species

Homo sapiens

Ensembl Protein

ENSP00000368884

InnateDB Gene

IDBG-50812 (RPS6KA3)

Protein Structure

UniProt Annotation

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. {ECO:0000269PubMed:10436156, ECO:0000269PubMed:16213824, ECO:0000269PubMed:16223362, ECO:0000269PubMed:17360704, ECO:0000269PubMed:18722121, ECO:0000269PubMed:8250835, ECO:0000269PubMed:9770464}.

Subcellular Localization

Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.

Disease Associations

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. {ECO:0000269PubMed:10094187, ECO:0000269PubMed:10528858, ECO:0000269PubMed:14986828, ECO:0000269PubMed:15214012, ECO:0000269PubMed:8955270, ECO:0000269PubMed:9837815}. Note=The disease is caused by mutations affecting the gene represented in this entry.Mental 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:0000269PubMed:10319851, ECO:0000269PubMed:17100996}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in many tissues, highest levels in skeletal muscle.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 49 experimentally validated interaction(s) in this database.
They are also associated with 3 interaction(s) predicted by orthology.

Experimentally validated
Total	49 [view]
Protein-Protein	48 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	3 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000287	magnesium ion binding
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0016773	phosphotransferase activity, alcohol group as acceptor
GO:0019901	protein kinase binding
GO:0043027	cysteine-type endopeptidase inhibitor activity involved in apoptotic process

Biological Process

GO:0001501	skeletal system development
GO:0002224	toll-like receptor signaling pathway
GO:0002755	MyD88-dependent toll-like receptor signaling pathway
GO:0002756	MyD88-independent toll-like receptor signaling pathway
GO:0006468	protein phosphorylation
GO:0007049	cell cycle
GO:0007165	signal transduction
GO:0007268	synaptic transmission
GO:0007411	axon guidance
GO:0007417	central nervous system development
GO:0009103	lipopolysaccharide biosynthetic process
GO:0030307	positive regulation of cell growth
GO:0032496	response to lipopolysaccharide
GO:0034134	toll-like receptor 2 signaling pathway
GO:0034138	toll-like receptor 3 signaling pathway
GO:0034142	toll-like receptor 4 signaling pathway
GO:0034146	toll-like receptor 5 signaling pathway
GO:0034162	toll-like receptor 9 signaling pathway
GO:0034166	toll-like receptor 10 signaling pathway
GO:0035556	intracellular signal transduction
GO:0035666	TRIF-dependent toll-like receptor signaling pathway
GO:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
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-dependent transcription in response to stress
GO:0045087	innate immune response
GO:0045597	positive regulation of cell differentiation
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0051403	stress-activated MAPK cascade

Cellular Component

GO:0005654	nucleoplasm
GO:0005829	cytosol
GO:0005840	ribosome
GO:0016020	membrane

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000961 AGC-kinase, C-terminal
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR010440 Lipopolysaccharide kinase
IPR011009 Protein kinase-like domain
IPR016239 Ribosomal protein S6 kinase II
IPR017892 Protein kinase, C-terminal
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF06293
PF00433

PRINTS

PR00109

PIRSF

PIRSF000606

SMART

SM00133
SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References