Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

RPS6KA3 (P51812) - Overview - Molecular Target Synopsis

Protein


RPS6KA3, Ribosomal protein S6 kinase alpha-3
Enzyme Classification 2.7.11.1
UniProt P51812

Also Known as KS6A3_HUMAN, RPS6KA3, ISPK1, MAPKAPK1B, RSK2

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. Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1. Phosphorylates SOS1 at 'Ser-1134' and 'Ser-1161' that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation (By similarity). Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). 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.

5D9K
RSK2 N-TERMINAL KINASE IN COMPLEX WITH BI-D1870
RCSB/PDB
Inspect Structure
See all 3D Structures for RPS6KA3

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: RPS6KA3 is active in the following subcellular-locations: cytoplasm, nucleus.
GO terms: RPS6KA3 is active in the following subcellular-locations: cytosol, nucleoplasm.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project RPS6KA3 has gain in 2 cell-lines, loss in 52 cell-lines and no signal in 950 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: COLO205, UACC_62, M14

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: Hep G2, NCI-H727, HuH-7

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HSMM, HeLa-S3

(see details)

RNA Interference


RPS6KA3 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: MCF12A, OVAS. (see details)

3D Structures


For RPS6KA3 there are:
13 structures (14 chains) solved
13 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


RPS6KA3 has been screened with 1435 compounds (2512 bioactivities), 203 compounds have bioactivities that show binding affinity of <= 500nM (242 bioactivities). (see details)