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

RPS6KB1 (P23443) - Overview - Molecular Target Synopsis

Protein


RPS6KB1, Ribosomal protein S6 kinase beta-1
Enzyme Classification 2.7.11.1
UniProt P23443

Also Known as KS6B1_HUMAN, RPS6KB1, STK14A

Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR (PubMed:11500364, PubMed:12801526, PubMed:14673156, PubMed:15071500, PubMed:15341740, PubMed:16286006, PubMed:17052453, PubMed:17053147, PubMed:17936702, PubMed:18952604, PubMed:19085255, PubMed:19720745, PubMed:19935711, PubMed:19995915, PubMed:23429703). Following activation by mTORC1, phosphorylates EPRS and thereby plays a key role in fatty acid uptake by adipocytes and also most probably in interferon-gamma-induced translation inhibition (PubMed:28178239). Interacts with PPP1R9A/neurabin-1 (By similarity). Interacts with RPTOR (PubMed:12150926). Interacts with IRS1 (PubMed:18952604). Interacts with EIF3B and EIF3C (PubMed:16286006). Interacts with TRAF4 (PubMed:12801526). Interacts with POLDIP3 (PubMed:15341740). Interacts (via N-terminus) with IER5 (PubMed:26496226).

5WBH
19 RESIDUE FRAGMENT OF
RIBOSOMAL PROTEIN S6 KINASE BETA-1
IN THE STRUCTURE OF
STRUCTURE OF THE FRB DOMAIN OF MTOR BOUND TO A SUBSTRATE RECRUITMENT PEPTIDE OF S6K1
RCSB/PDB
Inspect Structure
See all 3D Structures for RPS6KB1

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: RPS6KB1 is active in the following subcellular-locations: cell junction, cytoplasm, mitochondrion, mitochondrion outer membrane, nucleus, synapse, synaptosome.
GO terms: RPS6KB1 is active in the following subcellular-locations: cell junction, cell surface, cytoplasm, cytosol, mitochondrial outer membrane, mitochondrion, neuron projection, nucleoplasm, nucleus, perinuclear region of cytoplasm, synapse.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project RPS6KB1 has gain in 7 cell-lines, loss in 0 cell-lines and no signal in 998 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MCF7, NCI_H522, SR

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: MCF-7, KPL-1, HCC2911

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: MCF-7, NHLF, AG445

(see details)

RNA Interference


RPS6KB1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SUM44, MDAMB157. (see details)

3D Structures


For RPS6KB1 there are:
20 structures (22 chains) solved
18 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


RPS6KB1 has been screened with 2371 compounds (3124 bioactivities), 1009 compounds have bioactivities that show binding affinity of <= 500nM (1045 bioactivities). (see details)