Description: Homo sapiens ribosomal protein S6 kinase, 70kDa, polypeptide 1 (RPS6KB1), transcript variant 1, mRNA. RefSeq Summary (NM_003161): This gene encodes a member of the ribosomal S6 kinase family of serine/threonine kinases. The encoded protein responds to mTOR (mammalian target of rapamycin) signaling to promote protein synthesis, cell growth, and cell proliferation. Activity of this gene has been associated with human cancer. Alternatively spliced transcript variants have been observed. The use of alternative translation start sites results in isoforms with longer or shorter N-termini which may differ in their subcellular localizations. There are two pseudogenes for this gene on chromosome 17. [provided by RefSeq, Jan 2013]. Transcript (Including UTRs) Position: hg19 chr17:57,970,407-58,027,786 Size: 57,380 Total Exon Count: 15 Strand: + Coding Region Position: hg19 chr17:57,970,546-58,024,149 Size: 53,604 Coding Exon Count: 15
ID:KS6B1_HUMAN DESCRIPTION: RecName: Full=Ribosomal protein S6 kinase beta-1; Short=S6K-beta-1; Short=S6K1; EC=2.7.11.1; AltName: Full=70 kDa ribosomal protein S6 kinase 1; Short=P70S6K1; Short=p70-S6K 1; AltName: Full=Ribosomal protein S6 kinase I; AltName: Full=Serine/threonine-protein kinase 14A; AltName: Full=p70 ribosomal S6 kinase alpha; Short=p70 S6 kinase alpha; Short=p70 S6K-alpha; Short=p70 S6KA; FUNCTION: 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 preinitiation 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. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Inactivated by binding to URI1. Activation requires multiple phosphorylation events on serine/threonine residues. Activation appears to be first mediated by phosphorylation of multiple sites in the autoinhibitory domain, which facilitates phosphorylation at Thr-412, disrupting the autoinhibitory mechanism and allowing phosphorylation of Thr-252 by PDPK1. The active conformation of the kinase is believed to be stabilized by a mechanism involving three conserved phosphorylation sites located in the kinase domain activation loop (Thr-252) and in the AGC-kinase C-terminal domain (Ser-394 in the middle of the tail/linker region and Thr-412 within a hydrophobic motif at its end). Activated by mTORC1; isoform Alpha I and isoform Alpha II are sensitive to rapamycin, which inhibits activating phosphorylation at Thr-412. Activated by PDPK1. SUBUNIT: Interacts with PPP1R9A/neurabin-1 (By similarity). Interacts with RPTOR. Interacts with IRS1. Interacts with EIF3B and EIF3C. Interacts with POLDIP3 and TRAF4. INTERACTION: P08151:GLI1; NbExp=4; IntAct=EBI-1775921, EBI-308084; Q00005:PPP2R2B; NbExp=2; IntAct=EBI-1775921, EBI-1052159; SUBCELLULAR LOCATION: Cell junction, synapse, synaptosome (By similarity). Mitochondrion outer membrane. Mitochondrion. Note=Colocalizes with URI1 at mitochondrion. SUBCELLULAR LOCATION: Isoform Alpha I: Nucleus. Cytoplasm. SUBCELLULAR LOCATION: Isoform Alpha II: Cytoplasm. TISSUE SPECIFICITY: Widely expressed. DOMAIN: The autoinhibitory domain is believed to block phosphorylation within the AGC-kinase C-terminal domain and the activation loop. DOMAIN: The TOS (TOR signaling) motif is essential for activation by mTORC1 (By similarity). PTM: Phosphorylation at Thr-412 is regulated by mTORC1. The phosphorylation at this site is maintained by an agonist-dependent autophosphorylation mechanism (By similarity). Activated by phosphorylation at Thr-252 by PDPK1. Dephosphorylation by PPP1CC at Thr-412 in mitochondrion. 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 1 protein kinase domain.
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Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): RPS6KB1 CDC HuGE Published Literature: RPS6KB1 Positive Disease Associations: Multiple Sclerosis Related Studies:
Multiple Sclerosis Stephen Sawcer et al. Nature 2011, Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis., Nature.
[PubMed 21833088]
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.
ModBase Predicted Comparative 3D Structure on P23443
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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.
BioCarta from NCI Cancer Genome Anatomy Project h_ctcfPathway - CTCF: First Multivalent Nuclear Factor h_ptdinsPathway - Phosphoinositides and their downstream targets. h_rac1Pathway - Rac 1 cell motility signaling pathway h_eif4Pathway - Regulation of eIF4e and p70 S6 Kinase h_igf1mtorpathway - Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway h_il4Pathway - IL 4 signaling pathway h_mapkPathway - MAPKinase Signaling Pathway h_nfatPathway - NFAT and Hypertrophy of the heart (Transcription in the broken heart) h_mTORPathway - mTOR Signaling Pathway h_il2rbPathway - IL-2 Receptor Beta Chain in T cell Activation
Reactome (by CSHL, EBI, and GO)
Protein P23443 (Reactome details) participates in the following event(s):
R-HSA-165718 mTORC1 phosphorylation of RPS6KB1 (S6K) R-HSA-165726 Phosphorylation of Ribosomal protein S6 by activated S6K1 R-HSA-165758 Phosphorylation and inactivation of eEF2K by activated S6K1 R-HSA-165766 Phosphorylation and activation of eIF4G by activated S6K1 R-HSA-165777 Phosphorylation and activation of eIF4B by activated S6K1 R-HSA-166208 mTORC1-mediated signalling R-HSA-165159 mTOR signalling R-HSA-162582 Signal Transduction
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