Biology:P70-S6 Kinase 1

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Short description: Protein-coding gene in the species Homo sapiens


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Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the RPS6KB1 gene.[1][2] It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway.[3] As the name suggests, its target substrate is the S6 ribosomal protein.[4] Phosphorylation of S6 induces protein synthesis at the ribosome.

The phosphorylation of p70S6K at threonine 389 has been used as a hallmark of activation by mTOR and correlated with autophagy inhibition in various situations. However, several recent studies suggest that the activity of p70S6K plays a more positive role in the increase of autophagy.[5][6]

Function

This gene encodes a member of the S6K family of serine/threonine kinases, which phosphorylate several residues of the S6 ribosomal protein. The kinase activity of this protein leads to an increase in protein synthesis and cell proliferation. Amplification of the region of DNA encoding this gene and overexpression of this kinase are seen in some breast cancer cell lines. Alternate translational start sites have been described and alternate transcriptional splice variants have been observed but have not been thoroughly characterized.

mTOR

The p70S6 kinase is a downstream target of mTOR (mammalian target of rapamycin) signaling, specifically mTORC1, an mTOR-containing complex characterized by the inclusion of Raptor rather than Rictor (mTORC2). mTOR can be activated via an AND-gate-like mechanism at the lysosome, integrating signals about growth factors and bioavailability of important molecules. For instance, amino acids such as arginine and leucine can trigger lysosomal recruitment of mTORC1. Once at the lysosome, mTOR can be activated by Rheb, a small, lysosomal-resident GTPase, in its GTP-bound state. Rheb GTPase activity is stimulated (and therefore capacity to activate mTOR diminished) by the upstream TSC complex, which is inhibited by IGF signalling. Thus, the AND gate consists of proper localization by sufficiency of amino acids and activation by growth factors. Once mTOR has been properly localized and activated, it can phosphorylate downstream targets such as p70S6K, 4EBP, and ULK1 which are important for regulating protein anabolic/catabolic balance.

Physical exercise activates protein synthesis via phosphorylation (activation) of p70S6K in a pathway that is dependent on mTOR, specifically mTORC1. This has been demonstrated by using an inhibitor of mTOR, rapamycin, to block an increase in muscle mass, despite increases in load (e.g., exercise). Exercise has been shown to increase levels of IGF-1 in muscle, thus inducing the IGF-1/PI3K/Akt/p70S6K signaling pathway, and thereby increasing the protein synthesis is required to build muscle.

Clinical significance

Inhibition of the S6K1 protein, or a lack of it, slows the production of adipose (fat) cells by disrupting and retarding the initial "commitment stage" of their formation. The study could have implications for the treatment of obesity.[7]

Amplification of the region of DNA encoding this gene and overexpression of this kinase are seen in some breast cancer cell lines.

Another pathway for which P70 has proposed involvement is in muscle lengthening and growing. P70 is phosphorylated by passive stretch in the soleus muscle. This may be one of many protein kinases involved in muscle building.[8]

In its inactive state, S6K1 is bound to eIF3 and detaches following phosphorylation by mTOR/Raptor. Free S6K1 is then able to phosphorylate a number of its targets, including eIF4B.[9]

Interactions

P70-S6 Kinase 1 has been shown to interact with:


See also

References

  1. ↑ "Cloning and expression of two human p70 S6 kinase polypeptides differing only at their amino termini". Molecular and Cellular Biology 11 (11): 5541–50. Nov 1991. doi:10.1128/mcb.11.11.5541. PMID 1922062. 
  2. ↑ "Entrez Gene: RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6198. 
  3. ↑ "PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase". Nature 370 (6484): 71–75. 1994. doi:10.1038/370071a0. PMID 8015612. Bibcode: 1994Natur.370...71C. 
  4. ↑ "Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases.". Cell 69 (7): 1227–1236. 1992. doi:10.1016/0092-8674(92)90643-Q. PMID 1377606. 
  5. ↑ "mTOR/p70s6k signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza infection". Virology 452-453: 175–190. March 2014. doi:10.1016/j.virol.2014.01.008. PMID 24606695. 
  6. ↑ "ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells". Cell Death and Disease 5 (November 2014): 1–10. 2014. doi:10.1038/cddis.2014.506. PMID 25429619. 
  7. ↑ "S6K1 plays a critical role in early adipocyte differentiation". Developmental Cell 18 (5): 763–74. May 2010. doi:10.1016/j.devcel.2010.02.018. PMID 20493810. 
  8. ↑ "Stretch-activated signaling is modulated by stretch magnitude and contraction". Muscle & Nerve 49 (1): 98–107. Jan 2014. doi:10.1002/mus.23880. PMID 23620271. 
  9. ↑ Holz, Marina K.; Ballif, Bryan A.; Gygi, Steven P.; Blenis, John (2005). "mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events". Cell 123 (4): 569–580. doi:10.1016/j.cell.2005.10.024. PMID 16286006. 
  10. ↑ "Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism". FEBS Letters 578 (3): 357–62. Dec 2004. doi:10.1016/j.febslet.2004.10.091. PMID 15589845. 
  11. ↑ "Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17". The Journal of Biological Chemistry 281 (42): 31188–201. Oct 2006. doi:10.1074/jbc.M602618200. PMID 16895915. 
  12. ↑ "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events". Cell 123 (4): 569–80. Nov 2005. doi:10.1016/j.cell.2005.10.024. PMID 16286006. 
  13. ↑ "Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site". The Journal of Biological Chemistry 280 (20): 19445–8. May 2005. doi:10.1074/jbc.C500125200. PMID 15809305. 
  14. ↑ "PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals". Cellular Signalling 18 (12): 2283–91. Dec 2006. doi:10.1016/j.cellsig.2006.05.021. PMID 16837165. 
  15. ↑ "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action". Cell 110 (2): 177–89. Jul 2002. doi:10.1016/S0092-8674(02)00833-4. PMID 12150926. 
  16. ↑ "The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif". The Journal of Biological Chemistry 278 (18): 15461–4. May 2003. doi:10.1074/jbc.C200665200. PMID 12604610. 
  17. ↑ "Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase". The Journal of Biological Chemistry 280 (27): 25485–90. Jul 2005. doi:10.1074/jbc.M501707200. PMID 15899889. 
  18. ↑ "Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase". The Journal of Biological Chemistry 280 (28): 26089–93. Jul 2005. doi:10.1074/jbc.M504045200. PMID 15905173. 
  19. ↑ "Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro". The Journal of Biological Chemistry 274 (48): 34493–8. Nov 1999. doi:10.1074/jbc.274.48.34493. PMID 10567431. 
  20. ↑ "Rheb binds and regulates the mTOR kinase". Current Biology 15 (8): 702–13. Apr 2005. doi:10.1016/j.cub.2005.02.053. PMID 15854902. 
  21. ↑ "Characterization of the cloned full-length and a truncated human target of rapamycin: activity, specificity, and enzyme inhibition as studied by a high capacity assay". Biochemical and Biophysical Research Communications 332 (1): 304–10. Jun 2005. doi:10.1016/j.bbrc.2005.04.117. PMID 15896331. 
  22. ↑ "Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site". The Journal of Biological Chemistry 277 (22): 20104–12. May 2002. doi:10.1074/jbc.M201745200. PMID 11914378. 
  23. ↑ "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery". Cell 110 (2): 163–75. Jul 2002. doi:10.1016/S0092-8674(02)00808-5. PMID 12150925. 
  24. ↑ "Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells". Cancer Research 63 (23): 8451–60. Dec 2003. PMID 14679009. 
  25. ↑ "The FRB domain of mTOR: NMR solution structure and inhibitor design". Biochemistry 45 (34): 10294–302. Aug 2006. doi:10.1021/bi060976+. PMID 16922504. 
  26. ↑ "Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro". Genes to Cells 5 (9): 765–75. Sep 2000. doi:10.1046/j.1365-2443.2000.00365.x. PMID 10971657. 
  27. ↑ "RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1". Proceedings of the National Academy of Sciences of the United States of America 95 (4): 1432–7. Feb 1998. doi:10.1073/pnas.95.4.1432. PMID 9465032. Bibcode: 1998PNAS...95.1432B. 
  28. ↑ "Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex". The Journal of Biological Chemistry 280 (47): 39505–9. Nov 2005. doi:10.1074/jbc.M506096200. PMID 16183647. 
  29. ↑ "SKAR is a specific target of S6 kinase 1 in cell growth control". Current Biology 14 (17): 1540–9. Sep 2004. doi:10.1016/j.cub.2004.08.061. PMID 15341740. 
  30. ↑ "Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein". Proceedings of the National Academy of Sciences of the United States of America 96 (8): 4438–42. Apr 1999. doi:10.1073/pnas.96.8.4438. PMID 10200280. Bibcode: 1999PNAS...96.4438P. 
  31. ↑ "Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells". The Journal of Endocrinology 190 (2): 307–12. Aug 2006. doi:10.1677/joe.1.06368. PMID 16899564. 
  32. ↑ 32.0 32.1 "Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1". Biochemical and Biophysical Research Communications 369 (2): 339–43. May 2008. doi:10.1016/j.bbrc.2008.02.016. PMID 18279656. 

External links

  • Overview of all the structural information available in the PDB for UniProt: P23443 (Ribosomal protein S6 kinase beta-1) at the PDBe-KB.



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