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P70-S6 Kinase 1

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RPS6KB1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRPS6KB1, PS6K, S6K, S6K-beta-1, S6K1, STK14A, p70 S6KA, p70(S6K)-alpha, p70-S6K, p70-alpha, P70-S6 Kinase 1, ribosomal protein S6 kinase B1, p70S6K, p70S6 kinase
External IDsOMIM: 608938; MGI: 1270849; HomoloGene: 81703; GeneCards: RPS6KB1; OMA:RPS6KB1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6198

72508

Ensembl

ENSG00000108443

ENSMUSG00000020516

UniProt

P23443

Q8BSK8

RefSeq (mRNA)

NM_001272042
NM_001272043
NM_001272044
NM_001272060
NM_003161

NM_001114334
NM_028259
NM_001363162

RefSeq (protein)

NP_001107806
NP_082535
NP_001350091

Location (UCSC)Chr 17: 59.89 – 59.95 MbChr 11: 86.5 – 86.54 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6] It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway.[7] As the name suggests, its target substrate is the S6 ribosomal protein.[8] 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.[9][10]

Function

This gene encodes a member of the RSK family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates 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 functions as part of a signaling pathway that includes mTOR (the mammalian target of rapamycin). mTOR can be activated in distinct ways, thereby activating p70S6K. For example, branched chain amino acids such as leucine are sufficient to activate mTOR, resulting in an increase in p70S6K phosphorylation (and thereby activating it). mTOR is also in a pathway downstream of the kinase Akt. Akt is typically activated upon stimulation of a cell with a growth factor (such as IGF-1). Akt then activates mTOR (by inhibiting the Tsc complex), leading to p70S6K activation.

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 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.[11]

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.[12]

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.[13]

Interactions

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

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000108443 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020516 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Grove JR, Banerjee P, Balasubramanyam A, Coffer PJ, Price DJ, Avruch J, Woodgett JR (Nov 1991). "Cloning and expression of two human p70 S6 kinase polypeptides differing only at their amino termini". Molecular and Cellular Biology. 11 (11): 5541–50. doi:10.1128/mcb.11.11.5541. PMC 361924. PMID 1922062.
  6. ^ "Entrez Gene: RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1".
  7. ^ "PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase". Nature. 370 (6484): 71–75. 1994. doi:10.1038/370071a0. PMID 8015612. {{cite journal}}: Unknown parameter |authors= ignored (help)
  8. ^ "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. {{cite journal}}: Unknown parameter |authors= ignored (help)
  9. ^ Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, Lockshin RA, Garcia-Sastre A, Zakeri Z (2014). "mTOR/p70s6k signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza infection". Virology. 452–453 (march 2014): 175–190. doi:10.1016/j.virol.2014.01.008. PMC 4005847. PMID 24606695.
  10. ^ Ci Y, Shi K, An J, Yang Y, Hui K, Wu P, Shi L, Xu C (2014). "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. doi:10.1038/cddis.2014.506.
  11. ^ Carnevalli LS, Masuda K, Frigerio F, Le Bacquer O, Um SH, Gandin V, Topisirovic I, Sonenberg N, Thomas G, Kozma SC (May 2010). "S6K1 plays a critical role in early adipocyte differentiation". Developmental Cell. 18 (5): 763–74. doi:10.1016/j.devcel.2010.02.018. PMC 2918254. PMID 20493810.
  12. ^ Van Dyke JM, Bain JL, Riley DA (Jan 2014). "Stretch-activated signaling is modulated by stretch magnitude and contraction". Muscle & Nerve. 49 (1): 98–107. doi:10.1002/mus.23880. PMID 23620271.
  13. ^ 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: 569–580. doi:10.1016/j.cell.2005.10.024. PMID 16286006. Retrieved 1 March 2016.
  14. ^ Nemazanyy I, Panasyuk G, Zhyvoloup A, Panayotou G, Gout IT, Filonenko V (Dec 2004). "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. doi:10.1016/j.febslet.2004.10.091. PMID 15589845.
  15. ^ Panasyuk G, Nemazanyy I, Zhyvoloup A, Bretner M, Litchfield DW, Filonenko V, Gout IT (Oct 2006). "Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17". The Journal of Biological Chemistry. 281 (42): 31188–201. doi:10.1074/jbc.M602618200. PMID 16895915.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  17. ^ Ali SM, Sabatini DM (May 2005). "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. doi:10.1074/jbc.C500125200. PMID 15809305.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  19. ^ Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (Jul 2002). "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action". Cell. 110 (2): 177–89. doi:10.1016/S0092-8674(02)00833-4. PMID 12150926.
  20. ^ Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K (May 2003). "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. doi:10.1074/jbc.C200665200. PMID 12604610.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Chiang GG, Abraham RT (Jul 2005). "Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase". The Journal of Biological Chemistry. 280 (27): 25485–90. doi:10.1074/jbc.M501707200. PMID 15899889.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Holz MK, Blenis J (Jul 2005). "Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase". The Journal of Biological Chemistry. 280 (28): 26089–93. doi:10.1074/jbc.M504045200. PMID 15905173.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K (Nov 1999). "Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro". The Journal of Biological Chemistry. 274 (48): 34493–8. doi:10.1074/jbc.274.48.34493. PMID 10567431.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (Apr 2005). "Rheb binds and regulates the mTOR kinase". Current Biology. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMID 15854902.
  25. ^ Toral-Barza L, Zhang WG, Lamison C, Larocque J, Gibbons J, Yu K (Jun 2005). "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. doi:10.1016/j.bbrc.2005.04.117. PMID 15896331.
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