13. mTORC Signalling

 

13.1. mTORC1 Signalling 

 

Mammalian Target of Rapamycin (mTOR), which shapes the catalytic subunits of mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2), is a serine/threonine kinase and part of PI3K-related kinase family of kinase (PIKK) (Saxton R A and Sabatini D M., 2017).

 

As mTORC1 phosphorylates p70S6 kinase 1(S6K1) and eIF4E Binding protein (4EBP) then it induces protein synthesis (Saxton R A and Sabatini D M., 2017).

 

PDK1 phosphorylation and induction occur following mTORC1 phosphorylation of THr389 hydrophobic motif site of S6K1 (Saxton R A and Sabatini D M., 2017).

 

mRNA translation induction of substrates such as eIF4B takes place following their phosphorylation and activation by S6K1 (Holz M K et al., 2005) (Saxton R A and Sabatini D M., 2017). Furthermore, phosphorylation and deprivation of PDCD4, an inhibitor of eIF4B, also induced by S6K1 (Dorello N V et al., 2006 as cited in Saxton R A and Sabatini D M., 2017) (Saxton R A and Sabatini D M., 2017).

 

Inhibition of the assemblage of eIF4E complex occurs as a result of binding and confiscating 4EBP to eIF4E and consequently preventing translation. Furthermore, detachment of 4EBP from eIF4E takes place as a result of 4EBP phosphorylation of 4EBP at numerous sites by mTORC1 (Brunn G J et al., 1997 as cited in Saxton R A and Sabatini D M., 2017) (Gingras A C et al., 1999). This, in turn, results in the translation of 5’ cap-dependent mRNA (Saxton R A and Sabatini D M., 2017).

 

It is also known that Sterol Responsive Element Binding Protein (SREBP) transcription factors, regulating the expression of metabolic genes that are playing role in fatty acid and cholesterol biosynthesis, are induced by mTORC1 a factor, playing role in the synthesis of new lipid formation (Porstmann T et al., 2008) (Saxton R A and Sabatini D M., 2017). A S6K1 led mechanism can also promote SREBP separately, which is induced by mTORC1 signalling (Duvel K et al., 2010) in addition to another avenue, which involves phosphorylation of Lipin 1 that results in inactivation of SEREP when there is a lack of mTORC1 signalling (Saxton R A and Sabatini D M., 2017). 

 

Glucose metabolism alteration from oxidative phosphorylation to glycolysis is also induced by mTORC1, which results in growth and development (Saxton R A and Sabatini D M., 2017). In addition, the translation of HIF1α is raised by mTORC1, promoting the expression of phosphor-fructo kinase (PFK) and a number of other glycolytic enzymes (Duvel K et al., 2010) (Saxton R A and Sabatini D M., 2017).

 

mTORC1 Signalling References

 

1.        Brunn, G. J. et al. Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin. Science (80-. ). 277, 99–101 (1997).

2.        Dorrello, N. V. et al. S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth. Science (80-. ). 314, 467–471 (2006).

3.        Düvel, K. et al. Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1. Mol. Cell39, 171–183 (2010).

4.        Gingras, A.-C. et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 13, 1422–1437 (1999).

5.        Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events. Cell 123, 569–580 (2005).

6.        Porstmann, T. et al. SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth. Cell Metab. 8, 224–236 (2008).

7.        Saxton, R. A. & Sabatini, D. M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 168, 960–976 (2017).

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13.2. mTORC2 Signalling

 

Mammalian Target of Rapamycin 2 (mTORC2), mainly through phosphorylation of AGC members such as PKA, PKG and PKC kinases, is known to regulate proliferation and survival (Saxton R A and Sabatini D M., 2017). PKCα, which controls the actin cytoskeleton, is the primary substrate of mTORC2  (Jacinto E et al., 2004 as cited in Saxton R A and Sabatini D M., 2017) (Sarbassov D D et al., 2004) (Saxton R A and Sabatini D M., 2017). In addition, mTORC2 controls different facets of cytoskeletal remodeling and cell migration through phosphorylation of PKCδ (Gan X et al., 2012) PKCζ (Li X and Gao T., 2014) PKCϒ and PKCε (Thomanetz V et al., 2013) (Saxton R A and Sabatini D M., 2017).

 

Phosphorylation and induction of AKT/PKB, which plays a role in insulin/PI3K signaling is an essential role of mTORC2 (Sarbassov D D et al., 2005 as cited in Saxton R A and Sabatini D M., 2017) (Saxton R A and Sabatini D M., 2017). As AKT is induced then it results in phosphorylation and inactivation of FoxO1/3a, GSK3β and TSC2, which advances cell survival, proliferation, in addition to growth and development (Saxton R A and Sabatini D M., 2017).

 

mTORC2 Signalling References

 

1.        Dos D. Sarbassov et al. Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

2.        Gan, X. et al. PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12. Nat. Cell Biol. 14, 686–696 (2012).

3.        Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128 (2004).

4.        Li, X. & Gao, T. <scp>mTORC</scp> 2 phosphorylates protein kinase Cζ to regulate its stability and activity. EMBO Rep. 15, 191–198 (2014).

5.        Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex. Science (80-. ). 307, 1098–1101 (2005).

6.        Saxton, R. A. & Sabatini, D. M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 168, 960–976 (2017).

7.        Thomanetz, V. et al. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J. Cell Biol. 201, 293–308 (2013).