Extended Influence

Science Signaling  10 Aug 2010:
Vol. 3, Issue 134, pp. ec243
DOI: 10.1126/scisignal.3134ec243

Mammalian target of rapamycin (mTOR) is a serine and threonine kinase that is involved in cell growth and proliferation. It exists in the cell in two distinct complexes, mTORC1 and mTORC2, whose regulation, functions, and downstream targets differ. mTORC1 promotes protein synthesis and is a sensor of the metabolic state of the cell; its activity depends on the presence or absence of nutrients and growth factors. Whereas mTORC1 activity is inhibited by rapamycin, mTORC2 activity is not. In addition, mTORC1 is inhibited by an upstream complex consisting of the GTPase-activating protein TSC2 and TSC1, whereas the activity of mTORC2 is promoted by TSC1-TSC2. In cells deficient in Tsc1 and Tsc2, mTORC1 becomes constitutively activated, whereas mTORC2 activity is defective, and aberrant states of activity are unaffected by growth factors. Düvel et al. compared TSC-deficient mouse embryonic fibroblasts (MEFs) with wild-type MEFs that were cultured in the absence of growth factors to identify processes that depended solely on the activation of mTORC1. Genomic, metabolomic, and bioinformatic analyses showed that the expression of genes that encoded enzymes involved in specific metabolic pathways depended on mTORC1 activity. The mTORC1-dependent stimulation of glycolysis required hypoxia-inducible factor 1α, whereas stimulation of the pentose phosphate pathway and of lipid biosynthesis required sterol regulatory element-binding proteins 1 and 2, which in turn were regulated by the mTORC1 target S6 kinase. Together, these data suggest that the effects of mTORC1 activity extend beyond protein synthesis into other metabolic pathways that alter cell physiology.

K. Düvel, J. L. Yecies, S. Menon, P. Raman, A. I. Lipovsky, A. L. Souza, E. Triantafellow, Q. Ma, R. Gorski, S. Cleaver, M. G. Vander Heiden, J. P. MacKeigan, P. M. Finan, C. B. Clish, L. O. Murphy, B. D. Manning, Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010). [PubMed]