ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling
- 1 May 2011
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 300 (5), C1172-C1180
- https://doi.org/10.1152/ajpcell.00504.2010
Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that, when present in a complex referred to as mTOR complex 1 (mTORC1), acts as an important regulator of growth and metabolism. The activity of the complex is regulated through multiple upstream signaling pathways, including those involving Akt and the extracellular-regulated kinase (ERK). Previous studies have shown that, in part, Akt and ERK promote mTORC1 signaling through phosphorylation of a GTPase activator protein (GAP), referred to as tuberous sclerosis complex 2 (TSC2), that acts as an upstream inhibitor of mTORC1. In the present study we extend the earlier studies to show that activation of the Akt and ERK pathways acts in a synergistic manner to promote mTORC1 signaling. Moreover, we provide evidence that the Akt and ERK signaling pathways converge on TSC2, and that Akt phosphorylates residues on TSC2 distinct from those phosphorylated by ERK. The results also suggest that leucine-induced stimulation of mTORC1 signaling occurs through a mechanism distinct from TSC2 and the Akt and ERK signaling pathways. Overall, the results are consistent with a model in which Akt and ERK phosphorylate distinct sites on TSC2, leading to greater repression of its GAP activity, and consequently a magnified stimulation of mTORC1 signaling, when compared with either input alone. The results further suggest that leucine acts through a mechanism distinct from TSC2 to stimulate mTORC1 signaling.Keywords
This publication has 61 references indexed in Scilit:
- ERK1/2 Phosphorylate Raptor to Promote Ras-dependent Activation of mTOR Complex 1 (mTORC1)Published by Elsevier BV ,2011
- Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1Molecular Cell, 2010
- 4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in TumorsCancer Cell, 2010
- Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino AcidsCell, 2010
- An Emerging Role of mTOR in Lipid BiosynthesisCurrent Biology, 2009
- Nutrient control of TORC1, a cell-cycle regulatorTrends in Cell Biology, 2009
- Rapamycin administration in humans blocks the contraction‐induced increase in skeletal muscle protein synthesisThe Journal of Physiology, 2009
- Activation of the mammalian target of rapamycin complex 1 is both necessary and sufficient to stimulate eukaryotic initiation factor 2Bɛ mRNA translation and protein synthesisThe International Journal of Biochemistry & Cell Biology, 2008
- Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancersNature Medicine, 2008
- Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitiveNature, 2004