Abstract SY29-02: The TSC-mTOR pathway and control of anabolic tumor cell metabolism

Abstract

Abstract The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) plays an evolutionarily conserved role as a molecular link between cellular growth conditions and the anabolic processes promoting cell growth. This protein kinase complex has the ability to sense and integrate signals emanating from pathways that monitor cellular growth conditions, including the availability of intracellular nutrients and energy, the presence of specific growth factors and cytokines, and a variety of cellular stresses. Importantly, the integrated control over mTORC1 activity and cell growth is corrupted in most human tumors. mTORC1 senses many of these upstream signals through a small G protein switch involving the tuberous sclerosis complex (TSC) tumor suppressors, TSC1 and TSC2, and the Ras-related small G protein Rheb, an essential activator of mTORC1. The TSC1-TSC2 complex functions as a GTPase-activating protein (GAP) for Rheb, thereby stimulating its conversion to the inactive GDP-bound form and inhibiting its activation of mTORC1. Multi-site phosphorylation of the TSC1-TSC2 complex downstream of distinct signaling pathways accounts for much of the signal-integrating capacity of mTORC1. Importantly, both the oncogenic PI3K-Akt and Ras-Erk pathways phosphorylate and inhibit TSC2 to activate mTORC1. Aberrant regulation of the TSC1-TSC2 complex leading to constitutive activation of mTORC1 is a common molecular event in a large variety of pathological settings, including the majority of genetic tumor syndromes and sporadic cancers. However, the molecular mechanisms by which the TSC1-TSC2 complex is regulated and functions to properly control Rheb and mTORC1 are not well understood. Furthermore, the downstream consequences of dysregulated mTORC1 signaling in tumors remain poorly defined. This lecture will focus on recent studies in our laboratory to 1) characterize a third stoichiometric component of the TSC1-TSC2 complex and its role in mTOR regulation, and 2) the role of mTORC1 in the metabolic reprogramming of tumor cells induced by common oncogenic events. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY29-02. doi:1538-7445.AM2012-SY29-02