7 Growth Control through the mTOR Network

Abstract

Before traversing through the cell cycle, most dividing cells accumulate mass and grow in size. In unicellular organisms like budding yeast, environmental nutrients are the main regulators of cell growth, whereas animals employ additional levels of control in the form of growth factor-dependent signaling networks. The conserved serine/threonine protein kinase, Target of Rapamycin (TOR; known in mammals as mTOR, FRAP, or RAFT1), has emerged as a critical regulator of cellular growth in eukaryotes. In mammals, mTOR is the core component of a signaling network that integrates inputs derived from nutrients and growth factors to regulate cell growth, an effect mediated in part through the control of the protein synthesis machinery. In this chapter, we provide an overview of mTOR and its associated proteins and discuss in detail how nutrients and growth factors coordinately regulate the mTOR pathway. To conclude, we examine the wider implications of mTOR signaling in development and disease. mTOR AND ITS EFFECTORS mTOR was identified in studies aimed at defining the molecular target of the antiproliferative drug rapamycin (Brown et al. 1994; Chiu et al. 1994; Sabatini et al. 1994; Sabers et al. 1995), a macrolide antibiotic produced by the soil bacterium Streptomyces hygroscopicus (Sehgal et al. 1975; Vezina et al. 1975). After entering the cell, rapamycin interacts at varying affinities with several members of the FKBP family of prolyl isomerases. The complex of rapamycin with one member of this family, FKBP12, gains the capacity to bind and perturb the function of mTOR. Although originally valued for...