mTOR signaling at a glance

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation and survival. Discoveries that have been made over the last decade show that the mTOR pathway is activated during various cellular processes (e.g. tumor formation and angiogenesis, insulin resistance, adipogenesis and T-lymphocyte activation) and is deregulated in human diseases such as cancer and type 2 diabetes. These observations have attracted broad scientific and clinical interest in mTOR. This is highlighted by the growing use of mTOR inhibitors [rapamycin and its analogues (rapalogues)] in pathological settings, including the treatment of solid tumors, organ transplantation, coronary restenosis and rheumatoid arthritis. Here, we highlight and summarize the current understanding of how mTOR nucleates distinct multi-protein complexes, how intra- and extracellular signals are processed by the mTOR complexes, and how such signals affect cell metabolism, growth, proliferation and survival.The mTOR protein is a 289-kDa serine-threonine kinase that belongs to the phospho-inositide 3-kinase (PI3K)-related kinase family and is conserved throughout evolution. The poster depicts an overview of mTOR structural domains. mTOR nucleates at least two distinct multi-protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (reviewed by Guertin and Sabatini, 2007).mTORC1 has five components: mTOR, which is the catalytic subunit of the complex; regulatory-associated protein of mTOR (Raptor); mammalian lethal with Sec13 protein 8 (mLST8, also known as GβL); proline-rich AKT substrate 40 kDa (PRAS40); and DEP-domain-containing mTOR-interacting protein (Deptor) (Peterson et al., 2009). The exact function of most of the mTOR-interacting proteins in mTORC1 still remains elusive. It has been proposed that Raptor might affect mTORC1 activity by regulating assembly of the complex and by recruiting substrates for mTOR (Hara et al., 2002; Kim et al., 2002). The role of mLST8 in mTORC1 function is also unclear, as deletion of this protein does not affect mTORC1 activity in vivo (Guertin et al., 2006). PRAS40 and Deptor have been characterized as distinct negative regulators of mTORC1 (Peterson et al., 2009; Sancak et al., 2007; Vander Haar et al., 2007). When the activity of mTORC1 is reduced, PRAS40 and Deptor are recruited to the complex, where they promote the inhibition of mTORC1. It was proposed that PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding (Wang et al., 2007). Upon activation, mTORC1 directly phosphorylates PRAS40 and Deptor, which reduces their physical interaction with mTORC1 and further activates mTORC1 signaling (Peterson et al., 2009; Wang et al., 2007).mTORC2 comprises six different proteins, several of which are common to mTORC1 and mTORC2: mTOR; rapamycin-insensitive companion of mTOR (Rictor); mammalian stress-activated protein kinase interacting protein (mSIN1); protein observed with Rictor-1 (Protor-1); mLST8; and Deptor. There is some evidence that Rictor and mSIN1 stabilize each other, establishing the structural foundation of mTORC2 (Frias et al., 2006; Jacinto et al., 2006). Rictor also interacts with Protor-1, but the physiological function of this interaction is not clear (Thedieck et al., 2007; Woo et al., 2007). Similar to its role in mTORC1, Deptor negatively regulates mTORC2 activity (Peterson et al., 2009); so far, Deptor is the only characterized endogenous inhibitor of mTORC2. Finally, mLST8 is essential for mTORC2 function, as knockout of this protein severely reduces the stability and the activity of this complex (Guertin et al., 2006).Now that many mTOR-interacting proteins have been identified, additional biochemical studies will be needed to clarify the functions of these proteins in mTOR signaling and their potential implications in health and disease. Below, we discuss current understanding of the functions of mTORC1 and mTORC2.mTORC1 positively regulates cell growth and proliferation by promoting many anabolic processes, including biosynthesis of proteins, lipids and organelles, and by limiting catabolic processes such as autophagy. Much of the knowledge about mTORC1 function comes from the use of the bacterial macrolide rapamycin. Upon entering the cell, rapamycin binds to FK506-binding protein of 12 kDa (FKBP12) and interacts with the FKBP12-rapamycin binding domain (FRB) of mTOR, thus inhibiting mTORC1 functions (reviewed by Guertin and Sabatini, 2007). In contrast to its effect on mTORC1, FKBP12-rapamycin cannot physically interact with or acutely inhibit mTORC2 (Jacinto et al., 2004; Sarbassov et al., 2004). On the basis of these observations, mTORC1 and mTORC2 have been respectively characterized as the rapamycin-sensitive and rapamycin-insensitive complexes. However, this paradigm might not be entirely accurate, as chronic rapamy