Control of cell growth: Rag GTPases in activation of TORC1
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Cellular and Molecular Life Sciences
REVIEW
Control of cell growth: Rag GTPases in activation of TORC1 Huirong Yang • Rui Gong • Yanhui Xu
Received: 16 April 2012 / Revised: 1 October 2012 / Accepted: 11 October 2012 / Published online: 16 December 2012 Ó Springer Basel 2012
Abstract The target of rapamycin (TOR) is a central regulator controlling cell growth. TOR is highly conserved from yeast to mammals, and is deregulated in human cancers and diabetes. TOR complex 1 (TORC1) integrates signals from growth factors, cellular energy status, stress, and amino acids to control cell growth, mitochondrial metabolism, and lipid biosynthesis. The mechanisms of growth factors and cellular energy status in regulating TORC1 have been well established, whereas the mechanism by which amino acid induces TORC1 remains largely unknown. Recent studies revealed that Rag GTPases play a central role in the regulation of TORC1 activation in response to amino acids. In this review, we will discuss the recent progress in our understanding of Rag GTPase-regulated TORC1 activation in response to amino acids. Particular focus will be given to the function of Rag
H. Yang and R. Gong contributed equally to this work. H. Yang R. Gong Y. Xu (&) Cancer Institute, Shanghai Cancer Center, Fudan University, Shanghai 200032, People’s Republic of China e-mail: [email protected] H. Yang R. Gong Y. Xu Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China H. Yang R. Gong Y. Xu Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, People’s Republic of China Y. Xu State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, People’s Republic of China
GTPases in TORC1 activation and how Rag GTPases are regulated by amino acids. Keywords Target of rapamycin TORC1 Amino acid Rag GTPase Cell growth
Introduction The target of rapamycin (TOR) is a central regulator controlling cell growth and is highly conserved from yeast to human. TOR is a Ser/Thr protein kinase and exists in two structurally and functionally distinct protein complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1 integrates extracellular and intracellular signals and functions as a central regulator of cell growth (mass and size) and proliferation through regulation of a variety of cellular processes including translation, lipid synthesis, autophagy, and metabolism [1–9]. Compared to TORC1, our understanding of TORC2 is very limited. Deregulation of mammalian TORC1 (mTORC1) has been found in many human diseases, such as cancer and type 2 diabetes [10–14]. Thus, mTORC1 is an attractive drug target and its inhibitors (rapamycin, rapalogues, and ATP-competitive inhibitors) have been clinically used for the treatment of organ transplantation and solid tumors [15]. The protein kinase activity of mTORC1 is regulated by growth factors, cellular energy levels, stress, and amino acids. The mechanisms of mTORC1 regulation by growth f
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