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Role of Leucine in the Regulation of mTOR by Amino Acids: Revelations from Structure–Activity Studies^{1 ,2}

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033

³To whom correspondence and reprint requests should be addressed at The Pennsylvania State University College of Medicine, Department of Cellular and Molecular Physiology, 500 University Drive, Hershey, PA 17033. E-mail: clynch{at}psu.edu.

In this study an overview is presented of the mTOR signaling pathway and its regulation by amino acids, particularly L-leucine. Our laboratory is studying amino acid regulation of mTOR in adipocytes. Potential roles for mTOR in adipocytes that were previously posited include hypertrophic growth, leptin secretion, protein synthesis and adipose tissue morphogenesis. A current area of interest in the field is how amino acids regulate mTOR and which amino acids are regulatory. Revelations concerning mechanism and recognition are emerging from different laboratories that examined the structural requirements for stimulation and inhibition of the mTOR signaling pathway by leucine and amino acid analogs. In adipocytes and some other cell types, leucine appears to be the main regulatory amino acid. However, this is not uniformly the case. In those cells where mTOR is regulated by several amino acids, there is evidence that the mechanism of mTOR activation may be different from cells where mainly leucine is regulatory. Furthermore, in tissues where leucine regulates mTOR, the possible existence of different tissue-specific leucine recognition sites may be indicated.

KEY WORDS: • leucine • amino acids • mTOR • 4E-BP1 • p70 S6 kinase • protein synthesis • adipose tissue

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