Upstream Components of mTORC1.

Abstract

The target of rapamycin (TOR) is an evolutionally conserved protein kinase that belongs to the phosphoinositide-3-kinase-related protein kinase family. It resides in two distinct protein complexes which in mammals are referred to as mTORC1 and mTORC2. mTOR pathway plays a central role in cell growth and metabolism by integrating extracellular and intracellular signals, including nutrients, growth factors, energy and stresses to regulate a wide array of cellular processes through its target proteins such as S6K, 4EBP1, ULK1, AKT, SGK and PKC. Dysregulation of mTOR is involved in many human diseases, including cancer, cardiovascular disease, autoimmunity, and metabolic disorders. Therefore, understanding of mTOR regulation and function will shed light on developing therapeutics targeting those diseases. Significant emphasis has been placed on how mTOR activity is regulated by different signals. Recent biochemical and genetic studies made great progress demonstrating the Rag family GTPases, which belong to the ras superfamily, are key mediators between amino acids and mTORC1 activation. The Rag heterdimer can directly bind to raptor, a key subunit of mTORC1. It was proposed that amino acids promote the translocation of mTORC1 to the surface of the lysosome compartment in a Rag-dependent manner, where mTORC1 can colocalize with its activator, RHEB. In addition, a protein complex called Ragulator, which interacts with Rag GTPases, is reported to be responsible for mTORC1 translocation and necessary for its amino acid-dependent activation. In this thesis, I summarize my research in the past few years in three aspects. First, I identified Rab and Arf family GTPases as indispensible mediators of mTORC1 activity. Second, I identified MARK4 as an important negative regulator of mTORC1 activity. Although these studies did not fully answer the question where are these proteins positioned on the mTOR pathway, my research raises many important questions and will inspire further scientific inquiries.