Regulation of Autophagy through two Big Protein Complexes; TORC1 and class 3 PI3K

The mammalian target of rapamycin (mTOR), a master regulator of both growth and catabolic processes, plays a central role in signal transduction pathways mediated by a variety of stress factors. Consequently, dysregulation of mTOR is found in many cancers . Recently, much attention has been focused on TOR and its role in inhibiting the catabolic process of autophagy. Autopahgy, a lysosome dependent degradation pathway, have an established role in the maintenance of cellular homeostasis and is also often de regulated in human malignancies like cancer. However, too little is currently known about the pathways involved in the regulation of autophagy to say whether autophagy is suppressing tumor development or in fact promote survival of cancer cells. This unde rscores the importance to further investigate the connection between mTOR signaling pathways and autophagy. This proposal aims to identify novel components involved in the regulation of mTOR that controls autophagy. Specifically, I plan to characterize if the novel Akt phosphatases PHLPP1 and PHLPP2 function to regulatre autophagy through mTORC1. This proposal also suggest to characterize the role of PHLPP in regulating Ulk1, a kinase that is downstream of TORC1 in the control of autophagy. Altogether, th is project aims to understand how autophagy can be regulated in normal cells and how dysregulation of autophagy in cancer can be utilized therapeutically to better the prognosis of cancer patients.