Ras protein signaling and the control of cell growth

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DESCRIPTION (provided by applicant): A thorough description of the G0-like resting states of eukaryotic cells is essential for a complete understanding of the mechanisms controlling cell proliferation. Towards this end, we have been studying how the Ras/cAMP-dependent protein kinase (PKA) signaling pathway regulates the biology of one particular resting state, stationary phase in Saccharomyces cerevisiae. Interestingly, we have found that Ras/PKA signaling activity regulates autophagy, a highly conserved, degradative pathway required for resting cell survival. Autophagy is important for normal development in multicellular organisms and recent studies have linked this process to aging, programmed cell death, cancer, Huntington'.s disease and the cellular response to pathogens. Our recent data indicate that this Ras/PKA pathway directly targets a key regulator of autophagy, the Atg1 protein kinase. Interestingly, other work has shown that Atg1 is also regulated by two additional signaling pathways that have a central role in the control of eukaryotic cell growth. These latter two pathways involve the highly conserved Tor and AMP-activated (Snf1) protein kinases. The experiments here will examine how the Ras/PKA, Tor and Snf1 pathways work together to regulate Atg1 activity, and thus the induction of autophagy in eukaryotic cells. In addition, we will use autophagy, and other activities, as readouts in an attempt to develop a better understanding of how the activities of these three signaling pathways are coordinated to bring about the proper control of cell growth. Since the autophagy machinery is highly conserved, it is likely that the regulatory paradigms identified here will be used in other eukaryotes. Thus, these studies could provide important insights into how this process might be manipulated in clinically useful ways in humans. The Specific Aims of this proposal are: 1) to determine the mechanism by which PKA phosphorylation regulates the activity of the Atg1 protein kinase complex; and 2) to examine the interplay between the Ras/PKA, Tor and Snf1 signaling pathways during the control of autophagy and cell growth.