Advances in AMPK and Autophagy signaling

DATE: November 4th, 2015
TIME: 11:00am Pacific time, 2:00pm Eastern time

AMPK, a highly conserved sensor of cellular energy status, is found in all eukaryotic cells and maintains metabolic homeostasis by reprogramming growth, metabolism, and autophagy in the face of cellular stresses. AMPK is activated by direct binding of AMP and ADP to its regulatory subunits, which enhances its phosphorylation by the upstream kinase LKB1, a tumor suppressor gene frequently inactivated in sporadic human lung and cervical cancer. In addition to this direct connection to cancer, AMPK is activated by a number of diabetes therapeutics, leading to our close examination of the role of LKB1 and AMPK in genetically engineered mouse models of cancer and diabetes.  It is increasingly clear that LKB1 is a unique, energy-state sensitive regulator of growth and metabolic reprogramming that mediates its effects through AMPK. Over the past decade, our laboratory has combined phospho-proteomic, genetic, and bioinformatic approaches to identify highly conserved direct substrates of AMPK that mediate its effects on metabolism and growth control.  These studies have led to the identification of components of the mTOR signaling pathway, the autophagy pathway, and transcriptional regulators of metabolism, all as direct substrates of AMPK.  In addition, a significant effort has gone into characterizing the downstream kinase ULK1, a highly conserved kinase involved in autophagy initiation, and remarkably the only protein kinase in the core autophagy pathway.  We have recently developed small molecule inhibitors of ULK1 and tested their utility in proof-of-principle cell culture studies, blocking autophagy in combination with other targeted cancer therapies.