Marc R. Montminy

During fasting, pancreatic glucagon promotes hepatic gluconeogenesis through induction of the second messenger cAMP. Our laboratory characterized the CREB protein and showed that it stimulates gene expression following its phosphorylation in response to fasting signals. Now recognized as a predominant regulatory mechanism, CREB provided the first example of a transcription factor whose activity is modulated by phosphorylation. CREB is phosphorylated by a wide range of extracellular signals; recent studies indicate that a second family of CREB cofactors, called CRTCs, mediate target gene expression selectively in response to cAMP and calcium signals. One of these, CRTC2, triggers the gluconeogenic program in liver during fasting, when it undergoes de-phosphorylation and binds to CREB over relevant genes. Current studies focus on the mechanism by which different CRTCs contribute to energy balance by modulating CREB activity in other insulin sensitive tissues.