Marc R. Montminy
Clayton Foundation Laboratories for Peptide Biology
J.W. Kieckhefer Foundation Chair
Marc Montminy is a professor in the Clayton Foundation Laboratories for Peptide Biology. Montminy's lab isolated cDNA clones for the cAMP response element binding protein (CREB) in 1989. cAMP was found to regulate cellular genes via the PKA mediated phosphorylation of CREB at SER133. This modification was shown to promote target gene activation via the recruitment of the coactivator CBP. Structural studies of the CREB/CBP complex revealed that CREB phosphorylation promotes recruitment of CBP via allosteric and direct mechanisms. The structure also suggested the potential for developing small molecules that block target gene activation by disrupting the CREB: CBP complex.
Current work in the lab focuses on the identification of CREB target genes and characterization of agonists and antagonists that may be used to evaluate the importance of CREB in mediating cellular responses to various stimuli. Montminy also conducts research on the genetic basis of diabetes. Using knockout and transgenic approaches, the Montminy laboratory determined that CREB performs a critical role in glucose homeostasis during fasting. They found that CREB triggers the gluconeogenic program via induction of the nuclear hormone receptor coactivator PGC-1a. Following up on these studies, Montminy identified a second family of cAMP regulated CREB coactivators, called TORCs, which are critical for induction of gluconeogenic genes during fasting. They showed that TORC2 activity is inhibited by AMPK-mediated phosphorylation, providing an important link between energy-sensing and hormonal pathways. Indeed, oral hypoglycemic agents such as metformin, which activate AMPK, were found to reduce hepatic glucose production by inhibiting TORC2 activity. Future work using mice with knockouts in TORC family members will reveal the extent to which these coactivators promote energy balance in other insulin-sensitive tissues.
- B.S., Biochemistry, Harvard University
- M.D., Ph.D., Physiology, Tufts University School of Medicine
- Research fellow in Medicine, Tufts-New England Medical Center, Boston
Awards and Honors
- McKnight Neuroscience Development Award, 1991
- Richard E. Weitzman Award, Endocrine Society, 1990