Signaling Pathways in Insulin Action
Insulin-stimulated glucose transport is mediated by the glucose transporter Glut4, which translocates from intracellular compartments to the plasma membrane of muscle and fat cells in response to insulin. We discovered a novel signaling cascade initiated by the phosphorylation of the protooncogene c-Cbl, recruited to the receptor by the adapter protein SH2B2, and anchored to lipid raft microdomains by a multifunctional protein called CAP. And results in activation of the small GTPase TC10. TC10 interacts with different effectors, including the exocyst component Exo70.
The exocyst is an octameric complex first identified in yeast as a tethering site for targeted exocytosis. We discovered that this complex plays a key role in the regulation of glucose transport, targeting Glut4 vesicles to sites of docking and fusion in adipocytes. The assembly and recognition of the exocyst by Glut4 vesicles is controlled by distinct G proteins activated by a different process. The activation of TC10 recruits the exocyst to the plasma membrane, while activation of the vesicular G protein RalA is required for exocyst recognition. RalA is a target of insulin action, activated via phosphorylation of its cognate GAP protein that was cloned and characterized by our lab. We are focusing on upstream and downstream pathways in the control of RalA in vitro and in knockout mouse models.