Clip R-59: a novel regulator of Akt signaling

Tufts Medical Center, Boston MA

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Abstract

DESCRIPTION (provided by applicant): We have studied Akt, the direct effector of PI3K and the primary mediator of insulin's metabolic actions. In the course of those studies, we isolated ClipR-59, whose expression is elevated during adipocyte differentiation and decreased during development of obesity, as an Akt interaction protein. ClipR-59 does not involve Akt activation. Instead, it modulates Akt cellular compartmentalization following Akt activation, in particular, Akt membrane association. The regulation of Akt membrane association by ClipR-59 is critical for glucose transport, as evidenced by the finding that forced expression of ClipR-59 promotes, whereas silencing of ClipR-59 impairs, adipocyte glucose transport. Adipocyte glucose uptake is essential for the maintenance of whole-body glucose homeostasis. Due to the prevalence of obesity, type II diabetes has become epidemic and a major public health burden. Given that ClipR-59 interacts with Akt and regulates glucose transport, further studies of ClipR-59 are warranted studies. Our current studies indicated that a) expression of ClipR-59 in adipose tissue in mice results in reduced fat mass and increased glucose tolerance, an indication that ClipR-59 might play a role in maintaining whole-body glucose homeostasis; b) palmitoylation of ClipR-59, likely mediated by protein palmitoyltransferase DHHC17, is critical for ClipR-59 to modulate Akt cellular membrane association, implying that regulation of ClipR-59 palmitoylation by DHHC17 constitutes an important mechanism by which ClipR-59 modulates Akt signaling; and c) ClipR-59 is complexed with AS160, a Rab-GAP protein that connects insulin signaling and Glut4 vesicles. Because ClipR-59 also interacts directly with Akt, ClipR-59 may function as a scaffold protein to connect Akt signaling to AS160. To further study the function and regulation of ClipR-59, we proposed the experiments to address following specific questions: 1. Determine the impact of forced expression of ClipR-59 in adipose tissue on whole-body glucose homeostasis and on the development and progression of obesity, insulin resistance, and diabetes; 2. Determine the role of protein palmitoyltransferase DHHC17 in Akt signaling and adipocyte glucose transport by modulating ClipR-59 palmitoylation; and 3. Determine the functional importance of the interaction between ClipR-59 and AS160 in adipocyte glucose transport. Overall, the studies proposed here will demonstrate that how specified Akt insulin signaling by ClipR-59 modulates whole body glucose homeostasis and adipocyte function thereby, providing insight knowledge into the importance of specified Akt signaling in insulin action.