ClipR-59 is a member of Clip-170 protein family, characterized by presence of three ankyrin repeats and two cytoskeleton-associated protein-Glycine rich (CAP-Gly) domains (also referred as microtubule binding domain (MTB). However, unlike othor members of Clip-17 protein family, which bind to microtubules and regulate microtubule dynamics, ClipR-59 is associated with cell membrane and speculated to play a role in membrane related events. We have recently isolated ClipR-59, whose expression is elevated during adipocyte differentiation, as an Akt interacting protein ClipR-59. Our current studies indicate that ClipR-59 interacts with Akt and regulates Akt cellular compartmentalization. Moreover, ClipR-59 also interacts with AS160 a substrate for Akt in insulin-regulated glucose transport in the adipocyte. The current proposal is to investigate the function of ClipR-59 in adipocyte. We propose three specific aims: 1. We will determine the molecular mechanism under which ClipR-59 expression. Specifically, we will characterize mouse ClipR-59 promoter and identify the cis-acting-element that mediates the induction of ClipR-59 during adipocyte and differentiation;2. We will determine the mechanism under which ClipR-59 cellular localization is regulated by protein palmitoylation. Specifically, we will characterize the ClipR-59 palmitoyltransferase and determine its role in the regulation of Akt cellular compartmentalization;3. We will determine the functional importance of the interaction between ClipR-59 and AS160. Specifically, we will determine the relevant domains by which AS160 interacts with ClipR-59 and examine how interaction between AS160 and ClipR-59 regulates Akt dependent AS160 phosphorylation and its subsequent impact on glucose transport. Overall, the studies proposed here will demonstrate that ClipR-59 is a novel regulator of Akt signaling and may provide insight knowledge regarding how Akt signaling is specified.
Protein kinase Akt plays a major role in insulin regulated adipocyte glucose metabolism. Our studies are to dissect how Akt signal is specified in adipocytes through its association with ClipR-59. This research will provide invaluable knowledge to understand the development of adipocyte insulin resistance and identify a novel drug target for treatment of type II diabetes.
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