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The function of mammalian cells is critically dependent on membranes which are the sites for metabolic enzymatic reactions, signaling transduction, and controls the movement of cellular substances such as solutes and nutrients. The biological activities of membranes are determined by their associated proteins. Therefore, the regulation of membrane-protein interaction constitutes a basic mechanism to maintain cellular homeostasis.
One of mechanisms that regulates the interaction between protein and membranes is protein lipid modification through which a lipid molecule is attached to the proteins. There are three types of protein lipid modifications including myristorylation, prenylation and palmitoylation.
Our research is to understand the role of protein palmitoylation in the signal transduction and vesicle trafficking, thereby cell homeostasis. Our focusing on protein palmitoylation is because protein palmitoylation is the most common and only reversible lipid modification in mammalian cells. It is our believing that protein palmitoylation likely plays a critical role in the regulation of cellular homeostasis. To such a goal, we have developed an assay termed TPC (Thiopropyl Captiviation of palmitoylated protein) to analyze cellular palmitoylated proteins and collected all of mammalian palmitoyl acyltransferase (PAT) DHHC proteins.
Akt is a Ser/Thr protein kinase. Activated by growth factors and metabolic hormones through PI3K signaling pathway, Akt has been implicated a wide spectrum of biological processes including cell survival, glucose and lipid metabolism. Indeed, impaired Akt activity has been showed to result in abnormal cell growth, apoptosis and type II diabetes.
ClipR-59 is a membrane associated protein that undergoes palmitoylation at dual cysteine residues at 534 and 534 and is targeted to detergent resistant membrane domain (DRM, alas lipid raft). ClipR-59 interacts with active Akt and recruited Akt onto DRM. By recruiting Akt onto DRM, ClipR-59 has been shown to involve insulin dependent Glut4 membrane translocation, a process that is essential for maintenance of body glucose homeostasis. Our recent studies revealed that ClipR-59 palmitoylation is mediated by palmitoyl acyltransferase DHHC17 (also known as Hip14). In addition, ClipR-59 formed a complex with Elmo2, a protein that has implicated in the activation of small GTPase RAC1 activation. Our current studies are focused on how Elmo2 phosphorylation at Y48 and Y713 mediated by tyrosine receptor kinases such as IR and IGFR regulates interaction of Elmo2 with ClipR-59, thereby Akt signaling compartmentalization in glucose transport and how DHHC17 tyrosine phosphorylation modulates DHHC17 palmitoyltransferase activity, thereby Akt signaling in the context of glucose and lipid metabolism.
In mammalian cells, protein palmitoylation is regulated by a super family of DHHC proteins. So named as DHHC proteins because these proteins contain DHHC (Asp-His-His-Cys) motif within their cysteine rich catalytic domain (CRD). Our current studies are focused on two DHHC proteins DHHC3 and DHHC7 as we have found out that DHHC3 and DHHC7 are involved in insulin dependent Glut4 membrane translocation and the mice that harbored inactivated DHHC3 and DHHC7 developed insulin resistance and growth defect.
Currently, we are generated conditional knockout mice for DHHC3 and DHHC7 and hope to determine the specific role of DHHC3 and DHHC7 in specific tissues such as liver, muscle and adipose tissue in the regulation of glucose and lipid metabolism.
Keyong Du, PhD
Yingmin Sun, PhD