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Molecular Oncology Research Institute (MORI)

Du Laboratory

Keyong Du, PhD, Principal Investigator, MORI at Tufts Medical CenterOur research is to understand the regulation of adipose and hepatic glucose metabolism in the content of type II diabetes and Obesity. Currently, we are working on two different topics. These include a) the regulation of insulin signaling E3 ligase COP1 and membrane protein and b) adipose lipid modification. COP1 interacts with protein phosphatase PTP1B to enhance insulin signaling thereby hepatic glucose production whereas ClipR-59 interacts with Akt and AS160 to modulates adipocyte Glut4 membrane translocation.

Currently, we are trying to determine how membrane association is regulated and characterize ClipR-59 mice. To understand the role of lipid modification, we are focused on palmitoylation, the most common and reversible lipid modification. We have analyzed palmitoysome of primary adipose tissue and isolated more than 800 palmitoylated proteins. Currently we are focusing on the analysis of protein palmitoylated proteins that are involved in Glut4 membrane translocation and cell signaling and identify the palmitoyltransferase to our interested proteins.

Troubles with Tribbles

TRBs are newly emerged three member family proteins including: TRB1 TRB2 and TRB3. TRB family members are characterized by a strong homology to the kinase domain of Ser/Thr protein kinases. Since they lack an ATP binding domain and contain a variant catalytic core motif, TRBs do not function as a protein kinase. TRBs bind to Akt and inhibit Akt activation. TRB expression is enhanced during apoptosis as well as cell differentiation. TRB3 forms heterodimers with both TRB1 and TRB2. Remarkably, none of the TRBs form a homodimer nor do TRB1 and TRB2 form a heterodimer. Our future research is to elucidate the functional and structural importance of the TRB family members in cell differentiation, apoptosis.

TRBs bind to Akt and inhibit Akt activation. TRB expression is enhanced during apoptosis as well as cell differentiation. TRB3 forms heterodimers with both TRB1 and TRB2. Remarkably, none of the TRBs form a homodimer nor do TRB1 and TRB2 form a heterodimer. Our research will a) explore the role of TRB3 in muscle cell differentiation. We will also analyze how TRB3 modulates muscle cell specific gene expression. b) address the mechanism by which the expression of TRB3 is regulated. We will identify promoter sequences and other genetic elements required for the regulation of TRB expression cell differentiation. c) determine the structural and functional requirements for the heterodimerization of TRB3 with TRB1 and TRB2 and explore the structural and functional requirements for the interaction between Akt family members and TRB family members, as well as the functional outcome of these interactions.

Watch A (New) Clip

Glucose is a fundamental source of energy for all eukaryotic cells. In humans, all cells use glucose for their energy needs. Abnormal glucose metabolism usually associates with insulin-resistance, the hallmark of Type II Diabetes. To understand the functional importance of Akt, we have isolated a novel Akt interaction protein, Aclip.

Aclip binds to Akt and co-localizes with Glut4 in adipocytes. Overexpression of Aclip increases membrane localization of Glut4. Overexpression of Aclip in 3T3 L1 cells increases glucose uptake in 3T3 L1 adipocytes. This indicates that Aclip may play an important role in regulating glucose homeostasis. The current efforts are to characterize Aclip proteins and investigate the role of the Akt binding protein Aclip in insulin-stimulated glucose uptake in adipocytes. Specifically, we will characterize the Aclip protein and address the molecular mechanism under which Aclip modulates glucose uptake in adipocytes by overexpression and ablation of Aclip.

Keyong Du, PhD

View all publications via PubMed

Du, K., Herzig, S. and Montminy, M. 2003 TRB-3: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300: 1574-1576.

Du, K. and Montminy, M. 1998 CREB is a regulatory target for the protein kinase Akt/PKB. J. Biol. Chem. 273: 32377-9.