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[Research progress of several protein tyrosine phosphatases in diabetes.] [Ariticle in Chinese]

Chen Ming, SUN Jin-Peng, LIU Jing, YU Xiao^*

Shandong University School of Medicine, Institute of Physiology, Jinan 250012, China； Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, USA； The 309th Hospital of PLA, Beijing 100091, China

Abstract

Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet β cells and/or insulin resistance in liver,muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. Several protein tyrosine phosphatases, such as PTP1B(PTPN1), TCPTP (PTPN2), LYP (PTPN22), PTPIA-2, PTPMEG2 (PTPN9) or OSTPTP are involved in insulin signaling pathway,insulin secretion and autoreactive attack to pancreatic β cells. Genetic mutation or overexpression of these phosphotases has beenfound to cause or increase the risk of diabetes mellitus. Some population with high risk for type 2 diabetes has overexpressed PTP1B,a prototypical tyrosine phosphatase which down-regulates insulin and leptin signal transduction. Animal PTP1B knockout model andPTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares morethan 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substratesoverlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP mayhave role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic β cell apoptosis. The tyrosinephosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated totype 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutanthave impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanismof R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. Areceptor tyrosine phosphatase, PTPIA-2/β is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/β autoantibodiesis valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2are involved in type 2 diabetes via regulation of insulin production, β cell growth or insulin signaling. Research into understanding the mechanism of these tyrosine phosphatases in diabetes, such as their precise functions in the regulation of insulin secretion, the insulinresponse and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic andtherapeutic strategies for diabetes.

Key words: diabetes mellitus; protein tyrosine phosphatase; insulin; inhibitor

Received: 2009-11-30　　Accepted: 2010-01-20

Corresponding author: 于晓　　E-mail: yuxiao@sdu.edu.cn

Citing This Article：

Chen Ming, SUN Jin-Peng, LIU Jing, YU Xiao. [Research progress of several protein tyrosine phosphatases in diabetes.] [Ariticle in Chinese] . Acta Physiol Sin 2010; 62 (2): 179-189 (in Chinese with English abstract).