Comparative Analysis of Protein Tyrosine Phosphatases Regulating Microglial Activation

Protein tyrosine phosphatases (PTPs) are key regulatory factors in inflammatory signaling pathways. Although PTPs have been extensively studied, little is known about their role in neuroinflammation. In the present study, we examined the expression of 6 different PTPs (PTP1B, TC-PTP, SHP2, MEG2, LYP, and RPTPβ) and their role in glial activation and neuroinflammation. All PTPs were expressed in brain and glia. The expression of PTP1B, SHP2, and LYP was enhanced in the inflamed brain. The expression of PTP1B, TC-PTP, and LYP was increased after treating microglia cells with lipopolysaccharide (LPS). To examine the role of PTPs in microglial activation and neuroinflammation, we used specific pharmacological inhibitors of PTPs. Inhibition of PTP1B, TC-PTP, SHP2, LYP, and RPTPβ suppressed nitric oxide production in LPS-treated microglial cells in a dose-dependent manner. Furthermore, intracerebroventricular injection of PTP1B, TC-PTP, SHP2, and RPTPβ inhibitors downregulated microglial activation in an LPS-induced neuroinflammation model. Our results indicate that multiple PTPs are involved in regulating microglial activation and neuroinflammation, with different expression patterns and specific functions. Thus, PTP inhibitors can be exploited for therapeutic modulation of microglial activation in neuroinflammatory diseases.

Affect of protein tyrosine phosphatase non-receptor type 2 and nuclear factor-kappaB on periodontal destruction with diabetes / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the expression of protein tyrosine phosphatase non-receptor type 2 (PTPN2) and nuclear factor-kappaB (NF-kappaB), as well as the relationship between their expression and periodontal destruction in mice with diabetic periodontitis.</p><p><b>METHODS</b>Four weeks old healthy C57BL/6J mice were randomly divided into normal control group (Group N), periodontitis group (Group P) and diabetic periodontitis group (Group DP), and each group had six mice. Mice in Group P were inoculated Porphyromonas gingivalis orally to induce periodontitis. Mice in Group DP had high sugary and fatty food, streptozotocin intraperitoneal injection and Porphyromonas gingivalis oral inoculation to induce diabetic periodontitis. All mice were sacrificed 4 weeks after the last bacterium inoculation of Groups P and DP. Stereo microscope was chosen to detect morphological changes and bone loss areas of the alveolar bone. Hematoxylin-eosin (HE) staining was selected to observe loss heights of periodontal attachment. Immunohistochemical staining was used to detect PTPN2 and NF-kappaB expression in periodontal tissues.</p><p><b>RESULTS</b>Group P and Group DP had significantly more attachment loss heights and areas than Group N (P < 0.05), and showed less PTPN2 expression (P < 0.05) and higher NF-kappaB levels (P < 0.01).</p><p><b>CONCLUSION</b>PTPN2 may negatively regulate the development of diabetic periodontitis, while NF-kappaB may have opposite effects. PTPN2 down-regulation might contribute to NF-kappaB over-expression leading to exacerbated periodontal destruction.</p>

Research progress of several protein tyrosine phosphatases in diabetes / 生理学报

Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet beta 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 beta cells. Genetic mutation or overexpression of these phosphotases has been found 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 and PTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares more than 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substrates overlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP may have role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic beta cell apoptosis. The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated to type 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutant have impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanism of R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. A receptor tyrosine phosphatase, PTPIA-2/beta is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/beta autoantibodies is valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2 are involved in type 2 diabetes via regulation of insulin production, beta 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 insulin response and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic and therapeutic strategies for diabetes.