Receptor-type protein tyrosine phosphatase ε (PTPεM) is a negative regulator of insulin signaling in primary hepatocytes and liver
Receptor-type protein tyrosine phosphatase ε (PTPεM) is a negative regulator of insulin signaling in primary hepatocytes and liver
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DOI：
10.2108/zsj.22.169
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发表时间：
2005-02-01
影响因子：
0.9
通讯作者：
Miyazaki, Hitoshi
中科院分区：
文献类型：
--
作者：
Nakagawa, Yoshimi;Aoki, Naohito;Miyazaki, Hitoshi
胰岛素受体(IR)信号受损会导致胰岛素抵抗和2型糖尿病。几种IR酪氨酸激酶活性的抑制剂最近已被描述，并与人类胰岛素抵抗有关。在这些负调控因子中，蛋白酪氨酸磷酸酶(PTPs)可能在IR信号转导中发挥关键作用。转基因研究表明，PTP1B和TCPTP是主要的候选基因，但这些动物的IR最终可以被去磷酸化，这表明其他PTP也参与了IR的去磷酸化。在本研究中，我们发现受体型PTP epsilon(PTP Epsilon M)可使大鼠原代肝细胞IR去磷酸化，酪氨酸972、1158、1162和1163是PTP epsilon M的主要靶点。野生型PTP epsilon M和底物捕捉型DA形式的PTP epsilon M抑制IR下游酶Akt、细胞外调节激酶(ERK)和糖原合成酶激酶3(GSK3)的磷酸化。PTP epsilon M还可抑制胰岛素诱导的糖原合成，并抑制胰岛素诱导的原代肝细胞磷酸烯醇丙酮酸羧基激酶(PEPCK)的表达。此外，腺病毒导入的PTP epsilon M还显示出抑制小鼠肝脏中PEPCK表达的活性。这些结果表明，PTP epsilon M是IR信号的负调节因子，主要通过肝细胞和肝脏IR的直接去磷酸化和失活参与胰岛素诱导的葡萄糖代谢。
Impaired insulin receptor (IR) signaling leads to insulin resistance and type 2 diabetes mellitus. Several inhibitors of the IR tyrosine kinase activity have recently been described and associated with human insulin resistance. Among these negative regulators, protein tyrosine phosphatases (PTPs) are likely to play a pivotal role in IR signaling. Transgenic studies revealed that PTP1B and TCPTP are primary candidates but IR of these animals can be finally dephosphorylated, suggesting that other PTPs are also involved in the dephosphorylation of IR. In this study, we showed that receptor-type PTP epsilon (PTP epsilon M) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163 were primary targets of PTP epsilon M. Wild type as well as substrate-trapping DA forms of PTP epsilon M suppressed phosphorylation of IR downstream enzymes such as Akt, extracellular regulated kinase (ERK) and glycogen synthase kinase 3 (GSK3). It was also demonstrated that PTP epsilon M suppressed insulin-induced glycogen synthesis and inhibited insulin-induced suppression of phosphoenol pyruvate carboxylkinase (PEPCK) expression in primary hepatocytes. Furthermore, adenovirally introduced PTP epsilon M also exhibited inhibitory activity against suppression of PEPCK expression in mouse liver. These results suggest that PTP epsilon M is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.