Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP
Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP
复制标题
DOI：
10.1128/mcb.23.6.2096-2108.2003
复制
发表时间：
2003-03-01
影响因子：
5.3
通讯作者：
Tiganis, T
中科院分区：
文献类型：
--
作者：
Galic, S;Klingler-Hoffmann, M;Tiganis, T
人蛋白酪氨酸磷酸酶TCPTP以两种形式存在：内质网靶向的48-kDa形式（TC 48）和核45-kDa形式（TC 45）。尽管靶向细胞核，但TC 45可以响应于特异性刺激而退出以使细胞质底物去磷酸化。在这项研究中，我们研究了TCPTP下调胰岛素受体（IR）信号。响应于胰岛素刺激，TC 48-D182 A和TC 45-D182 A“底物捕获”突变体与293细胞中的内源性酪氨酸磷酸化IR β亚基形成稳定的复合物。此外，响应于胰岛素刺激，TC 45-D182 A突变体在过表达IR的细胞的细胞质中积累，并且部分与IR β亚基共定位在细胞外周。这些结果表明，IR可以作为TC 48和TC 45的细胞底物。在永生化的TCPTP-/-小鼠胚胎成纤维细胞中，胰岛素诱导的IR P-亚基酪氨酸磷酸化和蛋白激酶PKB/Akt活化相对于TCPTP+/+细胞中的值增强。重要的是，TC 45或TC 48表达至生理水平抑制了TCPTP-/-细胞中胰岛素诱导的信号传导增强。这些结果表明，TCPTP的差异定位的变体可以去磷酸化的IR和下调胰岛素诱导的信号在体内。
The human protein tyrosine phosphatase TCPTP exists as two forms: an endoplasmic reticulum-targeted 48-kDa form (TC48) and a nuclear 45-kDa form (TC45). Although targeted to the nucleus, TC45 can exit in response to specific stimuli to dephosphorylate cytoplasmic substrates. In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A "substrate-trapping" mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells. Moreover, in response to insulin stimulation, the TC45-D182A mutant accumulated in the cytoplasm of cells overexpressing the IR and in part colocalized with the IR beta-subunit at the cell periphery. These results indicate that the IR may serve as a cellular substrate for both TC48 and TC45. In immortalized TCPTP-/- murine embryo fibroblasts, insulin-induced IR P-subunit tyrosine phosphorylation and protein kinase PKB/Akt activation were enhanced relative to the values in TCPTP+/+ cells. Importantly, the expression of TC45 or TC48 to physiological levels suppressed the enhanced insulin-induced signaling in TCPTP-/- cells. These results indicate that the differentially localized variants of TCPTP may dephosphorylate the IR and downregulate insulin-induced signaling in vivo.