Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B
Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B
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DOI：
10.1074/jbc.m210194200
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发表时间：
2003-01-10
影响因子：
4.8
通讯作者：
Neel, BG
中科院分区：
文献类型：
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作者：
Haj, FG;Markova, B;Neel, BG
受体酪氨酸激酶（RTK）是细胞稳态的关键调节剂。基于体外和离体研究，蛋白酪氨酸磷酸酶-1B（PTP 1B）参与了几种RTK的调节，但缺乏PTP 1B的小鼠主要在胰岛素和瘦素受体信号传导方面表现出缺陷。为了解决这个明显的矛盾，我们研究了PTP 1B（-/-）小鼠的原代和永生化成纤维细胞中的RTK信号。生长因子处理后，缺乏PTP 1B的细胞表现出表皮生长因子受体（EGFR）和血小板衍生生长因子受体（PDGFR）的磷酸化增加和持续。然而，Erk激活仅略微增强，并且在PTP 1B缺陷细胞中Akt激活没有增加。我们的研究结果表明，PTP 1B确实在调节EGFR和PDGFR磷酸化中发挥作用，但其他信号传导机制可以在很大程度上弥补PTP 1B缺陷。凝胶内磷酸酶实验表明，其他PTP可能有助于调节PTP 1B成纤维细胞中的EGFR和PDGFR。这种和其他代偿机制防止了在没有PTP 1B的情况下广泛的、不受控制的RTK激活，并可能解释了小鼠中PTP 1B缺失的相对温和的影响。
Receptor tyrosine kinases (RTKs) are key regulators of cellular homeostasis. Based on in vitro and ex vivo studies, protein tyrosine phosphatase-1B (PTP1B) was implicated in the regulation of several RTKs, yet mice lacking PTP1B show defects mainly in insulin and leptin receptor signaling. To address this apparent paradox, we studied RTK signaling in primary and immortalized fibroblasts from PTP1B(-/-) mice. After growth factor treatment, cells lacking PTP1B exhibit increased and sustained phosphorylation of the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR). However, Erk activation is enhanced only slightly, and there is no increase in Akt activation in PTP1B-deficient cells. Our results show that PTP1B does play a role in regulating EGFR and PDGFR phosphorylation but that other signaling mechanisms can largely compensate for PTPlB deficiency. In-gel phosphatase experiments suggest that other PTPs may help to regulate the EGFR and PDGFR in PTP1B-fibroblasts. This and other compensatory mechanisms prevent widespread, uncontrolled activation of RTKs in the absence of PTP1B and probably explain the relatively mild effects of PTP1B deletion in mice.