Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling
Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling
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DOI：
10.1677/jme.1.01694
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发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Billestrup, N
中科院分区：
文献类型：
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作者：
Lund, IK;Hansen, JA;Billestrup, N
在瘦素结合后，瘦素受体被激活，导致JAK/STAT信号转导级联的刺激。JAK 2和STAT 3的酪氨酸磷酸化的瞬时特征表明蛋白酪氨酸磷酸酶（PTPs）作为该信号传导途径的负调节剂参与。具体而言，最近的证据表明，PTP 1B可能是瘦素信号传导的关键调节因子，基于对饮食诱导的肥胖的抵抗和在PTP 1B缺陷小鼠中观察到的瘦素信号传导增加。本研究旨在探讨PTP 1B介导瘦素信号转导停止的机制。瘦素诱导的STAT 3应答报告子的激活通过与PTP 1B共转染而剂量依赖性地抑制。当使用PTP 1B的催化失活突变体或共转染其他PTP时，没有观察到抑制作用。PTP 1B能够在体外使活化的JAK 2和STAT 3去磷酸化，而对分化簇45（CD 45）、PTP α和白细胞抗原相关（LAR）没有观察到或观察到最小的影响。通过利用选择性PTP 1B抑制剂，瘦素诱导的STAT 3活化在细胞中增强。总之，这些结果表明，PTP 1B对瘦素信号传导的负调节作用是通过JAK 2和STAT 3这两种信号传导分子的直接和选择性去磷酸化介导的。
Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transcluction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators of this signalling pathway. Specifically, recent evidence has suggested that PTP1B might be a key regulator of leptin signalling, based on the resistance to diet-induced obesity and increased leptin signalling observed in PTP1B-deficient mice. The present study was undertaken to investigate the mechanism by which PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co-transfected. PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTP alpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.