4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B.
4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B.
复制标题
DOI：
10.1016/j.freeradbiomed.2015.08.025
复制
发表时间：
2015-12
影响因子：
7.4
通讯作者：
Forman HJ
中科院分区：
文献类型：
--
作者：
Zhang H;Forman HJ
Src是一种参与多种生物学过程的非受体蛋白酪氨酸激酶，可通过氧化还原依赖性和非依赖性机制被激活。4-羟基-2-壬烯醛（HNE）是一种脂质过氧化产物，在与Src激活相关的病理生理条件下会增加。本研究探讨了HNE如何激活人c-Src。在经典途径中，Src活化通过pTyr 530的去磷酸化，随后构象变化引起Src在Tyr 419处的自磷酸化及其活化而起始。HNE以剂量和时间依赖性方式增加Src活化，同时也增加Src在Tyr 530（pTyr 530 Src）的磷酸化，表明HNE通过非经典机制激活Src。蛋白酪氨酸磷酸酶1B抑制剂（539741），在增加基础pTyr 530 Src的浓度下，也增加了基础Src活性，并显着降低HNE介导的Src激活。EGFR抑制剂AG 1478和EGFR沉默消除了HNE介导的EGFR激活，并抑制了基础和HNE诱导的Src活性。此外，AG 1478还消除了由PTP 1B抑制剂引起的基础Src活化的增加。总之，这些数据表明，HNE可以激活Src部分通过一个非经典的途径，涉及EGFR的激活和抑制PTP 1B。
Src, a non-receptor protein tyrosine kinase involved in many biological processes, can be activated through both redox-dependent and independent mechanisms. 4-Hydroxy-2-nonenal (HNE) is a lipid peroxidation product that is increased in pathophysiological conditions associated with Src activation. This study examined how HNE activates human c-Src. In the canonical pathway Src activation is initiated by dephosphorylation of pTyr530 followed by conformational change that causes Src auto-phosphorylation at Tyr419 and its activation. HNE increased Src activation in both dose- and time-dependent manner, while it also increased Src phosphorylation at Tyr530 (pTyr530 Src), suggesting that HNE activated Src via a non-canonical mechanism. Protein tyrosine phosphatase 1B inhibitor (539741), at concentrations that increased basal pTyr530 Src, also increased basal Src activity and significantly reduced HNE-mediated Src activation. The EGFR inhibitor, AG1478, and EGFR silencing, abrogated HNE-mediated EGFR activation and inhibited basal and HNE-induced Src activity. In addition, AG1478 also eliminated the increase of basal Src activation by a PTP1B inhibitor. Taken together these data suggest that HNE can activate Src partly through a non-canonical pathway involving activation of EGFR and inhibition of PTP1B.