title: 4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B.
abstract: 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.
authors.affiliation: Andrus Gerontology Center, Davis School of Gerontology, University of Southern, California.
authors.forename: Hongqiao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Andrus Gerontology Center, Davis School of Gerontology, University of Southern, California. Electronic address: peroxideman@gmail.com.
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C027576:4-hydroxy-2-nonenal
keywords: EGFR; Src kinase; lipid peroxidation; protein tyrosine phosphatase; redox signaling; signal transduction