title: SHP-2 binds to caveolin-1 and regulates Src activity via competitive inhibition of CSK in response to H2O2 in astrocytes.
abstract: Reactive oxygen species (ROS) regulate diverse cellular functions by triggering signal transduction events, such as Src and mitogen-activated protein (MAP) kinases. Here, we report the role of caveolin-1 and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) in H2O2-induced signaling pathway in brain astrocytes. H2O2-mediated oxidative stress induced phosphorylation of caveolin-1 and association between p-caveolin-1 and SHP-2. SHP-2 specifically bound to wild-type caveolin-1 similarly to c-Src tyrosine kinase (CSK), but not to phosphorylation-deficient mutant of caveolin-1 (Y14A), and interfered with complex formation between caveolin-1 and CSK. In the presence of CSK siRNA, binding between caveolin-1 and SHP-2 was enhanced by H2O2 treatment, which led to reduced Src phosphorylation at tyrosine (Tyr) 530 and enhanced Src phosphorylation at Tyr 419. In contrast, siRNA targeting of SHP-2 facilitated H2O2-mediated interaction between caveolin-1 and CSK and enhanced Src phosphorylation at Tyr 530, leading to subsequent decrease in Src downstream signaling, such as focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK). Our results collectively indicate that SHP-2 alters Src kinase activity by interfering with the complex formation between CSK and phosphotyrosine caveolin-1 in the presence of H2O2, thus functions as a positive regulator in Src signaling under oxidative stress in brain astrocytes.
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Ara
authors.initials: A
authors.lastname: Jo
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: So-Hee
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Hee Ja
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Youn-Hee
authors.initials: YH
authors.lastname: Choi
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D051242:Caveolin 1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11