title: PTPα-mediated Src activation by EGF in human breast cancer cells.
abstract: Protein tyrosine phosphatase alpha (PTPα) functions as an activator of Src by dephosphorylating Tyr527/530, a critical negative regulatory site. The increase of PTPα catalytic activity requires its phosphorylation at Ser180 and/or Ser204 and its dissociation from PTPα/Grb2 complex. Here, we show that epidermal growth factor (EGF) stimulation increases the ability of PTPα to activate Src by dephosphorylating Tyr530 in BT-20 and SKBR3 breast cancer cell lines. Treatment of these cells with EGF transiently decreased the association of PTPα with Grb2 and enhanced PTPα catalytic activity via Ser180 and Ser204 phosphorylation that was blocked by the protein kinase C delta (PKCδ) inhibitor rottlerin or knockdown of PKCδ by siRNA or by the overexpression of PTPαS180A/S204A mutant. PTPα siRNA blocked EGF-mediated Src activation in cancer cells and inhibited on colony formation, whereas control siRNA did not. These results suggested that PTPα links activation of epidermal growth factor receptor (EGFR) signaling with Src activation and may provide a novel therapeutic target for treatment of breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Wang
authors.forename: Lili
authors.initials: L
authors.lastname: Yu
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D014443:Tyrosine; D012694:Serine; D004815:Epidermal Growth Factor; C085746:rottlerin; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D051745:Protein Kinase C-delta; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4