title: Exogenous phosphotyrosine modulates epidermal growth factor receptor tyrosine phosphorylation.
abstract: Protein tyrosine phosphatases (PTPases) are potential tumor suppressor proteins which reverse the effects of protein tyrosine kinases (PTKs). We hypothesized that the induction of PTPase activity by the nutritional agent O-phospho-L-tyrosine (P-Tyr), a broad PTPase substrate, could potentially enhance total cellular PTPase activity and inhibit cell growth. In this study, we report that P-Tyr inhibited the growth of MDA-MB 468 cells in a dose-dependent fashion. P-Tyr incubation increased total cellular PTPase activity in MDA-MB 468 breast carcinoma cells. The increase of PTPase activity, as measured by a standard radioactive assay for PTPases, occurred within 10 min of P-Tyr incubation and was dependent on the concentration and time of incubation with P-Tyr. The increased PTPase activity in P-Tyr treated cells was also evident from a non-isotopic PTPase assay involving the dephosphorylation of epidermal growth factor receptor (EGFR). Epidermal growth factor (EGF)-mediated tyrosine phosphorylation of EGFR was decreased in situ in a time- and dose-dependent manner in P-Tyr-treated cells. Orthovanadate (100 microM for 4 h) inhibited this decrease, implicating the role of cellular PTPase in P-Tyr-mediated control of EGFR tyrosine phosphorylation. Further, EGFR kinase activity was found to be decreased in P-Tyr-treated cells. We conclude that P-Tyr may inhibit cell growth by decreasing cellular tyrosine phosphorylation. Both a decrease in activity of the EGFR kinase and increases in PTPase activity may have accounted for the growth inhibiting property of P-Tyr.
authors.affiliation: Department of Pathology, University of Maryland Cancer Center, Baltimore 21201.
authors.forename: S
authors.initials: S
authors.lastname: Mishra
authors.forename: A W
authors.initials: AW
authors.lastname: Hamburger
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
chemical_list: D019000:Phosphotyrosine; D014638:Vanadates; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases