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Phosphatase-Mediated Crosstalk Control of ERK and p38 MAPK Signaling in Corneal Epithelial Cells.

Wang Z, Yang H, Tachado SD, Capó-Aponte JE, Bildin VN, Koziel H, Reinach PS

Department of Biological Sciences, State University of New York, College of Optometry, New York, New York.

PURPOSE: To test the hypothesis that the protein phosphatases PP2A and MKP-1 are involved in controlling epidermal growth factor (EGF)-induced increases in rabbit corneal epithelial cell (RCEC) migration by mediating crosstalk between signaling pathways eliciting EGF receptor control of migration and proliferation. METHODS: Western blot analysis was used to determine the phosphorylation status of Erk1/2, p38, and the mitogen-activated protein kinase (MAPK) kinase (MEK1/2) using inhibitors of Erk1/2 or p38 and dominant-negative (d/n) Erk1 or d/n p38 cell lines. Coimmunoprecipitation was used to evaluate protein phosphatase (PP)2A and Erk1/2 interaction. Short-interfering RNA (siRNA) transfection was performed to analyze the involvement of MAPK phosphatase (MKP)-1 in crosstalk. Scratch-wound assay was used to determine EGF-dependent effects on cell migration. RESULTS: EGF (10 ng/mL) induced changes in activation of Erk1/2 and p38, which were enhanced by inhibition with 10 muM SB203580 and 10 muM PD98059, respectively. PP inhibition with sodium orthovanadate (100 muM), okadaic acid (10 nM), or Ro 31-8220 (10 muM) resulted in larger and more prolonged increases in the phosphorylation status of Erk1/2 and p38. After 1 hour, EGF induced 14-fold increases in MKP-1 protein expression. After MKP-1 siRNA transfection, EGF had induced a similar pattern of changes in the phosphorylation status in Erk1/2 and p38 following PP inhibition. EGF-induced cell migration was enhanced by Erk1/2 pathway inhibition and was accentuated after PP inhibition. Conversely, p38 pathway inhibition eliminated this response. CONCLUSIONS: EGF-induced changes in Erk1/2 and p38 phosphorylation status are dependent on PP-mediated crosstalk. This control modulates the magnitude of growth factor-induced increases in corneal epithelial cell migration.

Published 23 November 2006 in Invest Ophthalmol Vis Sci, 47(12): 5267-75.
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