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C.–K. Joo, J.–T. Kim, H.–S. Kim, J. Park, Y. Seomun; Role Of EGF Receptor Transactivation By TGF–beta In Epithelial Cells . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3655.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: TGF–beta elicits a wide range of cellular responses that regulate transdifferentiation, cell migration, cell arrest, apoptosis and ECM accumulation in epithelial cells. Previously, we reported that Src family tyrosine kinases (SFKs) of TGF–beta signaling, independent of Smads, are activated in an epithelial–specific manner. The present study investigates a role of SFKs induced by TGF–beta in its cellular responses and displays a novel signaling, EGFR transactivation induced by TGF–beta, which is involved in the regulation of MAP kinases. Methods: Analysis of EGFR transactivation induced by TGF–beta was performed by immunoprecipitation and then immunoblotting with anti–phosphotyrosine antibody. The activities of several kinases were analyzed by immunocomplex kinase assay using various substrates or immunoblotting with specific phospho–antibodies. In addition, to examine TGF–beta responses, we also utilized effective tools related to the analysis of transdifferentiation, migration, arrest, apoptosis and specific gene expressions. Results: The tyrosine phosphorylation of EGFR is transiently and rapidly induced by TGF–beta such as the activation of SFKs, and Src kinase specific inhibitors completely blocked the tyrosine phosphorylation of EGFR by TGF–beta. We further demonstrated that the activated EGFR is involved in the activations of ERK and JNK, not p38, using a specific inhibitor, AG1478. TGF–beta–induced SFKs/EGFR signaling differentially regulates TGF–beta responses, in which SFKs mediates extensively; otherwise, transactivated EGFR is limited to EMT and cell migration. Conclusion: Our data suggest that rapid SFKs/EGFR activation induced by TGF–beta may play a novel role in a variety of Smad–independent TGF–beta responses.
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