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Molecular and Cellular Biology, June 2005, p. 4703-4715, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4703-4715.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß (TGF-ß)-Smad Target Gene Protein Tyrosine Phosphatase Receptor Type Kappa Is Required for TGF-ß Function

Departments of Cancer Biology,¹ Medicine, Vanderbilt University School of Medicine,² Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, Tennessee 37232,³ Department of Life Sciences, Hanyang University, Seoul, South Korea⁴

Received 31 December 2004/ Returned for modification 1 February 2005/ Accepted 2 March 2005

Transforming growth factor ß (TGF-ß) inhibits proliferation and promotes cell migration. In TGF-ß-treated MCF10A mammary epithelial cells overexpressing HER2 and by chromatin immunoprecipitation, we identified novel Smad targets including protein tyrosine phosphatase receptor type kappa (PTPRK). TGF-ß up-regulated PTPRK mRNA and RPTP (receptor type protein tyrosine phosphatase kappa, the protein product encoded by the PTPRK gene) protein in tumor and nontumor mammary cells; HER2 overexpression down-regulated its expression. RNA interference (RNAi) of PTPRK accelerated cell cycle progression, enhanced response to epidermal growth factor (EGF), and abrogated TGF-ß-mediated antimitogenesis. Endogenous RPTP associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation. In MCF10A/HER2 cells, TGF-ß enhanced cell motility, FAK phosphorylation, F-actin assembly, and focal adhesion formation and inhibited RhoA activity. These responses were abolished when RPTP was eliminated by RNA interference (RNAi). In cells expressing RPTP RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTP positively regulates Src; (ii) HER2 signaling and TGF-ß-induced RPTP converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTP is required for both the antiproliferative and the promigratory effects of TGF-ß.

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