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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{dagger}

Shizhen Emily Wang,1 Frederick Y. Wu,2 Incheol Shin,1,4 Shimian Qu,1 and Carlos L. Arteaga1,2,3*

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{kappa} (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{kappa} 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{kappa} was eliminated by RNA interference (RNAi). In cells expressing RPTP{kappa} RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTP{kappa} positively regulates Src; (ii) HER2 signaling and TGF-ß-induced RPTP{kappa} converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTP{kappa} is required for both the antiproliferative and the promigratory effects of TGF-ß.

* Corresponding author. Mailing address: Division of Oncology, Vanderbilt University School of Medicine, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232-6307. Phone: (615) 936-3524. Fax: (615) 936-1790. E-mail: carlos.arteaga{at}vanderbilt.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2005, p. 4703-4715, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4703-4715.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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