This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, C.-H. Articles by Chen, R.-H. Search for Related Content PubMed PubMed Citation Articles by Shen, C.-H. Articles by Chen, R.-H.

Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion

¹ Institute of Molecular Medicine, ² Institute of Toxicology, College of Medicine, and ³ Institute of Biochemical Sciences, National Taiwan University; ⁴ Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan and ⁵ Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Ruey-Hwa Chen, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Phone: 886-2-27855696, ext. 6020; Fax: 886-2-27889759; E-mail: rhchen{at}gate.sinica.edu.tw.

Key Words: Brk • p190RhoGAP • EGF • proliferation • migration

Breast tumor kinase (Brk), an Src-like nonreceptor tyrosine kinase, is overexpressed in breast cancer and several other cancer types. Our previous study indicates that Brk promotes cell migration and tumor invasion by phosphorylating the focal adhesion protein paxillin. Here, we report the identification of p190RhoGAP-A (p190) as a Brk substrate. Brk phosphorylates p190 at the Y¹¹⁰⁵ residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120). As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively. In carcinoma cells expressing high levels of Brk, endogenous Brk functions as a key contributor to epidermal growth factor–induced p190 tyrosine phosphorylation. We present evidence showing that p190 phosphorylation plays essential roles in both migratory and proliferative effects of Brk. Furthermore, disruption of p190 phosphorylation–induced p190/p120 complex in breast cancer cells abolishes not only the abilities of Brk to regulate RhoA and Ras but also the stimulatory effects of Brk on proliferation, migration, invasion, transformation, and tumorigenicity. Together, our findings reveal a previously unknown function of Brk in regulating both RhoA and Ras by phosphorylating p190 and provide evidence for the crucial roles of this Brk-elicited signaling pathway in promoting breast malignancy. [Cancer Res 2008;68(19):7779–87]

This article has been cited by other articles:

				H. Ie Kim and S.-T. Lee Oncogenic Functions of PTK6 are Enhanced by Its Targeting to Plasma Membrane But Abolished by Its Targeting to Nucleus J. Biochem., July 1, 2009; 146(1): 133 - 139. [Abstract] [Full Text] [PDF]