Breast tumor kinase phosphorylates p190RhoGAP to regulate Rho and ras and promote breast carcinoma growth, migration, and invasion

Che Hung Shen, Hsin Yi Chen, Ming Shien Lin, Fang Yen Li, Cheng Chi Chang, Min Liang Kuo, Jeffrey Settleman, Ruey Hwa Chen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)7779-7787
Number of pages9
JournalCancer Research
Volume68
Issue number19
DOIs
Publication statusPublished - Oct 1 2008
Externally publishedYes

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Phosphotransferases
Breast Neoplasms
Growth
p120 GTPase Activating Protein
Phosphorylation
Paxillin
Neoplasms
Focal Adhesions
src-Family Kinases
Epidermal Growth Factor
Protein-Tyrosine Kinases
Cell Movement
Tyrosine
Breast
Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Breast tumor kinase phosphorylates p190RhoGAP to regulate Rho and ras and promote breast carcinoma growth, migration, and invasion. / Shen, Che Hung; Chen, Hsin Yi; Lin, Ming Shien; Li, Fang Yen; Chang, Cheng Chi; Kuo, Min Liang; Settleman, Jeffrey; Chen, Ruey Hwa.

In: Cancer Research, Vol. 68, No. 19, 01.10.2008, p. 7779-7787.

Research output: Contribution to journalArticle

Shen, Che Hung ; Chen, Hsin Yi ; Lin, Ming Shien ; Li, Fang Yen ; Chang, Cheng Chi ; Kuo, Min Liang ; Settleman, Jeffrey ; Chen, Ruey Hwa. / Breast tumor kinase phosphorylates p190RhoGAP to regulate Rho and ras and promote breast carcinoma growth, migration, and invasion. In: Cancer Research. 2008 ; Vol. 68, No. 19. pp. 7779-7787.
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AU - Chen, Hsin Yi

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AU - Chang, Cheng Chi

AU - Kuo, Min Liang

AU - Settleman, Jeffrey

AU - Chen, Ruey Hwa

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