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Molecular and Cellular Biology, December 2004, p. 10558-10572, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10558-10572.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Brk Activates Rac1 and Promotes Cell Migration and Invasion by Phosphorylating Paxillin

Hsin-Yi Chen, Che-Hung Shen, Yuh-Tyng Tsai, Feng-Chi Lin, Yuan-Ping Huang, and Ruey-Hwa Chen*

Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Received 20 April 2004/ Returned for modification 11 June 2004/ Accepted 9 September 2004

Brk (for breast tumor kinase) is a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. Brk was originally identified from a human metastatic breast tumor, and its overexpression is frequently observed in breast cancer and several other cancer types. However, the molecular mechanism by which this kinase participates in tumorigenesis remains poorly characterized. In the present study, we not only identified paxillin as the binding partner and substrate of Brk but also discovered a novel signaling pathway by which Brk mediates epidermal growth factor (EGF)-induced paxillin phosphorylation. We show that EGF stimulation activates the catalytic activity of Brk, which in turn phosphorylates paxillin at Y31 and Y118. These phosphorylation events promote the activation of small GTPase Rac1 via the function of CrkII. Through this pathway, Brk is capable of promoting cell motility and invasion and functions as a mediator of EGF-induced migration and invasion. In accordance with these functional roles, Brk translocates to membrane ruffles, where it colocalizes with paxillin during cell migration. Together, our findings identify novel signaling and biological roles of Brk and indicate the first potential link between Brk and metastatic malignancy.

* Corresponding author. Mailing address: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Phone: 886-2-23123456, ext. 5700. Fax: 886-2-23957801. E-mail: rhchen{at}ha.mc.ntu.edu.tw.

Molecular and Cellular Biology, December 2004, p. 10558-10572, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10558-10572.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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