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Molecular and Cellular Biology, March 2000, p. 2043-2054, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Etk, a Btk Family Tyrosine Kinase, Mediates Cellular Transformation by Linking Src to STAT3 Activation

Yuh-Tyng Tsai,1 Yi-Hsien Su,1 Shih-Shuan Fang,1 Tzye-Nan Huang,1 Yun Qiu,2 Yuh-Shan Jou,3 Hsiu-ming Shih,3 Hsing-Jien Kung,3,4 and Ruey-Hwa Chen1,*

Institute of Molecular Medicine, College of Medicine, National Taiwan University,1 and Division of Molecular and Genomic Medicine, National Health Research Institute,3 Taipei, Taiwan; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota2; and Cancer Center, University of California at Davis, Sacramento, California4

Received 23 June 1999/Returned for modification 11 August 1999/Accepted 13 December 1999

Etk (also called Bmx) is a member of the Btk tyrosine kinase family and is expressed in a variety of hematopoietic, epithelial, and endothelial cells. We have explored biological functions, regulators, and effectors of Etk. Coexpression of v-Src and Etk led to a transphosphorylation on tyrosine 566 of Etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of Etk. STAT3, which was previously shown to be activated by Etk, associated with Etk in vivo. To investigate whether Etk could mediate v-Src-induced activation of STAT3 and cell transformation, we overexpressed a dominant-negative mutant of Etk in an immortalized, untransformed rat liver epithelial cell line, WB, which contains endogenous Etk. Dominant-negative inactivation of Etk not only blocked v-Src-induced tyrosine phosphorylation and activation of STAT3 but also caused a great reduction in the transforming activity of v-Src. In NIH3T3 cells, although Etk did not itself induce transformation, it effectively enhanced the transforming ability of a partially active c-Src mutant (c-Src378G). Furthermore, Etk activated STAT3-mediated gene expression in synergy with this Src mutant. Our findings thus indicate that Etk is a critical mediator of Src-induced cell transformation and STAT3 activation. The role of STAT3 in Etk-mediated transformation was also examined. Expression of Etk in a human hepatoma cell line Hep3B resulted in a significant increase in its transforming ability, and this effect was abrogated by dominant-negative inhibition of STAT3. These data strongly suggest that Etk links Src to STAT3 activation. Furthermore, Src-Etk-STAT3 is an important pathway in cellular transformation.

* Corresponding author. Mailing address: 7 Chung Shan S. Rd., Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Phone: 886-2-23970800, ext. 5700. Fax: 886-2-23957801. E-mail: rhchen{at}ha.mc.ntu.edu.tw.

Molecular and Cellular Biology, March 2000, p. 2043-2054, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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