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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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