Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking src to STAT3 activation

Yuh Tyng Tsai, Yi Hsien Su, Shih Shuan Fang, Tzye Nan Huang, Yun Qiu, Yuh Shan Jou, Hsiu Ming Shih, Hsing-Jien Kung, Ruey Hwa Chen

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106 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2043-2054
Number of pages12
JournalMolecular and Cellular Biology
Volume20
Issue number6
DOIs
StatePublished - Mar 2000

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Tsai, Y. T., Su, Y. H., Fang, S. S., Huang, T. N., Qiu, Y., Jou, Y. S., Shih, H. M., Kung, H-J., & Chen, R. H. (2000). Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking src to STAT3 activation. Molecular and Cellular Biology, 20(6), 2043-2054. https://doi.org/10.1128/MCB.20.6.2043-2054.2000