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J Biol Chem, Vol. 274, Issue 53, 38204-38210, December 31, 1999

Kinase Activation of the Non-receptor Tyrosine Kinase Etk/BMX Alone Is Sufficient to Transactivate STAT-mediated Gene Expression in Salivary and Lung Epithelial Cells^*

Xin Wen, H. Helen Lin, Hsiu-Ming Shih^§, Hsing-Jien Kung^¶, and David K. Ann^**

From the  Department of Molecular Pharmacology and Toxicology and  Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California 90033, the ^§ Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan, Republic of China, and the ^¶ Cancer Center, University of California at Davis, Sacramento, California 95817

Etk/BMX is a non-receptor protein tyrosine kinase that requires a functional phosphatidylinositol 3-kinase via the pleckstrin homology domain to be activated by cytokine. In the present study, a conditionally active form of Etk was constructed by fusing the hormone-binding domain of estrogen receptor (ER) to an amino terminus truncated form of Etk, PH1-68Etk, to generate Etk:ER. In stably transfected Pa-4Etk:ER cells, the activity of Etk:ER was stimulated within minutes by the treatment of Etk:ER stimulant, estradiol, and sustained for greater than 24 h. A robust induction in the phosphorylation of signal transducers and activators of transcription (STAT) proteins, including STAT1, STAT3, and STAT5, was accompanied with Etk:ER activation. Moreover, the conditionally activated Etk stimulated STAT1- and STAT5-dependent reporter activities by ~160- and ~15-fold, respectively, however, elicited only a modest STAT3-mediated reporter activation. Qualitatively comparable results were obtained in lung A549 cells, indicating that Etk:ER inducible system could function in an analogous fashion in different epithelial cells. Furthermore, we demonstrated that Etk activation alone augmented cyclin D1 promoter/enhancer activity via its STAT5 response element in both Pa-4Etk:ER and A549 cells. Altogether, these findings support the notion that the activation of Etk kinase is sufficient to transactivate STAT-mediated gene expression. Hence, our inducible Etk:ER system represents a novel approach to investigate the biochemical events following Etk activation and to evaluate the contribution by kinase activation of Etk alone or in conjunction with other signaling pathway(s) to the ultimate biological responses.

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^* This work was supported in part by National Institutes of Health Research Grant RO1-DE10742 (to D. K. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. University of California, School of Pharmacy, PSC-210B, 1985 Zonal Ave., Los Angeles, CA 90033-1049. Tel.: 323-442-3146; Fax: 323-224-7473; E-mail: ann@hsc.usc.edu.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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