Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation.
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.
Tsai
Y T
YT
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Su
Y H
YH
Fang
S S
SS
Huang
T N
TN
Qiu
Y
Y
Jou
Y S
YS
Shih
H M
HM
Kung
H J
HJ
Chen
R H
RH
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051381:Rats; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D015534:Trans-Activators; C492367:BMX protein, human; C492365:Bmx protein, rat; D011505:Protein-Tyrosine Kinases