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

Abstract

Etk (also calledBmxEtk (also called Bmx) is a member of the Btk nonreceptor tyrosine kinase family (48,51,57). This family of kinases is characterized by a modular structure, including an N-terminal pleckstrin homology (PH) domain, a Tec homology domain, Src homology 2 (SH2) and SH3 domains, and a C-terminal kinase domain. Many members of the Btk family are predominantly expressed in cells of hematopoietic origin. Btk is expressed in B cells and myeloid cell lineages and is essential for B-cell development and signaling. Loss-of-function mutations in Btk result in human X-linked agammaglobulinemia and murine X-linked B-cell immunodeficiency (50,53

The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells

“…These data together suggest that Tec family kinases are bidirectional switches of cell growth and apoptosis. While the mechanism of this switch is presently unclear, we noted that Etk assumes two forms inside the cells: the wild-type form which requires upstream signals such as PI-3 kinase, FAK, PTPD1, and Src for its activation (Ekman et al, 2000;Jui et al, 2000;Tsai et al, 2000;Chen et al, 2001), and the caspase-8 truncated form which is constitutively active. We previously showed that the constitutively activated form induced apoptosis (Wu et al, 2001).…”

“…There are a number of reports suggesting a role of Tec family kinases in growth and antiapoptosis. For example, Etk has been shown to be a critical mediator of cellular transformation through a cascade link of vSrc-Etk-Stat3 (Tsai et al, 2000) in fibroblast and epithelial cells. Overexpression of Etk stimulates the proliferation of MCF-7 breast cancer cells and protects prostate cancer cells from ionization-and thapsigargininduced apoptosis (Xue et al, 1999;Bagheri-Yarmand et al, 2001).…”

“…As expected, the EGF-induced phosphorylation of the Etk was markedly abrogated in AG1498-treated MDA-MB-468 cells (Figure 1d, lane 3 versus lane 4), suggesting an essential role of the EGFR in Etk activation. Etk was previously reported to be activated by PI3-kinase and/or Src kinase (Qiu et al, 1998;Tsai et al, 2000). To test whether these kinases are also involved in the EGF/ EGFR-mediated Etk activation, MDA-MB-468 cells were treated with an Src kinase inhibitor, PP2, or a PI3-kinase inhibitor, LY294002, prior to the EGF stimulation.…”

“…Tec is expressed in most hematopoietic cells, and is involved in a variety of signal pathways including interleukin-3, stem-cell factor, and granulocyte colony-stimulating factor (Tang et al, 1994;Mano et al, 1995;Matsuda et al, 1995). Etk/Bmx was initially identified in bone marrow and subsequently in epithelial cells, fibroblast, and endothelial cells (Tamagnone et al, 1994;Robinson et al, 1996;Qiu et al, 1998;Tsai et al, 2000). Previous studies showed that Etk plays a pivotal role in IL-6-induced neuroendocrine differentiation and neuropeptide-induced androgen-independent growth of prostate cancer cells (Qiu et al, 1998;Lee et al, 2001).…”

“…Interestingly, upon caspase cleavage, the constitutively activated Etk becomes proapoptotic (Wu et al, 2001). Etk has also been shown to mediate Src-induced transformation of epithelial cells and fibroblasts through activation of Stat3, and to transform the breast cancer cells via activation of Pak1 (Tsai et al, 2000;Bagheri-Yarmand et al, 2001). In addition, Etk was also reported to be activated by IL-3 and GM-CSF in mast cells and by VEGF and angiopoietin in endothelial cells (Ekman et al, 2000;Rajantie et al, 2001;Chau et al, 2002).…”