Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3′-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells

Etk/Bmx is the newest member of Btk tyrosine kinase family that contains a pleckstrin homology domain, all src homology 3 domain, an src homology 2 domain, and a catalytic domain. Unlike other members of the Btk family kinases, which are mostly hemopoietic cell-specific, Etk/Bmx is preferentially expressed in epithelial and endothelial cells, We first identified this kinase in prostate cancer [Robinson, I),, He, F., Pretlow, T. Br Kung, H, J. (1996) Proc, Natl. Acad. Sci. USA 93, 5958-5962), Here we report that Etk is engaged in phosphatidylinositol 3 kinase (PU-kinase) pathway and plays a pivotal role in interleukin 6 (IL-6) signaling in a prostate cancer cell line, LNCaP, Our evidence that PI3-kinase is involved in Etk activation includes: (i) Wort mannin, a specific inhibitor of PI3-kinase, abolished the activation of Etk by IL-6; (ii) a constitutively active p110 subunit of PI3-kinase was able to activate Etk in the absence of IL-6; and (iii) a dominant negative p85 subunit of PI3-kinase mutant blocked the activation of Etk by IL-6. Interestingly, IL-6 treatment of LNCaP induced a remarkable neuroendocrine-like differentiation phenotype, with neurite extension and enhanced expression of neuronal markers. This phenotype could be abrogated by the overexpression of a dominant-negative Etk, indicating Etk is required for this differentiation process.