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

Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3644-9. doi: 10.1073/pnas.95.7.3644.

Abstract

Etk/Bmx is the newest member of Btk tyrosine kinase family that contains a pleckstrin homology domain, an 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, D., He, F., Pretlow, T. & Kung, H. J. (1996) Proc. Natl. Acad. Sci. USA 93, 5958-5962). Here we report that Etk is engaged in phosphatidylinositol 3-kinase (PI3-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) Wortmannin, 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • DNA, Complementary / isolation & purification
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Molecular Sequence Data
  • Neurosecretory Systems / pathology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Sequence Alignment
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Tumor Cells, Cultured

Substances

  • DNA, Complementary
  • BMX protein, human
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases

Associated data

  • GENBANK/AP045459