Activation of nonreceptor tyrosine kinase Bmx/Etk mediated by phosphoinositide 3-kinase, epidermal growth factor receptor, and ErbB3 in prostate cancer

Pathways activated downstream of constitutively active phosphatidylinositol ( PI) 3- kinase in PTEN- deficient prostate cancer ( PCa) cells are possible therapeutic targets. We found that the nonreceptor Tec family tyrosine kinase Bmx/ Etk was activated by tyrosine phosphorylation downstream of Src and PI 3- kinase in PTEN- deficient LNCaP and PC3 PCa cells and that Bmx down- regulation by short interfering RNA markedly inhibited LNCaP cell growth. Bmx also associated with ErbB3 in LNCaP cells, and heregulin-beta 1 enhanced this interaction and further stimulated Bmx activity. Epidermal growth factor ( EGF) similarly stimulated an interaction between Bmx and EGF receptor and rapidly increased Bmx kinase activity. Bmx stimulation in response to heregulin-beta 1 and EGF was Src- dependent, and heregulin-beta 1 stimulation of Bmx was also PI 3-kinase-dependent. In contrast, the rapid tyrosine phosphorylation and activation of Bmx in response to EGF was PI3-kinase-independent. Taken together, these results demonstrate that Bmx is a critical downstream target of the constitutively active PI 3- kinase in PTEN- deficient PCa cells and further show that Bmx is recruited by the EGF receptor and ErbB3 and activated in response to their respective ligands. Therefore, Bmx may be a valuable therapeutic target in PCa and other epithelial malignancies in which PI 3- kinase or EGF receptor family pathways are activated.