Protein kinase G type-I phosphorylates c-Src at serine-17 and promotes cell survival, proliferation and attachment in human mesothelioma and non-small cell lung cancer cells

Background Previously, we demonstrated that protein kinase G type-Ia (PKG-Ia) plays an important role in promoting cell survival in neural cells (N1E-115 neuroblastoma and NG10815 neuroblastoma-glioma hybrid cells) and significantly contributes to the serine-155 phosphorylation of BAD, an apoptosis-regulating protein [1]. We also found that PKGIa promotes cell survival and proliferation in mouse OP9 bone marrow stromal cells [2] and human ovarian cancer cells [3] [determined by using both pharmacological inhibitors (ODQ, DT-2 and DT-3) and gene knockdown (siRNA) to reduce PKG-Ia/b activity]. In the case of ovarian cancer cells, which predominantly express the PKG-Ia isoform, the pro-growth and pro-survival effects involved a novel interaction between PKG-Ia and the oncogenic protein c-Src [3]. For example, intracellular activation of PKG-Ia, assessed by VASP serine-239 phosphorylation, was dependent on c-Src-catalyzed tyrosine phosphorylation of PKG-Ia (i.e. VASP phosphorylation was blocked by Src inhibitors, SKI-1 or SU6656) and the intracellular activation of c-Src was (somehow) dependent on the kinase activity and expression levels of PKG-Ia (i.e. c-Src activation was decreased by DT-2 or siRNA-induced knockdown of PKG-Ia).