G-alpha 12/13 types of G-proteins play an important role in development, and are known to function as potent oncogenes when expressed in cultured cells. We have previously identified a homologue of Rho-guanine nucleotide exchange factor (GEF) in C. elegans (CeRhoGEF), which functions downstream of
gpa-12, the C. elegans homologue of G alpha 12/13. CeRhoGEF contains a PSD-95/Dlg/ZO-1 domain and a regulator of G protein signaling (RGS) domain upstream of the Dbl homology-pleckstrin homology region similar to mammalian RhoGEFs with RGS domains, PSD-95/Dlg/ZO-1-RhoGEF and leukemia-associated RhoGEF (Yau et al., 2003). Ronald Plasterk and colleagues used suppressor screen for
gpa-12 and identified suppressors in the
tpa-1 gene that encodes two protein kinase C isoforms (TPA-1A and TPA-1B) that are homologous to PKC theta/delta (Tabuse et al. 1995; van der Linden et al., 2003). TPA-1 mediates the action of tumor promoter PMA and results in feeding defects and developmental arrest. In human cancers including lung cancer and mesothelioma, PKC function is closely associated with vascular endothelial growth factor receptor (VEGFR). The VEGF (vascular endothelial growth factor) and its receptor VEGFR are up-regulated in a variety of malignant tissues, including lung cancer and mesothelioma. Our results on malignant cell lines (H513, H28, H2461, H2373, H2596, and MSTO) show that PKC and VEGFR are overexpressed in lung and mesothelioma and also in tumor tissues. Inhibition of PKC by Enzastaurin inhibits the phosphorylation of PKC-beta 1 and 2 induced by rhVEGF, and Enzastaurin is under clinical trials for lung cancer. Expression of a reporter GFP under the
tpa-1 promoter in C. elegans transgenic lines show expression of the reporter in nervous system sensory neurons, muscle cells, and somatic vulva, and this expression is reduced in animals exposed to Enzastaurin. This system provide high throughput screening platform for evaluating potential cancer drugs that mediate conserved signal transduction pathways across C. elegans and humans, and reveal novel genes that interact with PKC, VEGF and G-protein signaling. We thank J. Miwa and Y. Tabuse for discussion and strains.