Hyperactivation of the G12-mediated signaling pathway in Caenorhabditis elegans induces a developmental growth arrest via protein kinase C.

Abstract The G 12 type of heterotrimeric G-proteins play an important role in development and behave as potent oncogenes in cultured cells [1–5]. However, little is known about the molecular nature of the components that act in the G 12 -signaling pathway in an organism. We characterized a C . elegans Gα subunit gene, gpa-12 , which is a homolog of mammalian G 12 /G 13 α, and found that animals defective in gpa-12 are viable. Expression of activated GPA-12 (G 12 QL) results in a developmental growth arrest caused by a feeding behavior defect that is due to a dramatic reduction in pharyngeal pumping. To elucidate the molecular nature of the signaling pathways in which G 12 participates, we screened for suppressors of the G 12 QL phenotype. We isolated 50 suppressors that contain mutations in tpa-1 , which encodes two protein kinase C isoforms, TPA-1A and TPA-1B, most similar to PKCθ/δ. TPA-1 mediates the action of the tumor promoter PMA [6]. Expression of G 12 QL and treatment of wild-type animals with PMA induce an identical growth arrest caused by inhibition of larval feeding, which is dependent on TPA-1A and TPA-1B function. These results suggest that TPA-1 is a downstream target of both G 12 signaling and PMA in modulating feeding and growth in C . elegans . Taken together, our findings provide a potential molecular mechanism for the transforming capability of G 12 proteins.