Hyperactivation of the G12-Mediated Signaling Pathway in Caenorhabditis elegans Induces a Developmental Growth Arrest via Protein Kinase C

The G12 type of heterotrimeric G-proteins play an important role in development and behave as potent oncogenes in cultured cells . However, little is known about the molecular nature of the components that act in the G12-signaling pathway in an organism. We characterized a C. elegans Gα subunit gene, gpa-12, which is a homolog of mammalian G12/G13α, and found that animals defective in gpa-12 are viable. Expression of activated GPA-12 (G12QL) 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 G12 participates, we screened for suppressors of the G12QL 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 . Expression of G12QL 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 G12 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 G12 proteins. [Copyright &y& Elsevier]