Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins.

Functional analysis of polycystin-1, the product of the gene most frequently mutated in autosomal dominant polycystic kidney disease, has revealed that this protein is involved in the regulation of diverse signaling pathways such as the activation of the transcription factor AP-1 and modulation of Wnt signaling. However, the initial steps involved in the activation of such cascades have remained unclear. We demonstrated previously that the C-terminal cytosolic tail of polycystin-1 binds and activates heterotrimeric G proteins in vitro. To test if polycystin-1 can activate cellular signaling cascades via heterotrimeric G protein subunits, polycystin-1 C-terminal tail-mediated c-Jun N-terminal kinase (JNK) and AP-1 activities were assayed in transiently transfected 293T cells in the presence of dominant-negative, G protein inhibiting constructs, and in the presence of cotransfected Galpha subunits. The results showed that polycystin-1-mediated JNK/AP-1 activation is mediated by Galpha and Gbetagamma subunits. Polycystin-1-mediated AP-1 activity could be significantly augmented by cotransfected Galpha(i), Galpha(q), and Galpha(12/13) subunits, suggesting that polycystin-1 can couple with and activate several heterotrimeric G protein families.