Cellular activation triggered by the autosomal dominant polycystic kidney disease gene product PKD2

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes , PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon acti vation of the mitogen-activated protein kinases p38 and JNK1 and protein ki nase C (PKC) epsilon, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N',N' -t etraacetate], inhibited PKD2-mediated signaling, consistent with the involv ement of a calcium-independent PRC isozyme. Coexpression of PKD2 with the i nteracting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 act ivation. The synergistic signaling between PKD1 and PKD2 involved the activ ation of two distinct PKC isozymes, PKC alpha and PKC epsilon, respectively . Our findings are consistent with others that support a functional connect ion between PKD1 and PKD2 involving multiple signaling pathways that conver ge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. A ctivation of these signaling cascades may promote the full maturation of de veloping tubular epithelial cells, while inactivation of these signaling ca scades may impair terminal differentiation and facilitate the development o f renal tubular cysts.