The polycystic kidney disease 1 gene product mediates protein kinase C α-dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder that accounts far 8-10% of end stage renal disease, PKD1, one of two recently isolated ADPKD gene products, has been implicated in cell-cell and cell-matrix interactions, However, the signaling pathway of PKD1 remains undefined, We found that the C-terminal 226 amino acids of PKD1 transactivate an AP-1. promoter construct in human embryonic kidney cells (293T). PKD1-induced transcription is specific for AP-1; promoter constructs containing cAMP response element-binding protein, c-Fos, c-Myc, or NF kappa B-binding sites are unaffected by PKD1. In vitro kinase assays revealed that PKD1 triggers the activation of c-Jun N-terminal kinase (JNK), but not of mitogen-activated protein kinases p38 or p44, Dominant-negative Rac-1 and Cdc42 mutations abrogated PKD1-mediated JNK and AP-1 activation, suggesting a critical role for small GTP-binding proteins in PKD1-mediated signaling. Several protein kinase C (PRC) inhibitors decreased PKD1-mediated AP-1 activation, Conversely, expression of the C-terminal domain of PKD1 increased PRC activity in 293T cells, A dominant-negative PKC alpha, but not a dominant-negative PKC beta or delta, abrogated PKD1-mediated AP-1 activation, These findings indicate that small GTP-binding proteins and PKC alpha mediate PKD1-induced JNK/AP-1 activation, together comprising a signaling cascade that may regulate renal tubulogenesis.