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

J Biol Chem. 1998 Mar 13;273(11):6013-8. doi: 10.1074/jbc.273.11.6013.


Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder that accounts for 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 NFkappaB-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 (PKC) inhibitors decreased PKD1-mediated AP-1 activation. Conversely, expression of the C-terminal domain of PKD1 increased PKC 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism
  • Humans
  • Isoenzymes / metabolism*
  • JNK Mitogen-Activated Protein Kinases
  • Kidney / cytology
  • Kidney / metabolism*
  • Kidney Tubules / growth & development
  • Mitogen-Activated Protein Kinases*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Polycystic Kidney, Autosomal Dominant / metabolism
  • Protein Kinase C / metabolism*
  • Protein Kinase C-alpha
  • Proteins / genetics
  • Proteins / metabolism*
  • Recombinant Proteins / metabolism
  • TRPP Cation Channels
  • Transcription Factor AP-1 / metabolism*


  • Isoenzymes
  • Peptide Fragments
  • Proteins
  • Recombinant Proteins
  • TRPP Cation Channels
  • Transcription Factor AP-1
  • polycystic kidney disease 1 protein
  • PRKCA protein, human
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins