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

Mol Cell Biol. 1999 May;19(5):3423-34. doi: 10.1128/mcb.19.5.3423.

Abstract

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 activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase 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'-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC alpha and PKC epsilon, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

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 / genetics
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • GTP-Binding Proteins / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Membrane Proteins / genetics*
  • Mitogen-Activated Protein Kinases*
  • Mutation / genetics
  • Phosphorylation
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Protein Kinase C / metabolism
  • Proteins / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Signal Transduction
  • Staurosporine / pharmacology
  • TRPP Cation Channels
  • Transcription Factor AP-1 / genetics

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins c-jun
  • TRPP Cation Channels
  • Transcription Factor AP-1
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein
  • Egtazic Acid
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins
  • Staurosporine
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid