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 W...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-05, Vol.277 (22), p.19566-19572
Main Authors: Parnell, Stephen C., Magenheimer, Brenda S., Maser, Robin L., Zien, Christopher A., Frischauf, Anna-Maria, Calvet, James P.
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
c-Jun N-terminal kinase
Cell Line
Enzyme Activation
Genes, Dominant
GTP-Binding Proteins - metabolism
GTP-Binding Proteins - physiology
Humans
JNK Mitogen-Activated Protein Kinases
JNK protein
Mice
Mitogen-Activated Protein Kinases - metabolism
Models, Biological
polycystin 1
Protein Binding
Protein Structure, Tertiary
Proteins - chemistry
Proteins - metabolism
Signal Transduction
Transcription Factor AP-1 - metabolism
TRPP Cation Channels
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Summary: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 Gα subunits. The results showed that polycystin-1-mediated JNK/AP-1 activation is mediated by Gα and Gβγ subunits. Polycystin-1-mediated AP-1 activity could be significantly augmented by cotransfected Gαi, Gαq, and Gα12/13 subunits, suggesting that polycystin-1 can couple with and activate several heterotrimeric G protein families.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M201875200