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Updated: May 17, 2026

In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes
10:05

In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes

Published on: August 13, 2012

The Ion channel, CFTR, assembles with HIPPO pathway proteins TAZ and YAP in polycystic kidney disease

Abhishek Sharma1, Masoud Afshani1, Cristian Ciobanu1

  • 1Departments of Medicine and Physiology, Johns Hopkins University, Baltimore, Maryland, USA.

The Journal of Biological Chemistry
|May 15, 2026
PubMed

Insights

CFTR modulators like VX-809 inhibit cyst growth in polycystic kidney disease by affecting the Hippo pathway. This therapy reduces proliferation by altering the localization of CFTR, TAZ, and YAP proteins.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Adult-onset polycystic kidney disease (ADPKD) is characterized by progressive renal function decline due to cyst expansion.
  • Cyst formation in ADPKD is critically dependent on increased cell proliferation.
  • Targeting proliferation pathways is essential for developing effective ADPKD therapies.

Purpose of the Study:

  • To investigate the mechanism by which the CFTR modulator VX-809 inhibits cyst formation and proliferation in ADPKD.
  • To explore the association between CFTR, the Hippo pathway proteins TAZ and YAP, and cystogenesis in ADPKD models.

Main Methods:

  • Utilized pkd1R3277/R3277C (RC) mutant mice and cell lines to model ADPKD.
  • Examined the co-localization of CFTR, TAZ, and YAP proteins in normal and RC kidneys, with and without VX-809 treatment.
  • Assessed the nuclear localization of TAZ and YAP in RC kidneys.

Main Results:

  • CFTR was found to associate closely with TAZ and YAP in both normal and RC mice.
  • In untreated RC kidneys, CFTR, TAZ, and YAP abnormally accumulated at the apical membrane and co-localized with calnexin (ER marker).
  • VX-809 treatment restored CFTR, TAZ, and YAP to a basolateral location and reduced nuclear TAZ/YAP levels in RC kidneys.

Conclusions:

  • CFTR modulator therapy, exemplified by VX-809, reduces ADPKD cyst formation by inhibiting proliferation.
  • The therapeutic effect involves altering the cellular localization of CFTR, TAZ, and YAP, shifting them from the apical membrane and nucleus to a basolateral position.
  • This study provides mechanistic insight into how CFTR modulators impact the Hippo pathway, offering a potential therapeutic strategy for ADPKD.
Keywords:
ADPKDCFTRTAZYAPcysts

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