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In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes
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Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin

Ingyu Kim1, Cunxi Li, Dan Liang

  • 1Departmentof Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.

The Journal of Biological Chemistry
|September 11, 2008
PubMed

Insights

Deficiencies in fibrocystin/polyductin (FPC) worsen polycystic kidney disease by down-regulating polycystin-2 (PC2). Identifying binding domains reveals a shared mechanism in autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney diseases.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney diseases stem from mutations in Pkd1/Pkd2 and Pkhd1, encoding polycystins (PCs) and fibrocystin/polyductin (FPC).
  • Previous research indicated FPC deficiency exacerbates cystic disease in Pkd2 mutants and reduces PC2 levels in vivo, but the mechanism remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which FPC deficiency impacts PC2 levels and disease severity in polycystic kidney diseases.
  • To identify specific interaction domains between PC2 and FPC.

Main Methods:

  • Utilized deletion and mutagenesis strategies to map protein interaction domains.
  • Generated a mouse model of ADPKD with hypomorphic Pkd2 alleles (Pkd2nf3/nf3).
  • Assessed PC2 down-regulation and associated phenotypes in the generated mouse model.

Main Results:

  • Identified a PC2-binding domain in FPC's C terminus and an FPC-binding domain in PC2's N terminus.
  • Demonstrated that physical interaction between these domains prevents PC2 down-regulation caused by FPC loss.
  • Observed PC2 down-regulation and a phenotype resembling Pkhd1(-/-) mice in the Pkd2nf3/nf3 ADPKD model.

Conclusions:

  • Established a molecular basis for the physical interaction between PC2 and FPC.
  • Revealed that this interaction prevents PC2 down-regulation, suggesting a common pathway in ADPKD and ARPKD cystogenesis.
  • Provided insights into the molecular relationship between PC2 and FPC in the context of polycystic kidney diseases.

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