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Updated: Oct 29, 2025

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
06:56

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

Published on: September 6, 2024

535

Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

Janani Gopalan1, Mitchell H Omar1, Ankita Roy2,3

  • 1Department of Pharmacology, University of Washington, Seattle, United States.

Elife
|July 12, 2021
PubMed

Insights

Defects in kidney water balance can cause renal failure. This study reveals the AKAP220-PP1-HDAC6 pathway is crucial for primary cilia development, impacting kidney health.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Pathophysiological defects in water homeostasis and genetic disorders affecting kidney collecting ducts contribute to renal failure.
  • Abnormalities in cytoskeletal dynamics and signaling pathways within kidney cilia are implicated in chronic kidney disease.

Purpose of the Study:

  • To investigate the role of A-Kinase anchoring protein 220 (AKAP220) in kidney collecting duct development and primary cilia formation.
  • To elucidate the molecular mechanisms by which AKAP220 influences ciliogenesis and cytoskeletal dynamics.

Main Methods:

  • Utilized knockout mice lacking AKAP220 to study collecting duct phenotypes.
  • Employed mIMCD3 knock-in cell models expressing AKAP220 mutants to dissect molecular interactions.
  • Investigated the role of protein phosphatase 1 (PP1) and histone deacetylase 6 (HDAC6) in AKAP220-mediated effects.
  • Applied pharmacological inhibition of HDAC6 in kidney-on-chip and organoid models.

Main Results:

  • Mice lacking AKAP220 displayed enhanced primary cilia development in kidney collecting ducts.
  • AKAP220-associated PP1 was identified as a mediator, influencing HDAC6 stability and actin dynamics.
  • Phenotypes were replicated in cells expressing an AKAP220 mutant defective in PP1 targeting, highlighting PP1's adaptor function.
  • Pharmacological inhibition of HDAC6 modulated cilia development and reduced cystogenesis in kidney models.

Conclusions:

  • The AKAP220-PP1-HDAC6 pathway is a critical regulator of primary cilia development in kidney collecting ducts.
  • Targeting this pathway holds potential for therapeutic strategies against kidney diseases characterized by ciliopathies and cystogenesis.
Keywords:
AKAPInner medullary collecting ductbiochemistrycell biologychemical biologyhistone deacetylase 6mousepolycystic kidney diseaseprimary ciliaprotein phosphatase 1

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