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PKC412 normalizes mutation-related keratin filament disruption and hepatic injury in mice by promoting keratin-myosin

Raymond Kwan1,2, Lu Chen1,3, Koksun Looi1

  • 1Departments of Molecular & Integrative Physiology and of Medicine, University of Michigan, Ann Arbor, MI.

Hepatology (Baltimore, Md.)
|July 2, 2015
PubMed
Abstract

Insights

A novel kinase inhibitor, PKC412, corrects keratin filament defects caused by mutations. It enhances keratin association with nonmuscle myosin-IIA (NM-IIA), offering a potential therapeutic strategy for intermediate filament diseases.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Medicine

Background:

  • Keratin intermediate filament (IF) proteins are crucial for cell structure.
  • Mutations in keratins, particularly at conserved arginine residues, lead to severe disease phenotypes due to filament disruption.
  • Understanding the mechanisms underlying keratin filament organization and disruption is vital for developing therapeutic interventions.

Purpose of the Study:

  • To identify compounds that can normalize keratin filament organization disrupted by specific mutations.
  • To investigate the mechanism by which identified compounds restore keratin filament integrity.
  • To explore the therapeutic potential of targeting keratin-myosin interactions for intermediate filament-associated diseases.

Main Methods:

  • High-throughput screening of a kinase inhibitor library using cells expressing mutant keratin 18 (K18 Arg90Cys).
  • Assessment of keratin filament organization in cells and transgenic mouse models.
  • Analysis of protein-protein interactions using proteomics, co-immunoprecipitation, and immune staining.
  • Investigation of the role of nonmuscle myosin-IIA (NM-IIA) dephosphorylation in keratin association.

Main Results:

  • PKC412, a multikinase inhibitor, effectively ameliorated K18 Arg90Cys-mediated keratin filament disruption in cellular and animal models.
  • PKC412 protected cells and mouse livers from Fas-induced apoptosis.
  • Proteomic analysis revealed that PKC412 enhances the association of keratins with nonmuscle myosin heavy chain-IIA (NMHC-IIA) in a dephosphorylation-dependent manner.
  • NMHC-IIA knockdown abrogated the filament-normalizing effect of PKC412.

Conclusions:

  • The kinase inhibitor PKC412 normalizes keratin filament disruption by enhancing keratin association with NM-IIA, regulated by myosin dephosphorylation.
  • Targeting intermediate filament disorganization through modulation of keratin-associated protein interactions presents a novel therapeutic avenue for keratinopathies and other IF protein disorders.

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