Kindlin1 regulates microtubule function to ensure normal mitosis

J Mol Cell Biol. 2016 Aug;8(4):338-48. doi: 10.1093/jmcb/mjw009. Epub 2016 Mar 18.

Abstract

Loss of Kindlin 1 (Kin1) results in the skin blistering disorder Kindler Syndrome (KS), whose symptoms also include skin atrophy and reduced keratinocyte proliferation. Kin1 binds to integrins to modulate their activation and more recently it has been shown to regulate mitotic spindles and cell survival in a Plk1-dependent manner. Here we report that short-term Kin1 deletion in mouse skin results in impaired mitosis, which is associated with reduced acetylated tubulin (ac-tub) levels and cell proliferation. In cells, impaired mitosis and reduced ac-tub levels are also accompanied by reduced microtubule stability, all of which are rescued by HDAC6 inhibition. The ability of Kin1 to regulate HDAC6-dependent cellular ac-tub levels is dependent on its phosphorylation by Plk1. Taken together, these data define a novel role for Kin1 in microtubule acetylation and stability and offer a mechanistic insight into how certain KS phenotypes, such as skin atrophy and reduced cell proliferation, arise.

Keywords: HDAC6; Kindlin1; Plk1; microtubules; mitosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Centrosome / metabolism
  • Gene Deletion
  • Histone Deacetylase 6
  • Histone Deacetylases / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Microtubules / metabolism*
  • Mitosis*
  • Models, Biological
  • Neoplasm Proteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Tubulin / metabolism

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • FERMT1 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Tubulin
  • kindlin-1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases