EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation

J Cell Biol. 2011 Oct 3;195(1):131-45. doi: 10.1083/jcb.201008013. Epub 2011 Sep 26.

Abstract

EMILIN1 promotes α4β1 integrin-dependent cell adhesion and migration and reduces pro-transforming growth factor-β processing. A knockout mouse model was used to unravel EMILIN1 functions in skin where the protein was abundantly expressed in the dermal stroma and where EMILIN1-positive fibrils reached the basal keratinocyte layer. Loss of EMILIN1 caused dermal and epidermal hyperproliferation and accelerated wound closure. We identified the direct engagement of EMILIN1 to α4β1 and α9β1 integrins as the mechanism underlying the homeostatic role exerted by EMILIN1. The lack of EMILIN1-α4/α9 integrin interaction was accompanied by activation of PI3K/Akt and Erk1/2 pathways as a result of the reduction of PTEN. The down-regulation of PTEN empowered Erk1/2 phosphorylation that in turn inhibited Smad2 signaling by phosphorylation of residues Ser245/250/255. These results highlight the important regulatory role of an extracellular matrix component in skin proliferation. In addition, EMILIN1 is identified as a novel ligand for keratinocyte α9β1 integrin, suggesting prospective roles for this receptor-ligand pair in skin homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Dermis / cytology
  • Dermis / metabolism*
  • Down-Regulation / physiology
  • Enzyme Activation / physiology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Homeostasis / physiology
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / metabolism*
  • Integrin alpha4 / genetics
  • Integrin alpha4 / metabolism*
  • Integrin alpha4beta1 / genetics
  • Integrin alpha4beta1 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / physiology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism

Substances

  • Integrin alpha Chains
  • Integrin alpha4beta1
  • Membrane Glycoproteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • elastin microfibril interface located protein
  • integrin alpha9
  • Integrin alpha4
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3
  • PTEN Phosphohydrolase
  • Pten protein, mouse