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

EMILIN1 promotes alpha 4 beta 1 integrin-dependent cell adhesion and migration and reduces pro-transforming growth factor-beta 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 alpha 4 beta 1 and alpha 9 beta 1 integrins as the mechanism underlying the homeostatic role exerted by EMILIN1. The lack of EMILIN1- alpha 4/beta 9 integrin interaction was accompanied by activation of PI3K/Akt and Erk1/2 pathways as a result of the reduction of PTEN. The downregulation 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 alpha 9 beta 1 integrin, suggesting prospective roles for this receptor-ligand pair in skin homeostasis.