title: EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation.
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.
authors.affiliation: Division of Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Danussi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Petrucco
authors.forename: Bruna
authors.initials: B
authors.lastname: Wassermann
authors.forename: Eliana
authors.initials: E
authors.lastname: Pivetta
authors.forename: Teresa Maria Elisa
authors.initials: TM
authors.lastname: Modica
authors.forename: Lisa
authors.initials: L
authors.lastname: Del Bel Belluz
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Paola
authors.initials: P
authors.lastname: Spessotto
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D020405:Dermis / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D039001:Integrin alpha Chains; D039041:Integrin alpha4beta1; D008562:Membrane Glycoproteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C030340:elastin microfibril interface located protein; C084613:integrin alpha9; D039441:Integrin alpha4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse