Division of Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Italy.
J Cell Biol. 2011 Oct 3;195(1):131-45. doi: 10.1083/jcb.201008013. Epub 2011 Sep 26.
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.
EMILIN1 促进 α4β1 整联蛋白依赖性细胞黏附和迁移，并减少促转化生长因子-β的加工。使用 knockout 小鼠模型来揭示 EMILIN1 在皮肤中的功能，该蛋白在真皮基质中大量表达，并且 EMILIN1 阳性纤维到达基底角质形成细胞层。EMILIN1 的缺失导致真皮和表皮过度增殖并加速伤口闭合。我们确定 EMILIN1 与 α4β1 和 α9β1 整联蛋白的直接结合是 EMILIN1 发挥其体内平衡作用的机制。由于 PTEN 的减少，缺乏 EMILIN1-α4/α9 整联蛋白相互作用伴随着 PI3K/Akt 和 Erk1/2 途径的激活。PTEN 的下调使 Erk1/2 磷酸化能力增强，进而通过磷酸化残基 Ser245/250/255 抑制 Smad2 信号。这些结果突出了细胞外基质成分在皮肤增殖中的重要调节作用。此外，EMILIN1 被鉴定为角质形成细胞 α9β1 整联蛋白的新型配体，提示该受体-配体对在皮肤稳态中的潜在作用。
