EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation.
EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation.
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DOI：
10.1083/jcb.201008013
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发表时间：
2011-10-03
期刊：
影响因子：
--
通讯作者：
Spessotto P
中科院分区：
文献类型：
--
作者：
Danussi C;Petrucco A;Wassermann B;Pivetta E;Modica TM;Del Bel Belluz L;Colombatti A;Spessotto P
α4/α9整合素直接与细胞外基质糖蛋白EMILIN1结合，在转化生长因子-β信号的上游抑制皮肤细胞的增殖。EMILIN1促进α4β1整合素依赖的细胞黏附和迁移，并减少促转化生长因子-β的加工。使用基因敲除的小鼠模型来揭示EMILIN1在皮肤中的功能，其中EMILIN1蛋白在真皮基质中大量表达，并且EMILIN1阳性的纤维到达基底层角质形成细胞层。EMILIN1的缺失导致真皮和表皮过度增殖，加速伤口闭合。我们发现EMILIN1与α4β1和α9β1整合素的直接结合是EMILIN1发挥内环境平衡作用的机制。缺乏EMILIN1-α-4/α-9整合素相互作用伴随着PI3K/Akt和ERK1/2通路的激活，这是PTEN减少的结果。PTEN的下调使ERK1/2磷酸化，进而通过Ser245/250/255残基的磷酸化抑制Smad2信号转导。这些结果强调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整合素的一种新的配体，这表明该受体-配体对在皮肤内稳态中具有潜在的作用。
The α4/α9 integrins directly engage the ECM glycoprotein EMILIN1 to inhibit skin cell proliferation upstream of TGF-β signaling. 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.
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影响因子：
3.6
作者：
Chow JY;Cabral JA;Chang J;Carethers JM
通讯作者：
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