Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing
Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing
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DOI：
10.1074/jbc.m111.261677
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Alman, Benjamin A.
中科院分区：
文献类型：
--
作者：
Bielefeld, Kirsten A.;Amini-Nik, Saeid;Alman, Benjamin A.
-连环蛋白是皮肤创面修复过程中真皮成纤维细胞的重要调节因子。然而，在这一过程中调节β -连环蛋白活性的因素尚不完全清楚。我们研究了细胞外基质在调节β - catenin中的作用，发现暴露于各种细胞外基质成分的成纤维细胞中β - catenin介导的tcf依赖性转录活性增加。这是通过整合素介导的GSK3 β依赖途径发生的。这一机制的生理作用在额外结构域a-纤维连接蛋白缺陷小鼠的伤口修复过程中得到了证实，在愈合的增殖阶段，β -连环蛋白介导的信号传导减少。与野生型小鼠相比，额外结构域a -纤维连接蛋白缺陷小鼠的伤口在较低的拉伸强度下失败，并且含有较少的成纤维细胞。这种表型是通过基因或药理激活β -连环蛋白信号来挽救的。因为纤维连接蛋白是β -连环蛋白的转录靶点，这表明这两个分子之间存在一个反馈回路，在伤口修复过程中调节真皮成纤维细胞的行为。
beta-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate beta-Catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating beta-Catenin and found an increase in beta-Catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3 beta-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased beta-Catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of beta-Catenin signaling. Because fibronectin is a transcriptional target of beta-Catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.