School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
FASEB J. 2024 Jan 31;38(2):e23410. doi: 10.1096/fj.202302251R.
Skin wound healing is a complex and organized biological process, and the dermal fibroblasts play a crucial role. α-Catenin is known to be involved in regulating various cellular signals, and its role in wound healing remains unclear. Here, we have identified the pivotal role of the α-catenin/FAK/YAP signaling axis in the proliferation and migration of dermal fibroblasts, which contributes to the process of skin wound healing. Briefly, when α-catenin was knocked down specifically in dermal fibroblasts, the wound healing rate is significantly delayed. Moreover, interfering with α-catenin can impede the proliferation and migration of dermal fibroblasts both in vitro and in vivo. Mechanistically, the overexpression of α-catenin upregulates the nuclear accumulation of YAP and transcription of downstream target genes, resulting in enhanced the proliferation and migration of dermal fibroblasts. Furthermore, the FAK Tyr397 phosphorylation inhibitor blocked the promoting effects of α-catenin on YAP activation. Importantly, the continuous phosphorylation mutation of FAK Tyr397 reversed the retardatory effects of α-catenin knockdown on wound healing, by increasing the vitality of fibroblasts. Likewise, α-catenin/FAK was validated as a therapeutic target for wound healing in the db/db chronic trauma model. In summary, our findings have revealed a novel mechanism by which α-catenin facilitates the function of fibroblasts through the activity of the FAK/YAP signaling axis. These findings define a promising therapeutic strategy for accelerating the wound healing process.
皮肤创伤愈合是一个复杂而有序的生物学过程，真皮成纤维细胞起着至关重要的作用。α-连环蛋白（α-catenin）已知参与调节各种细胞信号，但其在创伤愈合中的作用尚不清楚。在这里，我们确定了α-连环蛋白/FAK/YAP 信号轴在真皮成纤维细胞增殖和迁移中的关键作用，这有助于皮肤创伤愈合过程。简而言之，当α-连环蛋白在真皮成纤维细胞中被特异性敲低时，创伤愈合速度显著延迟。此外，干扰α-连环蛋白可以阻碍真皮成纤维细胞在体外和体内的增殖和迁移。在机制上，α-连环蛋白的过表达上调了 YAP 的核积累和下游靶基因的转录，从而增强了真皮成纤维细胞的增殖和迁移。此外，FAK Tyr397 磷酸化抑制剂阻断了α-连环蛋白对 YAP 激活的促进作用。重要的是，FAK Tyr397 的持续磷酸化突变通过增加成纤维细胞的活力，逆转了α-连环蛋白敲低对创伤愈合的延迟作用。同样，α-连环蛋白/FAK 被验证为 db/db 慢性创伤模型中创伤愈合的治疗靶点。总之，我们的研究结果揭示了一种新的机制，即α-连环蛋白通过 FAK/YAP 信号轴的活性促进成纤维细胞的功能。这些发现为加速创伤愈合过程提供了一种有前途的治疗策略。
