Sustained cell migration is essential for wound healing and cancer metastasis. The epidermal growth factor receptor (EGFR) signaling cascade is known to drive cell migration and proliferation. While the signal transduction downstream of EGFR has been extensively investigated, our knowledge of the initiation and maintenance of EGFR signaling during cell migration remains limited. The metalloprotease TACE is responsible for producing active EGFR family ligands in the via ligand shedding. Sustained TACE activity may perpetuate EGFR signaling and reduce a cell's reliance on exogenous growth factors. Using a cultured keratinocyte model system, we show that depletion of α-catenin perturbs adherens junctions, enhances cell proliferation and motility, and decreases dependence on exogenous growth factors. We show that the underlying mechanism for these observed phenotypical changes depends on enhanced autocrine/paracrine release of the EGFR ligand TGF-α in a TACE-dependent manner. We demonstrate that proliferating keratinocyte epithelial cell clusters display waves of oscillatory extracellular signal-regulated kinase (ERK) activity, which can be eliminated by TACE knockout, suggesting that these waves of oscillatory ERK activity depend on autocrine/paracrine signals produced by TACE. These results provide new insights into the regulatory role of adherens junctions in initiating and maintaining autocrine/paracrine signaling with relevance to wound healing and cellular transformation.

持续的细胞迁移对于伤口愈合和癌症转移至关重要。已知表皮生长因子受体 (EGFR) 信号级联可驱动细胞迁移和增殖。虽然 EGFR 下游的信号转导已被广泛研究，但我们对细胞迁移过程中 EGFR 信号传导的启动和维持的了解仍然有限。金属蛋白酶 TACE 负责在通路配体脱落中产生活性 EGFR 家族配体。持续的 TACE 活性可以使 EGFR 信号持续存在并减少细胞对外源性生长因子的依赖。使用培养的角质形成细胞模型系统，我们表明 α-连环蛋白的消耗会干扰粘附连接，增强细胞增殖和运动性，并减少对外源性生长因子的依赖。我们表明，这些观察到的表型变化的潜在机制取决于 EGFR 配体 TGF-α 以 TACE 依赖性方式增强的自分泌/旁分泌释放。我们证明增殖的角质形成细胞上皮细胞簇显示出振荡的细胞外信号调节激酶 (ERK) 活性波，这可以通过 TACE 敲除消除，这表明这些振荡 ERK 活性波依赖于 TACE 产生的自分泌/旁分泌信号。这些结果为粘附连接在启动和维持与伤口愈合和细胞转化相关的自分泌/旁分泌信号传导中的调节作用提供了新的见解。我们证明增殖的角质形成细胞上皮细胞簇显示出振荡的细胞外信号调节激酶 (ERK) 活性波，这可以通过 TACE 敲除消除，这表明这些振荡 ERK 活性波依赖于 TACE 产生的自分泌/旁分泌信号。这些结果为粘附连接在启动和维持与伤口愈合和细胞转化相关的自分泌/旁分泌信号传导中的调节作用提供了新的见解。我们证明增殖的角质形成细胞上皮细胞簇显示出振荡的细胞外信号调节激酶 (ERK) 活性波，这可以通过 TACE 敲除消除，这表明这些振荡 ERK 活性波依赖于 TACE 产生的自分泌/旁分泌信号。这些结果为粘附连接在启动和维持与伤口愈合和细胞转化相关的自分泌/旁分泌信号传导中的调节作用提供了新的见解。