Suppression of alpha-catenin and adherens junctions enhances epithelial cell proliferation and motility via TACE-mediated TGF-alpha autocrine/paracrine signaling


Sustained cell migration is essential for wound healing and cancer metastasis. The epidermal growth factor receptor (EGFR) signaling cascade is known to fuel 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, also called ADAM17, is responsible for producing active ligands in the EGFR family 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 (AJ), 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 sheets and 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.

Molecular Biology of the Cell