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

• Published in: Molecular biology of the cell Vol. 32; no. 4; pp. 348 - 361
• Main Authors: Bunker, Eric N, Wheeler, Graycen E, Chapnick, Douglas A, Liu, Xuedong
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 15.02.2021
• Subjects: ADAM17 Protein - metabolism; ADAM17 Protein - physiology; Adherens Junctions - metabolism; Adherens Junctions - physiology; alpha Catenin - metabolism; alpha Catenin - physiology; Cell Line, Tumor; Cell Movement - physiology; Cell Proliferation; Epidermal Growth Factor - metabolism; Epithelial Cells - metabolism; ErbB Receptors - metabolism; HaCaT Cells; Humans; Metalloproteases - metabolism; Paracrine Communication - physiology; Phosphorylation; Signal Transduction; Transforming Growth Factor alpha - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E19-08-0474

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 (tumor necrosis factor alpha converting enzyme) 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 transforming growth factor alpha 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.