Epidermal Growth Factor Receptor/-Catenin/T-Cell Factor 4/Matrix Metalloproteinase 1: A New Pathway for Regulating Keratinocyte Invasiveness after UVA Irradiation

¹Institut National de la Santé et de la Recherche Médicale, U563; ²Université Paul-Sabatier; ³CHU Purpan, Service d'Hématologie; ⁴Institut de Recherche Pierre Fabre, Hôtel-Dieu; ⁵Plateau Technique d'Histopathologie Expérimentale, IFR30, CHU Purpan, Toulouse, France and ⁶National Nanotechnology Laboratories, Consiglio Nazionale delle Ricerche-Istituto Nazionale per la Fisica della Materia, University of Salento, Lecce, Italy

^* To whom correspondence should be addressed. E-mail: christine.jean{at}inserm.fr.

	Abstract

Previous studies have established that UV irradiation results in epidermal growth factor receptor (EGFR) activation in keratinocytes. However, the signaling pathways and cellular effects related to this process remain incompletely elucidated. Herein, we describe for the first time that UVA-mediated EGFR activation results in -catenin tyrosine phosphorylation at the Y654 residue responsible for the dissociation of E-cadherin/-catenin/-catenin complexes. Moreover, UVA induces an EGFR-dependent, but Wnt-independent, -catenin relocalization from the membrane to the nucleus followed by its association with T-cell factor 4 (TCF4). This newly formed -catenin/TCF4 complex binds to a specific site on matrix metalloproteinase 1 (MMP1) promoter and governs MMP1 gene and protein expression, as well as cell migration in collagen and gelatin. Altogether, these results suggest that UVA stimulates keratinocyte invasiveness through two coordinated EGFR-dependent processes: loss of cell-to-cell contact due to -catenin/E-cadherin/-catenin dissociation and increased cell migration through extracellular matrix component degradation due to -catenin/TCF4–dependent MMP1 regulation. These events may represent an important step in epidermis repair following UVA injury and their abnormal regulation could contribute to photoaging and photocarcinogenesis. [Cancer Res 2009;69(8):OF1–9]

Key Words: UVA, keratinocytes, -catenin, MMP, invasiveness