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

Christine Jean,Addolorata-Maria-Luce Coluccia,Amandine Blanc,Talal Al Saati,Guy Laurent,Eric Delabesse,LoïC Ysebaert,HéLèNe Hernandez-Pigeon,Marie-José Haure,NaïS Prade-Houdellier,Marie Charveron

doi:10.1158/0008-5472.can-08-1909

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 beta-catenin tyrosine phosphorylation at the Y654 residue responsible for the dissociation of E-cadherin/alpha-catenin/beta-catenin complexes. Moreover, UVA induces an EGFR-dependent, but Wnt-independent, beta-catenin relocalization from the membrane to the nucleus followed by its association with T-cell factor 4 (TCF4). This newly formed beta-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 beta-catenin/E-cadherin/alpha-catenin dissociation and increased cell migration through extracellular matrix component degradation due to beta-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.

Highlights

UVA constitutes 95% of natural sunlight–associated UV irradiation and plays an important role in photocarcinogenesis [1]
In HaCaT cells, UVA irradiation resulted in a rapid increase in Y654 phosphorylation level of h-catenin as revealed by Western blotting, but we were unable to detect any change in phosphorylation at Y142 and Y86 (Fig. 1A)
UVA decreased the interaction between HaCaT and normal human epithelial keratinocyte (NHEK) but not between Y654F HaCaT variants and NHEK (Fig. 4C). These results suggest that UVA irradiation alters cell-to-cell adhesion in keratinocytes and that this event is dependent on Y654 h-catenin phosphorylation

Summary

Introduction

UVA constitutes 95% of natural sunlight–associated UV irradiation and plays an important role in photocarcinogenesis [1]. The UVA mutagenic effect is thought to be due to DNA damage as a result of the generation of reactive oxygen species [2]. It is accepted that activation of intracellular pathways could play an important role. It has been described that UVA irradiation results in the activation of the phosphatidylinositol 3-kinase, Akt, signal transducer and activator of transcription 3, as well as the mitogen-activated protein kinase modules. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-08-1909 signaling pathways converge to negative regulation of apoptosis [3] or cause the release of tumor-promoting molecules such as cyclooxygenase-2 and matrix metalloproteinases I2009 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-1909 signaling pathways converge to negative regulation of apoptosis [3] or cause the release of tumor-promoting molecules such as cyclooxygenase-2 and matrix metalloproteinases (MMP; ref. 1)

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Conclusion