Spatial activation of ezrin by epidermal growth factor receptor and focal adhesion kinase co-ordinates epithelial cell migration.

Grace K Chan,Maddy Parsons,John A Mcgrath

doi:10.1098/rsob.210166

Abstract

Epidermal growth factor receptor (EGFR) plays a critical role in the promotion of epithelial cell proliferation and migration. Previous studies have suggested a cooperative role between EGFR and integrin signalling pathways that enable efficient adhesion and migration but the mechanisms controlling this remain poorly defined. Here, we show that EGFR forms a complex with focal adhesion kinase in epithelial cells. Surprisingly, this complex enhances local Src activity at focal adhesions to promote phosphorylation of the cytoskeletal adaptor protein ezrin at Y478, leading to actomyosin contractility, suppression of focal adhesion dynamics and slower migration. We further demonstrate this regulation of Src is due to the suppression of PTP1B activity. Our data provide new insight into EGF-independent cooperation between EGFR and integrins and suggest transient interactions between these kinases at the leading edge of cells act to spatially control signalling to permit efficient motility.

Highlights

Epidermal growth factor receptor (EGFR) is expressed throughout the epidermis [1,2,3] and is required for key keratinocyte functions, such as proliferation and differentiation
To define roles for EGFR kinase activity in this process, cells were treated with the EGFR kinase inhibitor AG1478, resulting in a significant reduction in spread cell area and in focal adhesion kinase (FAK)-containing focal adhesions at the cell periphery
To explore whether EGFR activity was triggered by adhesion in the absence of EGF, cells were plated on laminin for up to 60 min in serum-free media, and the activity of both EGFR and FAK was assessed by western blotting

Summary

Introduction

Epidermal growth factor receptor (EGFR) is expressed throughout the epidermis [1,2,3] and is required for key keratinocyte functions, such as proliferation and differentiation. EGFR plays a fundamental role during wound healing, through the upregulation of keratinocyte proliferation and migration and EGFR expression is increased following injury [10]. This in turn promotes the re-epithelization of the wound, which is disrupted when EGFR expression is lost [11]. Previous evidence has demonstrated that cooperative signalling between integrins and EGFR can act to enhance cell proliferation, migration and adhesion [12,13,14,15,16,17]. Of the potential pathways proposed to act at the nexus of the EGFR-integrin cooperative pathway, focal adhesion kinase (FAK) has been the most widely studied. The mechanisms that regulate EGFR/FAKdependent adhesion and migration remain poorly defined

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Results

Conclusion