CD9 Controls Integrin α5β1-Mediated Cell Adhesion by Modulating Its Association With the Metalloproteinase ADAM17

Yesenia Machado-Pineda,Beatriz Cardeñes,Joachim Grötzinger,Henar Suarez,Soraya López-Martín,María Yáñez-Mó,Carlos Cabañas,Víctor Toribio,Inken Lorenzen,Raquel Reyes,Paula Sánchez-Organero

doi:10.3389/fimmu.2018.02474

Abstract

Integrin α5β1 is a crucial adhesion molecule that mediates the adherence of many cell types to the extracellular matrix through recognition of its classic ligand fibronectin as well as to other cells through binding to an alternative counter-receptor, the metalloproteinase ADAM17/TACE. Interactions between integrin α5β1 and ADAM17 may take place both in trans (between molecules expressed on different cells) or in cis (between molecules expressed on the same cell) configurations. It has been recently reported that the cis association between α5β1 and ADAM17 keeps both molecules inactive, whereas their dissociation results in activation of their adhesive and metalloproteinase activities. Here we show that the tetraspanin CD9 negatively regulates integrin α5β1-mediated cell adhesion by enhancing the cis interaction of this integrin with ADAM17 on the cell surface. Additionally we show that, similarly to CD9, the monoclonal antibody 2A10 directed to the disintegrin domain of ADAM17 specifically inhibits integrin α5β1-mediated cell adhesion to its ligands fibronectin and ADAM17.

Highlights

Integrins constitute an important family of heterodimeric cellular receptors which, upon recognition and binding to specific ligands, mediate the adhesion of cells to components of the extracellular matrix as well as cell-cell adhesion phenomena with crucial relevance in a variety of physiological and pathophysiological processes [reviewed in [1,2,3]]
Recombinant ADAM17 has been reported to support integrin α5β1-dependent fibroblast and kidney mesangial cell adhesion, and such adhesion was demonstrated to occur through integrin binding to the disintegrin domain of ADAM17 [5,6,7]
We decided to build on these findings by assessing whether the adhesion of several other human cell lines derived either from solid tumors (“cancer cell lines”) or hematological malignancies (“leukocytic cell lines”) to immobilized recombinant ADAM17Fc was mediated by integrin α5β1

Summary

Introduction

Integrins constitute an important family of heterodimeric (αβ) cellular receptors which, upon recognition and binding to specific ligands, mediate the adhesion of cells to components of the extracellular matrix (such as fibronectin, laminin, collagens) as well as cell-cell adhesion phenomena with crucial relevance in a variety of physiological and pathophysiological processes [reviewed in [1,2,3]]. ADAM10 and ADAM17 are considered atypical members of the ADAM family since the extracellular cysteine-rich and EGFlike domains found in the rest of ADAMs are replaced in these two enzymes by a unique membrane proximal domain (MPD), which is involved in substrate recognition and binding as well as in regulation of their shedding activity [reviewed in [12, 13]]

Methods

Results

Conclusion