Integrin Clustering Is Driven by Mechanical Resistance from the Glycocalyx and the Substrate

Matthew J Paszek,Daniel A Hammer,Valerie M Weaver,David Boettiger,Douglas Lauffenberger

doi:10.1371/journal.pcbi.1000604

Abstract

Integrins have emerged as key sensory molecules that translate chemical and physical cues from the extracellular matrix (ECM) into biochemical signals that regulate cell behavior. Integrins function by clustering into adhesion plaques, but the molecular mechanisms that drive integrin clustering in response to interaction with the ECM remain unclear. To explore how deformations in the cell-ECM interface influence integrin clustering, we developed a spatial-temporal simulation that integrates the micro-mechanics of the cell, glycocalyx, and ECM with a simple chemical model of integrin activation and ligand interaction. Due to mechanical coupling, we find that integrin-ligand interactions are highly cooperative, and this cooperativity is sufficient to drive integrin clustering even in the absence of cytoskeletal crosslinking or homotypic integrin-integrin interactions. The glycocalyx largely mediates this cooperativity and hence may be a key regulator of integrin function. Remarkably, integrin clustering in the model is naturally responsive to the chemical and physical properties of the ECM, including ligand density, matrix rigidity, and the chemical affinity of ligand for receptor. Consistent with experimental observations, we find that integrin clustering is robust on rigid substrates with high ligand density, but is impaired on substrates that are highly compliant or have low ligand density. We thus demonstrate how integrins themselves could function as sensory molecules that begin sensing matrix properties even before large multi-molecular adhesion complexes are assembled.

Highlights

Cell adhesion to the extracellular matrix (ECM) is mediated by a family of heterodimeric surface receptors called integrins [1]
Using a newly developed model of the cell-matrix interface, in this work we detail a simple yet efficient mechanism by which integrins could ‘‘sense’’ important matrix properties, including chemical composition and mechanical stiffness, and cluster appropriately. This mechanism relies on mechanical resistance to integrinmatrix interaction provided by the glycocalyx, the slimy sugar and protein coating on the cell, as well as the stiffness of the matrix and the cell itself
The mechanical properties of the cell and ECM are altered in many prevalent diseases, such as cancer, and our work suggests how these mechanical perturbations might adversely influence integrin function

Summary

Introduction

Cell adhesion to the ECM is mediated by a family of heterodimeric surface receptors called integrins [1] In addition to their function as mechanical anchors, integrins participate in signal transduction and thereby regulate important cell behaviors, such as differentiation, motility, survival, and morphogenesis [2,3]. Integrins assemble laterally in the membrane and recruit structural and signaling proteins to form a clustered adhesion complex In addition to their signaling function, assembled adhesion complexes physically link the cell cytoskeleton to the ECM and transmit traction forces necessary for mechanical cell processes, such as motility and cell shape changes [4,5,6,7]. Since integrin clustering is functionally linked to signal transduction and cell behavior, matrix-regulated adhesion assembly serves as a key sensory process that enables a cell to interrogate and respond to its extracellular environment

Results

Discussion

Conclusion