Integrin clustering is driven by mechanical resistance from the glycocalyx and the substrate.

TitleIntegrin clustering is driven by mechanical resistance from the glycocalyx and the substrate.
Publication TypeJournal Article
Year of Publication2009
AuthorsPaszek MJ, Boettiger D, Weaver VM, Hammer DA
JournalPLoS Comput Biol
Date Published2009 Dec
KeywordsAlgorithms, Computer Simulation, Extracellular Matrix, Glycocalyx, Integrins, Ligands, Protein Binding, Stress, Physiological, Substrate Specificity

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.

Alternate JournalPLoS Comput. Biol.
PubMed ID20011123
PubMed Central IDPMC2782178
Grant ListBC044791 / BC / NCI NIH HHS / United States
GM53788 / GM / NIGMS NIH HHS / United States
HL085303 / HL / NHLBI NIH HHS / United States
R01 CA138818 / CA / NCI NIH HHS / United States