A Spatial Model for Integrin Clustering as a Result of Feedback between Integrin Activation and Integrin Binding

Abstract

Integrins are transmembrane adhesion receptors that bind extracellular matrix (ECM) proteins and signal bidirectionally to regulate cell adhesion and migration. In many cell types, integrins cluster at cell-ECM contacts to create the foundation for adhesion complexes that transfer force between the cell and the ECM. Even though the temporal and spatial regulation of these integrin clusters is essential for cell migration, how cells regulate their formation is currently unknown. It has been shown that integrin cluster formation is independent of actin stress fiber formation, but requires active (high-affinity) integrins, phosphoinositol-4,5-bisphosphate (PIP2), talin, and immobile ECM ligand. Based on these observations, we propose a minimal model for initial formation of integrin clusters, facilitated by localized activation and binding of integrins to ECM ligands as a result of biochemical feedback between integrin binding and integrin activation. By employing a diffusion-reaction framework for modeling these reactions, we show how spatial organization of bound integrins into clusters may be achieved by a local source of active integrins, namely protein complexes formed on the cytoplasmic tails of bound integrins. Further, we show how such a mechanism can turn small local increases in the concentration of active talin or active integrin into integrin clusters via positive feedback. Our results suggest that the formation of integrin clusters by the proposed mechanism depends on the relationships between production and diffusion of integrin-activating species, and that changes to the relative rates of these processes may affect the resulting properties of integrin clusters.

IPP Complex Reinforces Adhesion by Relaying Tension-Dependent Signals to Inhibit Integrin Turnover

“…Single-particle tracking studies using the mys b58 (V409D) mutation in S2 cells further support our findings (Mainali and Smith, 2013). In accordance with recent studies on mammalian ILK (Huet-Calderwood et al, 2014;Ye et al, 2013), we cannot exclude the possibility that the reduced integrin immobile fraction at the PM compromises the sustainability of integrin clustering (Welf et al, 2012).…”

Nestin regulates prostate cancer cell invasion by influencing FAK and integrin localisation and functions

“…Nestin also regulated the formation of a5b1 clusters, in a FAKrelated fashion, as FAK activity regulated cluster volume in control cells, but had no effect on cluster size or number in nestindownregulated cells. A recent paper describing a spatial model of integrin clustering (Welf et al, 2012) has shown that a small pool of active integrin is required to initiate integrin clustering, which triggers a positive-feedback loop to increase integrin binding and activation. In this context, it is plausible that the increase in integrin activity as a result of nestin downregulation could trigger Quantification of the amount of degraded matrix compared to the area covered by the cells, n53.…”

Activation of Rac by Asef2 promotes myosin II-dependent contractility to inhibit cell migration on type I collagen

“…Because binding of active (high-affinity state) integrins to the ECM initiates the assembly of adhesions (Hynes, 1992;Welf et al, 2012), Asef2 could affect adhesion turnover by altering the amount of active integrins at the cell membrane. To examine cell surface levels of active b1 integrin, a major integrin that binds to type I collagen, GFP and GFP-Asef2 cells were incubated with HUTS-4 antibody and subjected to flow cytometry.…”