Abstract
Nascent adhesions (NAs) are a general precursor to the formation of focal adhesions (FAs) that provide a fundamental mechanism for cell adhesion that is, in turn, involved in cell proliferation, migration, and mechanotransduction. Nascent adhesions form when cells come into contact with substrates at all rigidities and generally involve the clustering of ligated integrins that may recruit un-ligated integrins. Nascent adhesions tend to take on characteristic sizes in the range of O(100nm–150nm) in diameter and tend to contain integrin numbers of O(∼20–60). The flexible, adaptable model we present provides and clear explanation of how these conserved cluster features come about. Our model is based on the interaction among ligated and un-ligated integrins that arise due to deformations that are induced in the cell membrane-cell glycocalyx and substrate system due to integrin activation and ligation. This model produces a clearly based interaction potential, and from it an explicit interaction force among integrins, that our stochastic diffusion-interaction simulations then show will produce nascent clusters with experimentally observed characteristics. Our simulations reveal effects of various key parameters related to integrin activation and ligation as well as some unexpected and previously unappreciated effects of parameters including integrin mobility and substrate rigidity. Moreover, the model’s structure is such that refinements are readily incorporated and specific suggestions are made as to what is required for further progress in understanding nascent clustering and the development of mature focal adhesions in a truly predictive manner.
Highlights
Cells do not live alone, but instead vigorously interact with the environment which contains other cells as well as extracellular matrices (ECMs), the properties of which they sense by adhering and react to
With respect to integrin activation, we note that Bachir et al [66] have reported that whereas knidlin is recruited into nascent adhesions during their formation, talin follows in sequence just after, at least for α5β3 integrins in migrating CHO cells; the generality of this finding to other systems was unspecified
In a most interesting study of integrin mobility within focal adhesions (FAs), Rossier et al [93] reported variable diffusion coefficients for αv β3 and α5β1 integrins that depended on the state of confinement within the adhesion; integrins were defined as being “free” when they were outside FAs and unligated and
Summary
Cells do not live alone (non solus), but instead vigorously interact with the environment which contains other cells as well as extracellular matrices (ECMs), the properties of which they sense by adhering and react to. Wound healing [19,20], inter alia Cells perform these functions and are so regulated via the formation of focal adhesions (FA’s) [21,22,23,24] that anchor the cell either transiently (i.e., dynamically) or permanently [25,26] to, e.g., the ECM (aka the substrate); the precursor to FA’s are nascent adhesion clusters as sketched, that we analyze . In our case we consider the adhesome to utilize the plague proteins talin and vinculin; our force train consists of actin(myosin)-vinculin-talin-integrin-ligand (ECM/substrate) [29,30,31] Nascent cluster (a) sition to m tran atur ehdeasliaocnof talin actin engaged FA (b) retrograde flow talin
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