Integrins and the actin cytoskeleton
Introduction
Integrins are the main cell surface receptors for proteins within the extracellular matrix (ECM); they enable cells to migrate over ECM substrates, form strong adhesive junctions with the ECM, and respond to ECM contact by differentiating and/or proliferating (for recent reviews of integrin functions see [1, 2, 3]). It is well established that integrins require a connection with the cytoskeleton to perform their roles; in most cases this connection is with the actin cytoskeleton, with one main exception being the specialized integrin that connects with intermediate filaments to form hemidesmosomes (α6β4). While it has been possible to formulate models of how the cytoplasmic domain of the β4 subunit is connected to intermediate filaments using a small repertoire of intracellular adaptor proteins (see [4] for review), the connection between integrins and the actin cytoskeleton has proven to be unexpectedly complex. An initial compilation of proteins thought to be involved included >50 proteins [5] and new components continue to be added at a steady rate [6]. While some of this complexity undoubtedly reflects cell-type-specific functions of integrins, a large number of proteins are found to be associated with sites of integrin adhesion in a wide variety of contexts, and an explanation for why there are so many has so far remained elusive.
Integrins are unusual amongst membrane receptors in that they are clearly bidirectional (see Figure 1) [2, 7]. Not only do they behave like a classic receptor, by binding extracellular ligand and in response causing changes to the interior of the cell, but, conversely, the inside of the cell controls integrin function: the cell concentrates integrins in specific regions of the plasma membrane, is able to convert the integrin into an active state, and by applying mechanical force to the integrin adhesive site increases the size of the adhesive contact. In addition, the active integrins participate in the assembly of their ECM ligands outside the cell.
Our current working model for integrin adhesion is as follows. Prior to contact with the ECM, integrin heterodimers, composed of an α and a β subunit, are mostly in an inactive conformation, with their extracellular domain in a bent conformation and the two very short cytoplasmic domains bound to each other. Activation and ligand binding lead to an extended extracellular conformation and separation of the cytoplasmic domains, exposing the β subunit cytoplasmic domain and allowing it to initiate interactions with the actin cytoskeleton. There is no evidence to suggest that integrins bind actin directly; instead, they recruit and anchor a complex of proteins that connects to actin. At least three kinds of interactions with the actin cytoskeleton can be postulated: first, binding or capture of pre-existing actin filaments, possibly increasing their stability in the process; second, recruitment of proteins that nucleate new actin filaments; and third, somewhat counterintuitively, inhibition of actin-dependent processes. Like any pathway affecting the actin cytoskeleton, integrins intersect with the members of the Rho family of small GTPases; we will not discuss this aspect as it has already been well reviewed [8]. Finally, although integrin binding to the ECM may be sufficient to initiate the process of forming a contact with actin, there is good evidence that cytoskeleton contractility amplifies integrin adhesion via a positive-feedback loop. We are unable to cover this topic comprehensively in this short review; instead, we will discuss selected examples of recent work on the complex of proteins that mediate the interaction with the cytoskeleton and highlight recent insights into the nature of the interaction; the reader is also referred to a recent review [9].
Section snippets
Diversity of integrin junctions and their associated proteins
As mentioned above, the number of proteins that associate with sites of integrin adhesion is very large [5, 6]. Some diversity in the association of these proteins with different kinds of integrin adhesive structures has been documented in mammalian cells in culture. Integrins are first associated with small dot-like focal complexes that form at the edge of lamellipodia, and mature into elongated focal contacts at the periphery of the cell that are associated with stress fibers (see [10] for
Which proteins are essential for the link?
Genetic approaches provide a useful way of testing which of the intracellular integrin-associated proteins are essential for integrin function. Many have been knocked out in mouse, and fly and worm also provide good systems with the advantage of having less gene duplication and therefore less redundancy by closely related proteins. From the analysis so far, just a few proteins come through as undoubtedly essential: talin, integrin-linked-kinase (ILK) and its interacting proteins PINCH,
Connecting integrin-associated proteins to the actin cytoskeleton
Integrins are likely to make diverse connections with the actin cytoskeleton in different types of cells and different regions of a cell, so we expect that a number of different mechansisms will need to be elucidated. A number of integrin-associated proteins, including talin, parvin, filamin, α-actinin, and tensin, have actin-binding domains. However, it is not yet clear whether the primary function of these domains at the integrin junction is to bind to actin or to other proteins. As an
Role of force application in the assembly and dynamics of integrin adhesions
Evidence that force influences integrin-mediated adhesion comes from two types of observations (see also [39] for additional evidence). First, the type of adhesion formed and whether a transition occurs between types of adhesive structure is affected by force application or modification of the acto-myosin network of the cell. For example, focal complexes become focal contacts upon force application and mechanical force stimulates focal contact growth [40]. Moreover, in contrast to focal
Conclusions
The assembly of the cytoskeleton in response to integrin activation is a critical step in the process of adhesion. The intracellular proteins that are recruited by integrins have both actin binding activity and actin nucleating activity, but the way in which the large number of proteins recruited by integrins work together has yet to be revealed. Although many studies indicate that the composition of the link differs with varying physiological and mechanical conditions, the biological
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
We thank Sven Huelsmann and Katja Röper for helpful suggestions on the manuscript. We are supported by an EMBO fellowship (ID) and grants from the Wellcome Trust (69943) and BBSRC (D013011).
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