Bidirectional signaling between the cytoskeleton and integrins

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Abstract

Clustering of integrins into focal adhesions and focal complexes is regulated by the actin cytoskeleton. In turn, actin dynamics are governed by Rho family GTPases. Integrin-mediated adhesion activates these GTPases, triggering assembly of filopodia, lamellipodia and stress fibers. In the past few years, signaling pathways have begun to be identified that promote focal adhesion disassembly and integrin dispersal. Many of these pathways result in decreased myosin-mediated cell contractility.

Introduction

Adhesive interactions critically influence the organization of the cytoskeleton. Reciprocally, the cytoskeleton affects the organization and function of adhesive molecules such as integrins and cadherins. In this review, we focus on the relationship between the actin cytoskeleton and the organization of integrins. Integrins are receptors that form transmembrane links between the extracellular matrix (ECM) and the actin cytoskeleton. During the past decade, their importance as signal transducers from the ECM has been increasingly recognized. Integrins are frequently clustered into specialized adhesive structures, focal adhesions (FAs) and focal complexes, in which numerous signaling components are concentrated 1, 2, 3. Many aspects of integrin biology have recently been reviewed 4•, 5•, 6•. Here we concentrate on integrin clustering and dispersal as regulated by the cytoskeleton which, in turn, is regulated by the Rho family of G proteins. We discuss signaling pathways that feedback from integrins to modulate the cytoskeleton, and consider how the state of the actin cytoskeleton controls the organization of ECM.

Section snippets

Cytoskeletal clustering of integrins

Integrins that are not bound to ECM ligands are generally distributed diffusely over the cell surface and appear not to be linked to the actin cytoskeleton. Association with the actin cytoskeleton is induced upon binding of ECM ligands 7, 8, 9. Depending on the state of cytoskeletal organization, this can lead to clustering of integrins into FAs or focal complexes. FAs are large integrin aggregates found at the ends of prominent bundles of actin filaments (stress fibers). Both stress fibers and

Integrin dispersal from FAs

Migration involves cyclical changes in local adhesive strength: decreases in adhesion can result from changes in the affinity of integrins for their ECM ligands, from disassembly of the cytoskeletal protein complex that interacts with integrin cytoplasmic domains, or from the dispersal of clustered integrins. Several factors that antagonize integrin clustering in FAs and that promote the disassembly of FAs have been identified. It is important to note that there are significant cell type

Regulation of integrin distribution by microtubules and intermediate filaments

Most of the work studying the relationship between the Rho family of GTPases and the cytoskeleton has been aimed at understanding their control of actin organization; however, Rho has significant effects on the two other major filamentous systems, microtubules and intermediate filaments. Microtubules have long been known to affect the adhesion of fibroblasts as well as various aspects of fibroblast migration. Inhibitors of microtubule polymerization decrease the rate of fibroblast spreading

Integrin feedback to cytoskeletal reorganization

In studying the activation of Rho family GTPases most attention has been focused on the actions of soluble factors such as bioactive lipids, peptides and growth factors. Several studies, however, have begun to reveal that integrin-mediated adhesion can itself activate these GTPases (Figure 3). Long before Rho GTPases were identified, it was known that adhesion to ECMs induced extensive filopodia and membrane ruffling. These cytoskeletal/membrane protrusions are now recognized as the hallmarks

Cytoskeletal regulation of matrix assembly

There is a close relationship between the organization of the ECM and the actin cytoskeleton. This has been most studied with fibronectin (FN). Not only is there a parallel distribution of FN fibrils on the cell surface with submembranous bundles of actin filaments and FA proteins but disruption of microfilaments with agents such as cytochalasin leads to a parallel disruption of the fibrillar FN matrix on the outside [148]. Clues as to why ECM organization depends on cytoskeletal integrity have

Conclusions

Much has been learned about how RhoA stimulates integrin clustering into FAs and the role of myosin-mediated contractility in this process. In contrast, much less is known about the clustering of integrins into focal complexes in response to Rac and Cdc42. The crosstalk between Rho family GTPases appears more and more complicated. In some situations, Cdc42 and Rac activate RhoA, but the actions of RhoA are often antagonistic to Rac and Cdc42. Downstream effectors for Rac and Cdc42 have been

Acknowledgements

We are most grateful to our colleagues Bertolt Kreft, Betty Liu, Leslie Petch, Patricia Saling, Sarita Sastry and Becky Worthylake for their comments and advice on this manuscript. We gratefully acknowledge the support of a National Health and Medical Research Council (Australia) CJ Martin Postdoctoral Fellowship (SM Schoenwaelder) and National Institutes of Health grants GM29860 and HL45100 (K Burridge).

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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