MRC Laboratory for Molecular Cell Biology and Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK
(e-mail: dmcbjca{at}ucl.ac.uk)
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SUMMARY |
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Key words: Cell adhesion, Extracellular matrix, Cytoskeleton, Signaling, Cell structure
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Introduction |
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The first matrix adhesion receptors, integrins, were cloned in 1986. Subsequent investigations at the molecular level have revealed a multiplicity of roles for matrix-integrin interactions in the regulation of cell behavior. Cell-matrix interactions maintain and regulate cell adhesion and motility, initiate ECM assembly at cell surfaces, act as sites for transmission of mechanical force and elastic recoil between cells and ECM, localise and activate signaling molecules that regulate cell proliferation, behavior and survival and regulate gene expression (reviewed by Schwartz et al., 1995). Specificity of these activities is apparent with regard to individual matrix components and differentiated cell lineages (De Fougerolles et al., 2000
; Danen et al., 2000
). It is now appreciated that transmembrane proteoglycans and integrin-associated proteins also participate in these roles (Woods and Couchman, 2000
; Hemler, 1998
). However, there remains a gap in integrating this molecular information to the evident diversity of matrix-contact structures and their 3D forms in intact cells. What are the molecular requirements for formation of different types of matrix contacts? What factors determine the subcellular distribution and dynamics of individual matrix contacts? How does matrix specificity operate at the level of assembly of contact structures? How do single cells coordinate or polarise the formation of different types of matrix contacts? How is the assembly of different forms of contacts important for transduction of information from the ECM?
There are many reasons why answers to such questions are of fundamental importance. In addition to the inherent fascination of biological patterning, routes to manipulate cell phenotype or motile behavior, without gross perturbations of cell-matrix adhesion that would compromise cell viability, are desirable goals for biological therapies of acute and chronic human diseases. An understanding of how matrix contacts are assembled and coordinated by cells could open up new and elegant strategies to manipulate cell locomotion, matrix assembly, or cell interactions in tissue engineering applications. In this review, I briefly describe the various types of matrix contacts that have been identified by morphological or biochemical criteria and discuss recent advances in understanding the molecular processes by which matrix contacts are coordinated and regulated by cells.
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Types of cell-matrix contacts |
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Protrusive contacts are those in which dynamic extensions of the plasma membrane make contact with the matrix. These regions can be very localised and of highly defined shape, as in filopodia, spikes or podosomes. Alternatively, they can occupy broad, irregular regions of the plasma membrane as in the case of lamellipodia and associated ruffles, invadopodia or pseudopodia. Protrusive contacts are considered to be needed as membrane extensions by which cells make transient adhesions, sample the surrounding environment beyond the cell body and maintain a polarised leading edge during cell locomotion.
Contractile contacts, exemplified by focal adhesions and the various types of matrix assembly sites, make physically closer and/or more prolonged matrix attachments than protrusive contacts. By engaging actomyosin-based cellular contractility, these contacts transmit the isometric tension between cells that is needed for matrix assembly, the maintenance of stable cell-matrix adhesion and the cyclical traction and release of the cell body during cell locomotion (Lauffenberger and Horwitz, 1996; Zamir et al., 2000
; Riveline et al., 2001
).
Hemidesmosomes (Borradori and Sonnenberg et al., 1999) and retraction fibers (Chen, 1981
; Lin et al., 1996
) form mechanically supportive contacts that maintain matrix adhesion and stabilise the plasma membrane under conditions of varying mechanical force or stabilise the rear end of cells against tail release during cell crawling.
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Cellular coordination of matrix contacts |
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Notwithstanding these indications of rich diversity, understanding of the formation and functions of protrusive contacts has remained patchy. Reliance on morphological characterisations and static images of these dynamic and non-stereotypical structures, plus a lack of robust experimental systems in which to study particular structures under well controlled conditions, has resulted in a multiplicity of interpretations and parallel nomenclatures. An increasing knowledge of biochemical markers that are specific to particular matrix contacts, in combination with advances in imaging technologies, is now beginning to dispel these problems, to foster an upsurge in interest in all forms of matrix contacts and to provoke new questions about the mechanisms by which contact assembly and turnover are attuned to cell behavior.
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Mechanisms of contact regulation |
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Initiation and spatial segregation of contacts
To assemble a functional matrix contact, the association of all the necessary molecular components and an appropriate spatial placing of the contact is needed (Fig. 3). These processes are best understood for integrin-mediated adhesions. To bind to ligand, integrin /ß heterodimers must be in an active conformation (Fig. 3b). Ligand binding in itself alters integrin conformation and affinity and, in the case of multivalent ligands, integrin clustering. The conformational change in the extracellular domain of integrin induces activation of the
/ß cytoplasmic domains, which then coordinate de novo assembly of the linker complex in a process termed outside-in signaling (reviewed by Calderwood et al., 2000
). Many integrins are constitutively active, whereas others, principally the ß2 integrins of leukocytes and
IIbß3 of platelets, require cellular activation signals. In both cases, ligand-binding capacity is further modulated or activated by cell-type specific, inside-out signals, which act either on the linker complex or the integrin subunit cytoplasmic domains to bring about a conformational shift in the extracellular ligand-binding site. These processes are termed integrin inside-out signaling (reviewed by Woodside et al., 2001
). In vitro, activation of extracellular ligand binding can be achieved by a spatial separation of the intracellular, juxtamembrane regions of the heterodimer subunits (Takagi et al., 2001
).
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Whether spatially localised activation of adhesion receptors and downstream signals occur during the initiation of other types of matrix contacts is a question of great interest. The assembly of a cell protrusion has special additional requirements for localised polymerisation of F-actin, concentration of actin crosslinking proteins and expansion of the plasma membrane to mediate the outward extension of the contact. Delivery of mRNAs for actin and actin crosslinking proteins to lamellipodial margins and spikes may also facilitate extension of the membrane and cytoskeleton by translation of essential molecules at their sites of function (reviewed by Bassell and Singer, 1997). In general, actin nucleation occurs at the edges of lamellipodia and the tips of filopodia and is coordinated by the activities of the Arp2/3 complex to produce Y-branched actin filaments (reviewed by Borisy and Svitkina, 2000
). Lamellipodia are also sites of enhanced membrane trafficking, and the localised delivery of vesicles may assist rapid increases in local membrane surface area and the maintenance of polarity in protrusive contacts (reviewed by Mellman, 2000
). Localisation of vesicle docking also depends on cytoskeletal interactions; for example, the GTPase dynamin, which is active in endocytic vesicle trafficking, also localises at membrane ruffles where its interaction with the actin-binding protein cortactin has consequences for cell shape (McNiven et al., 2000
). Other recent studies place dynamin within the podosomes of osteoclasts (Ochoa et al., 2000
).
Although transmembrane proteoglycans, exemplified by syndecan-4, have traditionally been considered as coreceptors with integrins in contractile contacts (reviewed by Woods and Couchman, 2000), there is growing evidence for early roles of glycosaminoglycan-based interactions and proteoglycans in the formation of initial protrusive contacts. Glycosaminoglycan-dependent attachment of cells has long been associated with the formation of microspikes and lamellipodia (Fig. 2K). The stable formation of fascin microspikes upon cell adhesion to thrombospondin-1 requires the transmembrane proteoglycan syndecan-1 and is dependent upon intracellular coupling by the syndecan-1 cytoplasmic domain (Adams et al., 2001
) (Fig. 2L). Layilin, a transmembrane protein that is concentrated in the ruffles of spreading or migrating cells, binds to hyaluronan, a glycosaminoglycan that contributes to the hydration and fluidity of pericellular matrix. Layilin binds to talin intracellularly and is proposed to mediate transient matrix adhesions in lamellipodia (Bono et al., 2001
). It would be interesting to know how the roles of proteoglycans in protrusive contacts relate to those of active, unoccupied integrins at lamellipodial margins.
Self-attenuating protein complexes
A second key aspect of regulation is that, once assembled, matrix contacts can be turned over to enable their repositioning or interconversion. This is important for maintaining adhesion and spreading during changes in cell shape, locomotion or physiological activity and for enabling cell rounding during mitosis (Fig. 2; Fig. 3). Information emerging from studies of podosomes and focal adhesions demonstrates that proteins within the linker complex ensure that contact growth is self limited. This is elegantly achieved by their participation in self-attenuating protein complexes. In osteoclasts, podosome formation depends on signaling from the vß3 integrin, with Src and RhoA as key mediators (Chellaiah et al., 2000
) (Fig. 3A). Thus Src-null mice develop osteopetrosis owing to poor osteoclast function (Soriano et al., 1991
). In culture, Src-null osteoclasts initially form podosomes, but these are replaced within hours by focal-adhesion-like structures. The cells migrate poorly and do not undergo proper formation of the sealing-ring structures that are needed for bone resorption (Sanjay et al., 2001
). The molecular mechanism that underlies these abnormalities in matrix contacts depends on Pyk2 (proline-rich tyrosine kinase 2), which is expressed at particularly high levels in osteoclasts and is activated proximally in
vß3-initiated signaling. In normal osteoclasts, this leads to formation of a protein complex that contains autophosphorylated Pyk2, c-Cbl and activated Src; Pyk2 and c-Cbl both bind to Src. c-Cbl binds through its PTB domain to the autophosphorylation site of Src (residue Y416), thus acting, in the complex, to inhibit Src kinase activity and
vß3-mediated cell attachment (Sanjay et al., 2001
). These findings place the Cbl-Src interaction as a feedback mechanism, which achieves the rapid turnover of podosomes by ensuring that Src kinase activity and thereby Src-dependent inside-out activation signals to the
vß3 integrin are time limited (Fig. 3A). Without this process, podosome turnover, and therefore osteoclast migration and bone resorption, are impaired (Sanjay et al., 2001
).
Within the linker complex of focal adhesions, paxillin has emerged as an important coordinator of multiple protein complexes that make regulatory contributions to the assembly and disassembly of focal adhesions and to cell motility (reviewed by Turner, 2000). Paxillin binds to multiple structural and signaling molecules through its N-terminal domain, which contains four LD motifs, and through the C-terminal region, which contains four LIM (Lin-11, Isl-1, and Mec-3) domains. One protein complex is initiated by the binding of FAK to the second LD motif and the subsequent phosphorylation of residues Y31 and Y118 of paxillin by FAK. These newly created SH2-binding sites bind to Crk proteins, which recruit the Src substrate p130cas after its phosphorylation by Src. P130cas is also the major substrate of PT-PEST (protein tyrosine phosphatase-PEST), which becomes recruited onto LIM domains 3 and 4. The presence of PTP-PEST within the linker complex may provide a mechanism for focal-adhesion disassembly by dephosphorylation of p130cas. Paxillin residues Y31 and Y118, and PTP-PEST are also involved in a second set of binding interactions that recruit Csk kinase into focal adhesions. Csk phosphorylates and downregulates Src kinase activity and thus may, in a manner anologous to the activity of c-Cbl in podosomes, initiate local attenuation of contact assembly processes (Fig. 3B).
A third protein complex, which is formed around the LD motif 4 of paxillin, has a separate role in localising and regulating the activities of PAK (p21-activated kinase). PAK is an important downstream effector of the small GTPases Cdc42 and Rac, which has roles in cytoskeletal organisation and cell migration (Kiosses et al., 1999). A novel protein, p95PKL (paxillin-kinase linker), acts as adaptor between LD motif 4 and the Cdc42/Rac guanine nucleotide exchange factor, PIX. PIX binds directly to PAK, and PAK brings Nck into the complex (Turner et al., 1999
). This complex supports PAK kinase activity, and experimental perturbations of the complex on LD motif 4 have inhibitory effects on lamellipodia formation and cell migration (Turner et al., 1999
). In particular, expression of an LD4-deleted form of paxillin in fibroblasts alters the parameters of spreading, such that cells have enlarged and persistent lamellipodia and retraction fibers as well as increased random migration on fibronectin (West et al., 2001
). These effects correlate with sustained Rac activation, are Rac-dependent and are phenotypically similar to the effects of a mutant form of p95PKL that does not bind to paxillin (West et al., 2001
). Assembly of the paxillin-PKL complex thus marks a contribution of paxillin to the assembly of protrusive contacts, perhaps by localising PAK activity, as well as to the turnover of focal adhesions (Fig. 3b).
Cellular integration of contact remodeling
The regulatory processes I have discussed so far act from within a matrix contact or localised membrane area. Mechanisms for the integration, balance and remodeling of matrix contacts are also needed at the whole cell level and, in this regard, molecular processes involving the small GTPase Rho, microtubules and regulated proteolysis are all emerging as significant.
The activities of Rho
Rho GTPase has a key role in stimulating focal adhesion assembly through the activation of cell contractility (reviewed by Ridley, 1997). Conversely, inhibition of Rho activity by C3 exotransferase or by overexpression of RhoGAP (GTPase activating protein) or by Rho GDI (GDP dissociation inhibitor) reduces cell spreading and focal contact organisation and promotes the formation of unusual arborised cell projections (Noren et al., 2000
; Anastasiadis et al., 2000
). However, initial cell spreading and formation of protrusive contacts on fibronectin depend on the activities of Cdc42 and Rac and not on Rho (Clark et al., 1998
; Price et al., 1998
). During initial spreading on fibronectin, cellular Rho activity is decreased (Ren et al., 1999
). The stable formation of cortical fascin spikes and lamellipodia by cells adherent on thrombospondin-1 also depends on Cd42 and Rac and is not inhibited by dominant-negative versions of Rho. Interestingly, Rac and Cdc42 activities are sustained over longer times in cells on a TSP-1 matrix than in matched cells on fibronectin (Adams and Schwartz, 2000
). Inclusion of tenascin-C in a mixed fibronectin-fibrinogen provisional matrix also results in decreased Rho activity (Wenk et al., 2000
). The existence of similar biochemical effects in different matrix contexts suggests that modulation of Rho activity could participate in the integration of protrusive and contractile matrix contacts. This is a nascent area of study, and it is evident that there are multiple molecular pathways by which Rho can be inhibited.
In suspended cells treated with the GRGDSP peptide, a monomeric ligand that activates integrins but does not induce integrin clustering, downregulation of cellular Rho activity depends on the phosphorylation and activation of p190RhoGAP by Src, leading to an increased rate of RhoGTP hydrolysis (Arthur et al., 2000). Analyses of adherent cells have highlighted novel activities of p120 catenin (p120ctn), a cadherin-binding armadillo repeat protein that is also a substrate of Src, in suppression of Rho. Overexpression of p120ctn in fibroblasts or epithelial cells leads to formation of filopodia, branched cellular processes, lamellipodia and a major reduction in focal adhesions. This activity is a cadherin-independent property of cytoplasmic p120ctn, which is suppressed when p120ctn associates at the membrane with E-cadherin (Anastasiadis et al., 2000
; Noren et al., 2000
; Grosheva et al., 2001
). Regions within the N-terminal domain, armadillo repeats 3-5 and the C-terminus of p120ctn are each important in the Rho inhibitory properties of p120ctn (Grosheva et al., 2001
), and several molecular interactions have been defined that contribute to Rho inhibition. One is a specific GDI activity of p120ctn for RhoGDP (Anastasiadis et al., 2000
; Noren et al., 2000
). A second process appears to depend on activation of Cdc42 and Rac by p120ctn, in that overexpression of p120ctn increases the active pools of both GTPases and the morphological effects of p120ctn are blocked by dominant-negative versions of Cdc42 and Rac (Noren et al., 2000
; Grosheva et al., 2001
). This mechanism appears to depend on the physical association and activity of the Rac/Cdc42 GEF (guanine nucleotide exchange factor), Vav2, with p120ctn (Noren et al., 2000
).
Microtubule targeting
Microtubule depolymerisation in adherent cells results in an increased size and number of focal adhesions, increased integrin signaling and decreased lamellipodial protrusion and cell migration (Bershadsky et al., 1996). These effects depend on Rho GTPase activity (Liu et al., 1998
). Time-lapse videomicroscopy of cells colabelled for tubulin and focal adhesion components has now revealed that focal complexes and focal adhesions are actively and transiently targeted by the distal (plus) ends of individual microtubules and that this process results in the stasis or disappearance of contacts (Kaverina et al., 1999
). In the absence of microtubules, cells develop large retraction structures; thus negative regulation by microtubules probably also contributes to focal-adhesion disassembly during retraction of the rear edge of locomoting cells (Ballestrem et al., 2000
).
The molecular basis for selection of particular focal adhesions by microtubules and the mechanism of contact dissolution both remain to be established. Proteins that specifically associate with the distal ends of microtubules could conceivably regulate microtubule dynamics to faciliate targeting of focal adhesions. The identification of paxillin as a novel tubulin-binding protein raises the possibility that paxillin could act as a focal adhesion recognition protein (Herreros et al., 2000). Tubulin dimers bind to Rac GTP and thus might disassemble the contacts by a direct Rac-dependent inhibition of Rho activity (Saunder et al., 1999
). High-resolution methods to localise active Rho are needed to examine this possibility.
The principle of negative regulation by microtubules does not apply to other types of matrix contacts. Lamellipodia characteristically contain few microtubules, and the growth or taxol-stabilisation of microtubules activates Rac and leads to lamellipodial protrusion (Waterman-Storer et al., 1999). However, microtubules themselves are not essential for protrusion of lamellipodia and ruffles (Ballestrem et al., 2000
). In complete contrast, the formation of podosomes in macrophages is microtubule dependent (Linder et al., 2000
). It would be interesting to know if this process also involves dynamic physical targeting of podosomes by microtubules. The relationship of microtubule targeting to specific matrix contexts has not been explored; for example, it is not known whether focal adhesions nucleated on different integrin heterodimers have equivalent sensitivities to microtubule targeting or whether proteoglycan-dependent contacts are also physically regulated by microtubules.
Regulated proteolysis
A third mode of contact turnover is provided by regulated proteolysis (Fig. 3D). Intracellular components of focal adhesions, which include the ß3 integrin subunit cytoplasmic domain and talin, are substrates of the calcium-dependent protease, calpain (Beckerle et al., 1987; Du et al., 1995
; Bialkowska et al., 2000
). Calpain-mediated proteolysis contributes to focal-adhesion turnover and is needed for the release and retraction of the tail end of migrating cells and for the complex regulation of
IIbß3 integrin activity in platelets (Huttenlochner et al., 1997
; Schoenwaelder et al., 2000
). Calpain also acts in the formation of filopodia and lamellipodia, presumably by facilitating rapid reprocessing of cytoskeletal structures, although the critical target substrates in these structures remain to be identified (Potter et al., 1998
). The possible role of proteolysis in regulation of other types of matrix contacts deserves attention.
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Future prospects |
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ACKNOWLEDGMENTS |
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