Summary

Classical cadherin adhesion molecules are not only essential for the formation of cell-cell junctions but also act as adhesion-activated signaling receptors involved in a diverse range of physiological processes. Cadherins through their association with catenin proteins interact with the actin cytoskeleton and cadherin-mediated signaling pathways, acting in part through Rho GTPases, regulate cadherin anchoring to the actin cytoskeleton. The microtubule (MT) network recently emerged as having a role in cadherin-mediated cell-cell adhesion. Indeed, MT have been shown to serve as tracks for directed cadherin-containing vesicles movement toward the cell periphery and for the turnover of the junction. In addition, cadherin-based adhesion regulates MT dynamics, which become stabilized. Finally recent data have proposed that association of proteins of the catenin family to MT might be important for linking the MT ends to the F-actin-rich cortex and thus orienting mitotic spindles and the placement of the cytokinetic furrow during cell division.

Introduction

Cadherins are homophilic cell-cell adhesion molecules essential for the organization of cells into tissues during embryonic development. They are also involved in cell growth, migration and differentiation.^1,2 Cell-cell adhesion is often modified in cancer cells and during cell invasion. ^3,4 We focus in this chapter on the classical cadherins, defined by their characteristic and highly conserved cytoplasmic domain. Cadherins found in adherens junctions constitute the major family of transmembrane glycoproteins that mediate cell-cell adhesion by virtue of their ability to self-associate in a Ca²⁺-dependent manner. This homophilic binding is mediated by the N-terminal extracellular domain, which consists of five 110 amino acid repeats (EC1-EC5). Cadherins provide anchoring sites for the actin cytoskeleton through the binding of catenins.⁵ β-catenin and γ-catenin (plakoglobin) bind directly to the distal region of the cadherin cytoplasmic tail and interact with α-catenin, which associates with actin filaments.⁶ A fourth catenin, the phosphoprotein p120 interacts with the juxtamembrane region of cadherins thereby modulating their dimerization and adhesive function⁷ (see fig. 1).

Figure 1

Signaling pathways triggered by cadherin receptors differ with the cell type. A schematic diagram of the proteins that constitute the cadherin-dependent cell-cell adhesion site. Dimers of cadherin molecules associated with cytoplasmic catenins are found (more...)

Cadherins are not only structural components of adherens junction but also act as adhesive receptors and induce signaling programs leading for example to cell differentiation.⁸ In particular, Rho family GTPases activity is changed by the formation of cadherin-dependent cell-cell contacts. Rac1 is activated after VE- or E-cadherin activation,⁹¹³ so is Cdc42.¹⁴ RhoA activity is inhibited in E-cadherin-expressing MDCK cells while it is stimulated after N-cadherin-mediated adhesion^8,9 (fig. 2). These differences are likely due to the cell types used. In fact, cadherins display tissue specific expression (E- in epithelia, N- in neuronal, cardiac and skeletal muscle,...) as well as spatio-temporally regulated expression profile which might generate complex downstream signaling pathways to coordinate tissue development.

Figure 2

MT are involved in a kinesin-dependent transport of N-cadherin-containing cargo. a) Schematic distribution of N-cadherin in the golgi, in secretory and endocytotic vesicles and at the plasma membrane. The N-cadherin-containing vesicles are moved along (more...)

In addition, adherens junctions are highly dynamic structures that turn over rapidly. During embryonic development or tumor progression, changes in cadherin function and availability at cell-cell contacts have been reported. For example, during epithelium-mesenchyme transitions, which occur during specific stages of embryonic development (see also Chapters 1-4) but also under pathological conditions (see also Chapters 8: Arnoux et al and 9: Van Marck and Bracke), intercellular adhesions are disrupted through downregulation of E-cadherin activity.⁴ Similarly, during migration of neural crest cells, the localization and function of N-cadherin is regulated (see refs. 15, 16 and see also Chapter 3: Newgreen). One possible mechanism for modulation of adhesive function could occur through the turn-over of cadherins at the cell surface. The availability of cadherins might be modulated through changes in either secretory or endocytotic pathways. The observation that a recycling E-cadherin pool increases in the absence of stable cell-cell contacts supports this hypothesis.¹⁷ Rho-family GTPases RhoA, Rac1 and Cdc42 are key regulators of cadherin-mediated cell-cell adhesion (see ref. 18 and see also Chapter 18: Nakagawa et al). Again the consequence of GTPase signaling depends on the cellular context. In epithelial cells and keratinocytes, inactivation of RhoA inhibits the accumulation of E-cadherin at sites of cell-cell contact the same way Rac1 inactivation does.¹⁹²³ Consistently, Tiam1, a guanine exchange factor (GEF) for Rac1, increases E-cadherin-mediated adhesion and inhibits hepatocyte growth factor-induced-cell scattering in MDCK cells.²⁴ In epithelial cells, Rac1 activation after initial contact formation seems to be important to extend the regions of contact.^11,25 Nevertheless, in other studies in the same cell type, Rac1 has opposite effects. Beyond experimental differences, this might illustrate that Rac1 is a key regulator of both adherens junction assembly and disassembly. Although Rac1 regulates adherens junction assembly through reorganization of the actin cytoskeleton, it also regulates adherens junction disassembly via endocytosis of E-cadherin.²⁶ Cdc42 is also required for E-cadherin-mediated cell-cell adhesion.^22,27 In myoblasts, stable localization of N-cadherin at cell-cell contacts requires RhoA activity , whereas inhibition of either Rac1 or Cdc42 has no effect ((8); MC and CGR, personal observations). Further studies are required to elucidate if these discrepancies are due to the cellular context, the cadherin molecule itself or illustrate the existence of a complex kinetics of Rho GTPases activation after cadherin engagement.

Activated GTP-bound Rho GTPases interact with specific effectors, some of which are involved in the regulation of cadherin-mediated adhesion. The Rac1 and Cdc42 effector IQGAP1 negatively regulates E-cadherin-mediated cell-cell adhesion by interacting with β-catenin.²⁸³⁰ The RhoA effector mDia1, a member of the formin-homology family of proteins, promotes the formation of α-catenin/β-catenin complexes and localizes adherens junction components to the cell periphery.³¹ E-cadherin interacts with the Arp2/3 actin nucleator complex, whose activity is controlled by Rac1 and Cdc42.³² Finally, cytosolic p120 can interact with Vav2, a guanine exchange factor for Rho GTPases, suggesting that p120 localization is associated with Rho GTPase activation.^33,34 Various mechanisms may therefore exist to ensure Rho GTPases-dependent cadherin adhesion.

While it is clear that cadherin complexes associate with the actin cytoskeleton, evidences involving the MT network in the regulation of cadherin-mediated adhesion came only very recently. MT are essential for many cellular functions including vesicle transport, cell motility, polarity and division. MT are polarized tubular structures which are produced by linear polymerization of α/β tubulin heterodimers, with a faster assembly at the plus end over the minus end. The plus ends of MT display dynamic instability modulated by a number of MT-associated proteins (MAP).³⁵ Post-translational modifications of tubulin have also been described.³⁶ For example the best studied which is tubulin detyrosination, occurs in stabilized MT. Nevertheless, it seems that detyrosination is not involved in MT stabilization per se but regulates the interaction of motor proteins and organelles with stable MT.³⁷ In migrating cells, in fibroblasts, and in white blood cells, MT are organized with their minus ends anchored to the centrosome adjacent to the nucleus or free and facing toward the cell center and their plus ends extending toward the cell periphery. In many differentiated cells, such as the polarized epithelial cells and neurons, MT are noncentrosomal but are nevertheless uniformly polarized with their plus ends oriented towards the basal surface, or the growth cone, respectively.³⁸ In these cell types, MT are less dynamic but also support vesicular trafficking and polarity. Finally, connections between MT and F-actin exist since MT interact with F-actin and MT plus ends are targeted to focal adhesion complexes and modulate their turnover.³⁹⁴¹

Delivery of Cadherin and Catenin to the Cell Periphery through Microtubules

In 1983, Geller and Lilien have proposed that gp130/4.8, now called N-cadherin, is dynamically inserted into the plasma membrane through a MT-dependent fashion.⁴² To reach this conclusion, these authors have dissociated embryonic chick neural retina cells by trypsinization in the absence of divalent cations and then analyzed iodinatable polypeptides appearing at the cell surface during cellular repair by two-dimensional polyacrylamide gel electrophoresis. Recently, analyzing the behavior of a GFP-tagged N-cadherin construct by videomicroscopy in myoblasts or fibroblasts, we have demonstrated that the initial formation of N-cadherin-dependent cell-cell contacts results from the recruitment of the intracellular pool of N-cadherin to the plasma membrane.⁴³ Most of this intracellular pool is present in vesicular structures associated with and moving along MT in a kinesin-dependent way (fig. 2). This MT-dependent secretory pathway might be an efficient and controlled mechanism to deliver N-cadherin to specific sites at the plasma membrane. This key role for MT in the maintenance of cell-cell adhesion was also reported in newt lung epithelial cells but not in keratinocytes.^44,45 Other studies are required to understand such discrepancies and to analyze whether other cadherin might be similarly transported along MT. N-cadherin is the only cadherin described so far as using a MT-dependent secretory pathway to reach the plasma membrane. MT might also be important for the endocytosis of cadherin occuring during normal and pathological epithelium to mesenchyme transition.⁴⁶ In addition, p120 catenin was recently found associated with MT.^46a,46b This observation open new research avenues and it is possible that MT localization is important for the activity of p120 towards Rho family GTPases. Moreover, Rho proteins have been shown to be involved in MT-associated transport. RhoA and RhoG interact with kinectin, a membrane-anchoring protein for kinesin motor.⁴⁷ In addition, lysophosphatidic acid induces Rho-mediated stabilization of MT.⁴⁸ Once capped and stabilized, these MT might be for example detyrosinated and thus be involved in preferential interaction of vesicles and organelles leading to a cadherin-mediated polarization of MT toward the cell-cell contacts. Thus Rho GTPases could affect membrane trafficking of cadherin/catenin-containing cargo through their effects on a MT-dependent transport.

Cadherin-Dependent Cell-Cell Contact Regulates Microtubules Stability

As mentioned in the introduction, cadherin-based adhesion initiates intracellular signals allowing adapted cell responses during cell proliferation, migration and differentiation. One of these cell responses is the regulation of MT dynamic. Indeed, the dynamic behavior of MT plus ends is affected by cell-cell contacts.⁴⁴ Analysis of individual MT by time-lapse digital fluorescence microscopy reveals that plus end dynamic instability is suppressed in fully contacted cells, with individual MT exhibiting an extended state of pause, suggested that they become capped. Several proteins have been described to localize specifically to MT plus ends, including CLIP-170, EB-1, adenomatous polyposis coli (APC) and dynein. Interestingly, dynein, a MT-based motor which belongs to a multiprotein complex containing dynactin, p150Glued and dynamitin involved in both anterograde and retrograde MT transport, is localized at adherens junction in epithelial cells where it interacts by β-catenin.⁴⁹ These data suggest that cytoplasmic dynein found at adherens junctions might capture and tether MT at these sites. Whether dynein at cell-cell contact sites is involved in a retrograde transport of cargo remains to be analyzed. Another interesting candidate is the MT tip protein CLIP-170 described to associate with the Rac1 and Cdc42 effector IQGAP.⁵⁰ In fibroblasts, IQGAP is localized at the polarized leading edge and might interact with both CLIP-170 and activated Rac1 and Cdc42 acting as a linker between the plus ends of MT and cortical actin. IQGAP is also found localized at cell-cell contact sites in epithelial cells. At this place, IQGAP may also act as a linker between activated Rac1 or Cdc42 and CLIP-170 and participate in MT capture. Since Rac1 activity increases after E-cadherin-mediated adhesion, this is conceivable. Two other candidates for a function in the possible link between cadherin and MT dynamics are APC and the APC-binding protein EB1.^51,52 Moreover, cadherin-mediated MT stabilization may also act through regulating the activity of proteins such as stathmin/op18 or MAP. In addition to regulating MT plus end dynamics, cadherin-mediated adhesion stabilizes MT minus ends.⁵³ The importance of MT capture processes for the formation of cell-cell junction per se and /or for the cellular organization or polarization remains to be determined (fig. 3). Most of the proteins which control MT dynamic and capture are themselves controlled by Rho GTPases, key regulators of the actin cytoskeleton indicating that these two cytoskeletal components are coordinately regulated.

Figure 3

Potential mechanisms for how cadherin-mediated adhesion could regulate aspects of the microtubule cytoskeleton. Cadherin-mediated adhesion activates Rho GTPases which in turn might induce change in MT organization and dynamics. Rho GTPases control downstream (more...)

M-cadherin, which is specifically expressed in skeletal muscle cells is also associated with MT.⁵⁴ This association was reported to occur at the cell boundary and might allow the organization of the MT network parallel to the longitudinal axis. Interestingly, differentiating myoblasts display stabilized microtubules.⁵⁵ M-cadherin-dependent cell signaling may have a role in both the regulation of MT stability and polarity.

Catenin-Dependent Regulation of Spindle Localization

The position of the mitotic spindle plays a key role in the spatial control of cell division. In combination to polarity cues, the position of the spindle ensures the correct segregation of cell-fate determinants during development.⁵⁶ The correct spindle position is achieved through interactions between spindle, astral MT and cortical actin (see fig. 4). Interestingly, in the syncytial Drosophila embryo, the β-catenin homolog Armadillo is required to tether the spindle to cortical actin.⁵⁷ The entire complex contains α-catenin, β-catenin and a protein related to APC, and it is likely to interact with a protein of the EB1 family which localizes to the plus end of growing MT.⁵⁸ The same type of complex might allow cadherin/catenin to regulate MT dynamics in interphasic cells (see previous section). Asymmetrical distributed DE-cadherin is essential to determine the mitotic spindle orientation.⁵⁹ The small GTPase Cdc42, acting through a Par6-atypical protein kinase C (aPKC) complex, is also required to establish asymmetric cell division. Whether Cdc42 regulates glycogen synthase kinase-3β and APC in the context of asymmetric cell division remains to be determined.⁶⁰

Figure 4

Hypothetical model of the interaction of the α-catenin/β-catenin/APC complex with cortical F-actin and spindle and astral MTs. α-catenin anchors the complex to cortical F-actin. The anchoring to astral MT is mediated either by (more...)

Concluding Remarks

Taken together, the observations discussed above point out a picture in which cadherin-mediated adhesion not only controls the actin cytoskeleton but also the MT dynamics and polarity. Rho GTPases are key players in these processes and are involved in the bidirectional signaling between cadherin and these two cytoskeletal elements. The formation of new cadherin cell-cell contacts may lead to the activation of small GTPases, which would then induce changes in both MT-based transport and MT organization and dynamics. Alternatively, MT reorganization induced after cadherin-dependent adhesion could somehow regulate the activity of Rho GTPases. Several RhoGEFs have been described to interact with MT, their activity might be sensitive to the MT organization and dynamics.

Acknowledgements

We are grateful to A. Blangy and P. Fort for critical reading of the manuscript and to V. Braga and P. Anastasiadis for sharing image and data. Research activity was supported by grants from Association pour la Recherche contre le Cancer, Ligue contre le Cancer and Association Fran_se contre les Myopathies.

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