Lamellipodium extension and cadherin adhesion: two cell responses to cadherin activation relying on distinct signalling pathways

Journal of Cell Science - Tập 117 Số 2 - Trang 257-270 - 2004
Julie Gavard1, Mireille Lambert1, Inna Grosheva2, Véronique Marthiens1, Théano Irinopoulou1, Jean‐François Riou3, Alexander D. Bershadsky2, René‐Marc Mège1
1Signalisation et Différenciation Cellulaires dans les Systèmes Nerveux et Musculaire, U440 INSERM - UPMC, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France
2Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot 76100, Israel
3Equipe Biologie Expérimentale, Laboratoire de Biologie du Développement, UMR 7622 CNRS - UPMC, 9 quai Saint-Bernard, 75005 Paris, France

Tóm tắt

Cell adhesion molecules of the cadherin family contribute to the regulation of cell shape and fate by mediating strong intercellular adhesion through Ca2+-dependent interaction of their ectodomain and association of their cytoplasmic tail to actin. However, the mechanisms co-ordinating cadherinmediated adhesion with the reorganization of the actin cytoskeleton remain elusive. Here, the formation of de novo contacts was dissected by spreading cells on a highly active N-cadherin homophilic ligand. Cells responded to N-cadherin activation by extending lamellipodium and organizing cadherin-catenin complexes and actin filaments in cadherin adhesions. Lamellipodium protrusion, associated with actin polymerization at the leading edge sustained the extension of cadherin contacts through a phosphoinositide 3-kinase (PI 3-kinase)-Rac1 pathway. Cadherin adhesions were formed by PI 3-kinase-independent, Rac1-dependent co-recruitment of adhesion complexes and actin filaments. The expression and localization of p120 at the plasma membrane, associated with an increase in membrane-associated Rac1 was required for both cell responses, consistent with a major role of p120 in signalling pathways initiated by cadherin activation and contributing to Rac1-dependent contact extension and maturation. These results provide additional information on the mechanisms by which cadherin coordinates adhesion with dynamic changes in the cytoskeleton to control cell shape and intercellular junction organization.

Từ khóa


Tài liệu tham khảo

Adams, C. L. and Nelson, W. J. (1998). Cytomechanics of cadherin-mediated cell-cell adhesion. Curr. Opin. Cell Biol.10, 572-577.

Anastasiadis, P. Z., Moon, S. Y., Thoreson, M. A., Mariner, D. J., Crawford, H. C., Zheng, Y. and Reynolds, A. B. (2000). Inhibition of RhoA by p120 catenin. Nat. Cell Biol.2, 637-644.

Anastasiadis, P. Z. and Reynolds, A. B. (2001). The p120 catenin family: complex roles in adhesion, signaling and cancer. J. Cell Sci.113, 1319-1334.

Aono, S., Nakagawa, S., Reynolds, A. B. and Takeichi, M. (1999). p120ctn acts as an inhibitory regulator of cadherin function in colon carcinoma cells. J. Cell Biol.145, 551-562.

Braga, V. M. M., Machesky, L. M., Hall, A. and Hotchin, N. A. (1997). The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J. Cell Biol.137, 1421-1431.

Brieher, W. M., Yap, A. S. and Gumbiner, B. M. (1996). Lateral dimerization is required for homophilic binding activity of C-cadherin. J. Cell Biol.135, 487-496.

Brummelkamp, T. R., Bernards, R. and Agami, R. (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science296, 550-553.

Charrasse, S., Meriane, M., Communale, F., Blangy, A. and Gauthier-Rouvière, C. (2002). N-cadherin-dependent cell-cell contact regulates Rho GTPases and β-catenin localization in mouse C2C12 myoblasts. J. Cell Biol.158, 953-965.

Chrzanowska-Wodnicka, M. and Burridge, K. (1996). Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol.133, 1403-1415.

Ehrlich, J. S., Hansen, M. D. and Nelson, W. J. (2002). Spatio-temporal regulation of Rac1 localization and lamellipodia dynamics during epithelial cell-cell adhesion. Dev. Cell3, 259-270.

Fleming, I. N., Elliott, C. M. and Exton, J. H. (1996). Differential translocation of Rho family GTPases by lysophoshatidic acid, endothelin-1, and platelet-derived growth factor. J. Biol. Chem.271, 33067-33073.

Friedlander, D. R., Mège, R. M., Cunningham, B. A. and Edelman, G. M. (1989). Cell sorting-out is modulated by both the specificity and amount of different cell adhesion molecules (CAMs) expressed on cell surfaces. Proc. Natl. Acad. Sci. USA86, 7043-7047.

Geiger, B., Bershadsky, A. D., Pankov, R. and Yamada, K. M. (2001). Transmembrane extracellular matrix-cytoskeleton crosstalk. Nat. Rev. Mol. Cell. Biol.2, 793-805.

Goodwin, M., Kovacs, E. M., Thoreson, M. A., Reynolds, A. B., and Yap, A. S. (2003). Minimal mutation of the cytoplasmic tail inhibits the ability of E-cadherin to activate rac but not PI3-kinase. Direct evidence of a role for cadherin-activated Rac signaling in adhesion and contact formation. J. Biol. Chem.278, 20533-20539.

Grosheva, I., Shtutman, M., Elbaum, M. and Bershadsky, A. D. (2001). p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell-cell contact formation and regulation of cell locomotion. J. Cell Sci.114, 695-707.

Gumbiner, B. M. (1996). Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell84, 345-357.

Hansen, M. D., Ehrlich, J. S. and Nelson, W. J. (2002). Molecular mechanism for orienting membrane and actin dynamics to nascent cell-cell contacts in epithelial cells. J. Biol. Chem.277, 45371-45376.

Hynes, R. O. (1999). Cell adhesion: old and new questions. Trends Cell Biol.9, 33-37.

Hynes, R. O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell110, 673-687.

Ireton, R. C., Davis, M. A., van Hengel, J., Mariner, D. J., Barnes, K., Thoreson, M. A., Anastasiadis, P. Z., Matrisian, L., Bundy, L. M., Sealy, L. et al. (2002). A novel role for p120 catenin in E-cadherin function. J. Cell Biol.159, 465-476.

Kovacs, E. M., Ali, R. G., McCormack, A. J. and Yap, A. S. (2002a). E-cadherin homophilic ligation directly signals through Rac and Phosphatidyl 3-kinase to regulate adhesive contacts. J. Biol. Chem.277, 6708-6718.

Kovacs, E. M., Goodwin, M., Ali, R. G., Paterson, A. D. and Yap, A. S. (2002b). Cadherin-directed actin assembly: E-cadherin physically associates with the Arp2/3 complex to direct assembly in nascent adhesive contacts. Curr. Biol.12, 379-382.

Lambert, M., Padilla, F. and Mège, R. M. (2000). Immobilized dimers of N-cadherin-Fc chimera mimic cadherin-mediated cell contact formation: Contribution of both inside-out and outside in signals. J. Cell Sci.113, 2207-2219.

Lambert, M., Choquet, D. and Mège, R. M. (2002). Dynamics of ligand induced, Rac1-dependent anchoring of cadherins to the actin cytoskeleton. J. Cell Biol.157, 469-479.

Mary, S., Charrasse, S., Meriane, M., Comunale, F., Travo, P., Blangy, A. and Gauthier-Rouvière, C. (2002). Biogenesis of N-cadherin-dependent cell-cell contacts in living fibroblasts is a microtubule-dependent kinesindriven mechanisms. Mol. Biol. Cell13, 285-301.

Matsuzaki, F., Mège, R. M., Jaffe, S. H., Friedlander, D. R., Gallin, W. J., Goldberg, J. I., Cunningham, B. A. and Edelman, G. M. (1990). cDNAs of cell adhesion molecules of different specificity induce changes in cell shape and border formation in transfected S180 cells. J. Cell Biol.110, 1239-1252.

Mège, R. M., Matsuzaki, F., Gallin, W. J., Goldberg, J. I., Cunningham, B. A. and Edelman, G. M. (1988). Construction of epithelioid sheets by transfection of mouse sarcoma cells with cDNAs for chicken cell adhesion molecules. Proc. Natl. Acad. Sci. USA85, 7274-7278.

Michaelson, D., Silletti, J., Murphy, G., D'Eustachio, P., Rush, M. and Philips, M. R. (2001). Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J. Cell Biol.152, 111-126.

Nobes, C. D. and Hall, A. (1995). Rho, rac and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibres, lamellipodia and filopodia. Cell14, 1583-1589.

Noren, N. K., Liu, B. P., Burridge, K. and Kreft, B. (2000). p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J. Cell Biol.150, 567-579.

Noren, N. K., Niessen, C. M., Gumbiner, B. M. and Burridge, K. (2001). Cadherin engagement regulates Rho family GTPases. J. Biol. Chem.276, 33305-33308.

Ohkubo, T. and Ozawa, M. (1999). p120ctn binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity. J. Biol. Chem.274, 21409-21415.

Ozawa, M. and Kemler, R. (1998). The membrane-proximal region of the E-cadherin cytoplasmic domain prevents dimerization and negatively regulates adhesion activity. J. Cell Biol.142, 1605-1613.

Pece, S., Chiariello, M., Murga, C. and Gutkind, S. (1999). Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell-cell junctions. J. Biol. Chem.274, 19347-19351.

Perret, E., Benoliel, A. M., Nassoy, P., Pierres, A., Delmas, V., Thiery, J. P., Bongrand, P. and Feracci, H. (2002). Fast dissociation kinetics between individual E-cadherin fragments revealed by flow chamber analysis. EMBO. J.21, 2537-2546.

Radice, G. L., Rayburn, H., Matsunami, H., Knudsen, K. A., Takeichi, M. and Hynes, R. O. (1997). Developmental defects in mouse embryos lacking N-cadherin. Dev. Biol.181, 64-78.

Sako, Y., Nagafuchi, A., Tsukita, S., Takeichi, M. and Kusumi, A. (1998). Cytoplasmic regulation of the movement of E-cadherin on the free cell surface was studied by optical tweezers and single particle tracking: corralling and tethering by the membrane skeleton. J. Cell Biol.140, 1227-1240.

Small, V. J., Stradal, T., Vignal, E. and Rottner, K. (2002). The lamellipodium: where motility begins. Trends Cell Biol.12, 112-120.

Stevenson, B. R., Gallin, W. J. and Paul, D. L. (1992). Cell-cell interactions: A practical approach. The practical approach series (ed. D. Rickwood and B. D. Hames), Oxford: Oxford University Press.

Takeichi, M. (1977). Functional correlation between cell adhesive properties and some cell surface proteins. J. Cell Biol.75, 464-474.

Takeichi, M. (1995). Morphogenic roles of classic cadherins. Curr. Opin. Cell Biol.7, 619-627.

Tepass, U., Truong, K., Godt, D., Ikura, M. and Peifer, M. (2000). Cadherins in embryonic and neural morphogenesis. Nat. Rev. Mol. Cell. Biol.1, 91-100.

Thoreson, M. A., Anastasiadis, P. Z., Daniel, J. M., Ireton, R. C., Wheelock, M. J., Johnson, K. R., Hummingbird, D. H. and Reynolds, A. B. (2000). Selective uncoupling of p120ctn from E-cadherin disrupts strong adhesion. J. Cell Biol.148, 189-201.

Uchida, N., Honjo, Y., Johnson, K. R., Wheelock, M. J. and Takeichi, M. (1996). The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J. Cell Biol.135, 767-779.

Umbhauer, M., Penzo-Mendez, A., Clavilier, L., Boucaut, J. and Riou, J. F. (2000). Signaling specificities of fibroblast growth factor receptors in early Xenopus embryo. J. Cell Sci.113, 2865-2875.

Vasioukhin, V., Bauer, C., Yin, M. and Fuchs, E. (2000). Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell100, 209-219.

Woodfield, R. J., Hodgkin, M. N., Akhtar, N., Morse, M. A., Fuller, K. J., Saqib, K., Thompson, N. T. and Wakelam, M. J. (2001). The p85 subunit of phosphoinositide 3-kinase is associated with beta-catenin in the cadherin-based adhesion complex. Biochem. J.360, 335-344.

Wu, J., Mariner, D. J., Thoreson, M. A. and Reynolds, A. B. (1998). Production and characterization of monoclonal antibodies to the catenin p120ctn. Hybridoma17, 175-183.

Yaffe, D. and Saxel, O. (1977). Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature270, 725-727.

Yap, A. S., Brieher, W. M. and Gumbiner, B. M. (1997a). Molecular and functional analysis of cadherin-based adherens junctions. Annu. Rev. Cell Dev. Biol.13, 119-146.

Yap, A. S., Brieher, W. M., Pruschy, M. and Gumbiner, B. M. (1997b). Lateral clustering of the adhesive ectodomain: a fundamental determinant of cadherin function. Curr. Biol.7, 308-315.

Yap, A. S., Niessen, C. M. and Gumbiner, B. M. (1998). The juxtamembrane region of the cadherincytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. J. Cell Biol.141, 779-789.

Yap, A. S. and Kovacs, E. M. (2003). Direct cadherin-activated cell signaling: a view from the plasma membrane. J. Cell Biol.160, 11-16.

Zamir, E., Katz, M., Posen, Y., Erez, N., Yamada, K. M., Katz, M., Lin, S., Lin, D. C., Bershadsky, A. D. and Geiger, B. (2000). Dynamics and segregation of cell-matrix adhesions in cultured fibroblasts. Nat. Cell Biol.2, 191-196.