Cell adhesion and signalling by cadherins and Ig-CAMs in cancer - Nature Reviews Cancer
- ️Christofori, Gerhard
- ️Sun Feb 01 2004
Boveri, T. Zur Frage der Entstehung Maligner Tumoren (Gustav Fischer, Jena, 1914).
Yagi, T. & Takeichi, M. Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev. 14, 1169–1180 (2000).
Perez-Moreno, M., Jamora, C. & Fuchs, E. Sticky business: orchestrating cellular signals at adherens junctions. Cell 112, 535–548 (2003). A comprehensive review on the molecular regulation of the formation and function of cadherin-mediated cell adhesion.
He, W., Cowin, P. & Stokes, D. L. Untangling desmosomal knots with electron tomography. Science 302, 109–113 (2003). Recent novel insights into the structure of cadherin adhesion complexes by electron tomography.
Aplin, A. E., Howe, A., Alahari, S. K. & Juliano, R. L. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol. Rev. 50, 197–264 (1998).
Juliano, R. L. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu. Rev. Pharmacol. Toxicol. 42, 283–323 (2002).
Birchmeier, W. & Behrens, J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta 1198, 11–26 (1994).
Hirohashi, S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am. J. Pathol. 153, 333–339 (1998).
Vleminckx, K., Vakaet, L. Jr, Mareel, M., Fiers, W. & van Roy, F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66, 107–119 (1991).
Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998). First demonstration in vivo that the loss of E-cadherin function is causally involved in tumour progression.
Strathdee, G. Epigenetic versus genetic alterations in the inactivation of E-cadherin. Semin. Cancer Biol. 12, 373–379 (2002).
Guilford, P. et al. E-cadherin germline mutations in familial gastric cancer. Nature 392, 402–405 (1998).
Batlle, E. et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biol. 2, 84–89 (2000).
Cano, A. et al. The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76–83 (2000).
Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001).
Hajra, K. M., Chen, D. Y. & Fearon, E. R. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 62, 1613–1618 (2002).
Perez-Moreno, M. A. et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial–mesenchymal transitions. J. Biol. Chem. 276, 27424–27431 (2001). References 13–17 give novel insights into the transcriptional repression of the E-cadherin gene, an important process causing loss of E-cadherin function.
Fujita, N. et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 113, 207–219 (2003). Results that connect oestrogen-receptor signalling with the control of E-cadherin expression.
Di Croce, L. & Pelicci, P. G. Tumour-associated hypermethylation: silencing E-cadherin expression enhances invasion and metastasis. Eur. J. Cancer 39, 413–414 (2003).
Nawrocki-Raby, B. et al. Upregulation of MMPs by soluble E-cadherin in human lung tumor cells. Int. J. Cancer 105, 790–795 (2003).
Ino, Y., Gotoh, M., Sakamoto, M., Tsukagoshi, K. & Hirohashi, S. Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis. Proc. Natl Acad. Sci. USA 99, 365–370 (2002).
Behrens, J. et al. Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/β-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J. Cell Biol. 120, 757–766 (1993).
Fujita, Y. et al. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nature Cell Biol. 4, 222–231 (2002). Elegant demonstration of how tyrosine phosphorylation of E-cadherin leads to its ubiquitylation and subsequent degradation.
Hamaguchi, M. et al. p60v-src causes tyrosine phosphorylation and inactivation of the N-cadherin-catenin cell adhesion system. EMBO J. 12, 307–314 (1993).
Taddei, M. L. et al. β-catenin interacts with low-molecular-weight protein tyrosine phosphatase leading to cadherin-mediated cell-cell adhesion increase. Cancer Res. 62, 6489–6499 (2002).
Morali, O. G. et al. IGF-II induces rapid β-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene 20, 4942–4950 (2001).
Lopez, T. & Hanahan, D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1, 339–353 (2002). References 26–27 show that the IGF1 receptor interacts with E-cadherin and downregulates its function, leading to tumour metastasis.
Pennisi, P. A., Barr, V., Nunez, N. P., Stannard, B. & Le Roith, D. Reduced expression of insulin-like growth factor I receptors in MCF-7 breast cancer cells leads to a more metastatic phenotype. Cancer Res. 62, 6529–6537 (2002).
Kamei, T. et al. Coendocytosis of cadherin and c-Met coupled to disruption of cell–cell adhesion in MDCK cells: regulation by Rho, Rac and Rab small G proteins. Oncogene 18, 6776–6784 (1999).
Davies, G., Jiang, W. G. & Mason, M. D. HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells. Int. J. Mol. Med. 7, 385–388 (2001).
Takahashi, K. & Suzuki, K. Density-dependent inhibition of growth involves prevention of EGF receptor activation by E-cadherin-mediated cell-cell adhesion. Exp. Cell Res. 226, 214–222 (1996).
Pece, S. & Gutkind, J. S. Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell–cell contact formation. J. Biol. Chem. 275, 41227–41233 (2000).
Kovacs, E. M., Ali, R. G., McCormack, A. J. & Yap, A. S. E-cadherin homophilic ligation directly signals through Rac and phosphatidylinositol 3-kinase to regulate adhesive contacts. J. Biol. Chem. 277, 6708–6718 (2002).
Zantek, N. D. et al. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Differ. 10, 629–638 (1999).
Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signaling. Cell 103, 311–320 (2000).
Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
Orsulic, S., Huber, O., Aberle, H., Arnold, S. & Kemler, R. E-cadherin binding prevents β-catenin nuclear localization and β-catenin/LEF-1-mediated transactivation. J. Cell Sci. 112, 1237–1245 (1999).
Gottardi, C. J., Wong, E. & Gumbiner, B. M. E-cadherin suppresses cellular transformation by inhibiting β-catenin signaling in an adhesion-independent manner. J. Cell Biol. 153, 1049–1060 (2001).
Stockinger, A., Eger, A., Wolf, J., Beug, H. & Foisner, R. E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity. J. Cell Biol. 154, 1185–1196 (2001).
Wong, A. S. & Gumbiner, B. M. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J. Cell Biol. 161, 1191–1203 (2003). References 37–40 demonstrate that E-cadherin-mediated cell adhesion is able to suppress WNT signal transduction, and that β-catenin might have an additional signalling function that is independent of TCF/LEF1 transcriptional activity.
Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nature Rev. Cancer 2, 133–142 (2002).
Noren, N. K., Arthur, W. T. & Burridge, K. Cadherin engagement inhibits RhoA via p190RhoGAP. J. Biol. Chem. 278, 13615–13618 (2003). Insights into the mechanisms by which E-cadherin inhibits RHO activity.
Noren, N. K., Liu, B. P., Burridge, K. & Kreft, B. p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J. Cell Biol. 150, 567–580 (2000).
Anastasiadis, P. Z. & Reynolds, A. B. The p120 catenin family: complex roles in adhesion, signaling and cancer. J. Cell Sci 113, 1319–1334 (2000).
Daniel, J. M. & Reynolds, A. B. The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol. Cell. Biol. 19, 3614–3623 (1999). References 43–45 provide recent novel insights into the involvement of p120-catenin in the regulation of the activity of small GTPases.
Lambert, J. M. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biol. 4, 621–625 (2002).
Michiels, F., Habets, G. G., Stam, J. C., van der Kammen, R. A. & Collard, J. G. A role for Rac in Tiam1-induced membrane ruffling and invasion. Nature 375, 338–340 (1995).
Sander, E. E. et al. Matrix-dependent Tiam1/Rac Signaling in epithelial cells promotes either cell–cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J. Cell Biol. 143, 1385–1398 (1998).
Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867–871 (2002).
Kawasaki, Y., Sato, R. & Akiyama, T. Mutated APC and Asef are involved in the migration of colorectal tumour cells. Nature Cell Biol. 5, 211–215 (2003).
Kuroda, S. et al. Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin-mediated cell–cell adhesion. Science 281, 832–835 (1998).
Takemoto, H. et al. Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by E-cadherin in gastric cancers. Int. J. Cancer 91, 783–788 (2001).
Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).
Itoh, K. et al. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nature Med. 5, 221–225 (1999). References 53 and 54 demonstrate a functional role of RHOC and the RHO effector ROCK in in vivo models of tumour progression.
Tomita, K. et al. Cadherin switching in human prostate cancer progression. Cancer Res. 60, 3650–3654 (2000).
Li, G. & Herlyn, M. Dynamics of intercellular communication during melanoma development. Mol. Med. Today 6, 163–169 (2000).
Feltes, C. M., Kudo, A., Blaschuk, O. & Byers, S. W. An alternatively spliced cadherin-11 enhances human breast cancer cell invasion. Cancer Res. 62, 6688–6697 (2002).
Shimazui, T. et al. Expression of cadherin-6 as a novel diagnostic tool to predict prognosis of patients with E-cadherin-absent renal cell carcinoma. Clin. Cancer Res. 4, 2419–2424 (1998).
Takeuchi, T. et al. Loss of T-cadherin (CDH13, H-cadherin) expression in cutaneous squamous cell carcinoma. Lab. Invest. 82, 1023–1029 (2002).
Hazan, R. B., Phillips, G. R., Qiao, R. F., Norton, L. & Aaronson, S. A. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J. Cell Biol. 148, 779–790 (2000).
Li, G., Satyamoorthy, K. & Herlyn, M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 61, 3819–3825 (2001).
Nieman, M. T., Prudoff, R. S., Johnson, K. R. & Wheelock, M. J. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J. Cell Biol. 147, 631–644 (1999). References 60–62 demonstrate that gain of N-cadherin function contributes to tumour-cell migration and invasion.
Doherty, P. & Walsh, F. S. CAM-FGF receptor interactions: a model for axonal growth. Mol. Cell. Neurosci. 8, 99–111 (1996).
Cavallaro, U., Niedermeyer, J., Fuxa, M. & Christofori, G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nature Cell Biol. 3, 650–657 (2001). Identification of a signalling complex containing NCAM, FGFR, and N-cadherin. Modulation of integrin-mediated cell adhesion by the NCAM–FGFR–N-cadherin complex.
Peluso, J. J. N-cadherin-mediated cell contact regulates ovarian surface epithelial cell survival. Biol. Signals Recept. 9, 115–121 (2000).
Suyama, K., Shapiro, I., Guttman, M. & Hazan, R. B. A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2, 301–314 (2002). Demonstration of a functional interaction between N-cadherin and FGR1 and novel insights into the mechanisms of how N-cadherin might modulate FGF-induced FGFR signal transduction.
Williams, E. J. et al. Identification of an N-cadherin motif that can interact with the fibroblast growth factor receptor and is required for axonal growth. J. Biol. Chem. 276, 43879–43886 (2001). Demonstration of N-cadherin-mediated FGFR responses in neurons in the absence of FGFs.
Van Aken, E. H. et al. Invasion of retinal pigment epithelial cells: N-cadherin, hepatocyte growth factor, and focal adhesion kinase. Invest. Ophthalmol. Vis. Sci. 44, 463–472 (2003).
Tran, N. L., Adams, D. G., Vaillancourt, R. R. & Heimark, R. L. Signal transduction from N-cadherin increases Bcl-2. Regulation of the phosphatidylinositol 3-kinase/Akt pathway by homophilic adhesion and actin cytoskeletal organization. J. Biol. Chem. 277, 32905–32914 (2002).
Takino, T. et al. CrkI adapter protein modulates cell migration and invasion in glioblastoma. Cancer Res. 63, 2335–2337 (2003).
Arregui, C., Pathre, P., Lilien, J. & Balsamo, J. The nonreceptor tyrosine kinase fer mediates cross-talk between N-cadherin and β1-integrins. J. Cell Biol. 149, 1263–1274 (2000). Potential role of the non-receptor tyrosine kinase FER in the communication between N-cadherin and integrin.
Lilien, J., Balsamo, J., Arregui, C. & Xu, G. Turn-off, drop-out: functional state switching of cadherins. Dev. Dyn. 224, 18–29 (2002). Insights into the role of the phosphotyrosine phosphatase PTP1B in the regulation of the cell-adhesive and signalling functions of N-cadherin.
Dejana, E., Bazzoni, G. & Lampugnani, M. G. Vascular endothelial (VE)-cadherin: only an intercellular glue? Exp. Cell Res. 252, 13–19 (1999).
Carmeliet, P. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 (1999).
Shay-Salit, A. et al. VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc. Natl Acad. Sci. USA 99, 9462–9467 (2002). References 74 and 75 demonstrate the interaction of the endothelial-cell-specific VE-cadherin with VEGF receptor and its potential functional implications.
Jaggi, M., Wheelock, M. J. & Johnson, K. R. Differential displacement of classical cadherins by VE-cadherin. Cell Commun. Adhes. 9, 103–115 (2002).
Matsumura, T., Wolff, K. & Petzelbauer, P. Endothelial cell tube formation depends on cadherin 5 and CD31 interactions with filamentous actin. J. Immunol. 158, 3408–3416 (1997).
Kiss, J. Z. & Muller, D. Contribution of the neural cell adhesion molecule to neuronal and synaptic plasticity. Rev. Neurosci. 12, 297–310 (2001).
Cavallaro, U. & Christofori, G. Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim. Biophys. Acta 1552, 39–45 (2001).
Perl, A. K. et al. Reduced expression of neural cell adhesion molecule induces metastatic dissemination of pancreatic β tumor cells. Nature Med. 5, 286–291 (1999). Demonstration of a causal role of loss of NCAM function in the metastatic dissemination to regional lymph nodes.
Kiselyov, V. V. et al. Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure (Camb) 11, 691–701 (2003). Detailed structure–functional analysis of the NCAM–FGFR interaction.
Gluer, S., Schelp, C., von Schweinitz, D. & Gerardy-Schahn, R. Polysialylated neural cell adhesion molecule in childhood rhabdomyosarcoma. Pediatr. Res. 43, 145–147 (1998).
Komminoth, P., Roth, J., Lackie, P. M., Bitter-Suermann, D. & Heitz, P. U. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am. J. Pathol. 139, 297–304 (1991).
Lantuejoul, S. et al. NCAM (neural cell adhesion molecules) expression in malignant mesotheliomas. Hum. Pathol. 31, 415–421 (2000).
Lantuejoul, S., Moro, D., Michalides, R. J., Brambilla, C. & Brambilla, E. Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am. J. Surg. Pathol. 22, 1267–1276 (1998).
Trouillas, J. et al. Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion. J. Neurosurg. 98, 1084–1093 (2003).
Angata, K. & Fukuda, M. Polysialyltransferases: major players in polysialic acid synthesis on the neural cell adhesion molecule. Biochimie 85, 195–206 (2003).
Hammarstrom, S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin. Cancer Biol. 9, 67–81 (1999).
Plunkett, T. A. & Ellis, P. A. CEACAM1: a marker with a difference or more of the same? J. Clin. Oncol. 20, 4273–4275 (2002).
Fournes, B., Sadekova, S., Turbide, C., Letourneau, S. & Beauchemin, N. The CEACAM1-L Ser503 residue is crucial for inhibition of colon cancer cell tumorigenicity. Oncogene 20, 219–230 (2001).
Obrink, B. CEA adhesion molecules: multifunctional proteins with signal-regulatory properties. Curr. Opin. Cell Biol. 9, 616–626 (1997).
Wagener, C. & Ergun, S. Angiogenic properties of the carcinoembryonic antigen-related cell adhesion molecule 1. Exp. Cell Res. 261, 19–24 (2000).
Volpert, O. et al. Inhibition of prostate tumor angiogenesis by the tumor suppressor CEACAM1. J. Biol. Chem. 277, 35696–35702 (2002).
Fearon, E. R. DCC: is there a connection between tumorigenesis and cell guidance molecules? Biochim. Biophys. Acta 1288, M17–M23 (1996).
Fazeli, A. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997).
White, R. L. Tumor suppressing pathways. Cell 92, 591–592 (1998).
Hilgers, W. et al. Homozygous deletions inactivate DCC, but not MADH4/DPC4/SMAD4, in a subset of pancreatic and biliary cancers. Genes Chromosom. Cancer 27, 353–357 (2000).
Tarafa, G. et al. DCC and SMAD4 alterations in human colorectal and pancreatic tumor dissemination. Oncogene 19, 546–555 (2000).
Barbera, V. M. et al. The 18q21 region in colorectal and pancreatic cancer: independent loss of DCC and DPC4 expression. Biochim. Biophys. Acta 1502, 283–296 (2000).
Livesey, F. J. Netrins and netrin receptors. Cell. Mol. Life Sci. 56, 62–68 (1999).
Kenwrick, S. & Doherty, P. Neural cell adhesion molecule L1: relating disease to function. Bioessays 20, 668–675 (1998).
Primiano, T. et al. Identification of potential anticancer drug targets through the selection of growth-inhibitory genetic suppressor elements. Cancer Cell 4, 41–53 (2003).
Thies, A. et al. Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Eur. J. Cancer 38, 1708–1716 (2002).
Voura, E. B., Ramjeesingh, R. A., Montgomery, A. M. & Siu, C. H. Involvement of integrin α(v)β(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells. Mol. Biol. Cell 12, 2699–2710 (2001).
Xie, S. et al. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res. 57, 2295–2303 (1997).
Mills, L. et al. Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma. Cancer Res. 62, 5106–5114 (2002).
Satyamoorthy, K., Muyrers, J., Meier, F., Patel, D. & Herlyn, M. Mel-CAM-specific genetic suppressor elements inhibit melanoma growth and invasion through loss of gap junctional communication. Oncogene 20, 4676–4684 (2001).
Wu, G. J. et al. Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression. Gene 279, 17–31 (2001).
Anfosso, F. et al. Activation of human endothelial cells via S-endo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK). J. Biol. Chem. 273, 26852–26856 (1998).
Alais, S. et al. HEMCAM/CD146 downregulates cell surface expression of β1 integrins. J. Cell Sci. 114, 1847–1859 (2001).
Dhodapkar, K. M., Friedlander, D., Scholes, J. & Grumet, M. Differential expression of the cell-adhesion molecule Nr-CAM in hyperplastic and neoplastic human pancreatic tissue. Hum. Pathol. 32, 396–400 (2001).
Sehgal, A., Ricks, S., Warrick, J., Boynton, A. L. & Murphy, G. P. Antisense human neuroglia related cell adhesion molecule hNr-CAM, reduces the tumorigenic properties of human glioblastoma cells. AntiCancer Res. 19, 4947–4953 (1999).
Eliceiri, B. P. Integrin and growth factor receptor crosstalk. Circ. Res. 89, 1104–1110 (2001).
Schwartz, M. A. Integrin signaling revisited. Trends Cell Biol. 11, 466–470 (2001).
Ponta, H., Sherman, L. & Herrlich, P. A. CD44: from adhesion molecules to signalling regulators. Nature Rev. Mol. Cell Biol. 4, 33–45 (2003).
Edelman, G. M., Gallin, W. J., Delouvee, A., Cunningham, B. A. & Thiery, J. P. Early epochal maps of two different cell adhesion molecules. Proc. Natl Acad. Sci. USA 80, 4384–4388 (1983).
Hatta, K. & Takeichi, M. Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development. Nature 320, 447–449 (1986).
Bendel-Stenzel, M. R., Gomperts, M., Anderson, R., Heasman, J. & Wylie, C. The role of cadherins during primordial germ cell migration and early gonad formation in the mouse. Mech. Dev. 91, 143–152 (2000).
DeLuca, S. M. et al. Hepatocyte growth factor/scatter factor promotes a switch from E- to N-cadherin in chick embryo epiblast cells. Exp. Cell Res. 251, 3–15 (1999). References 116–119 illustrate the involvement of the cadherin switch in embryonic development.
Nakagawa, S. & Takeichi, M. Neural crest emigration from the neural tube depends on regulated cadherin expression. Development 125, 2963–2971 (1998).
Linask, K. K. et al. N-cadherin/catenin-mediated morphoregulation of somite formation. Dev. Biol. 202, 85–102 (1998).
Radice, G. L. et al. Developmental defects in mouse embryos lacking N-cadherin. Dev. Biol. 181, 64–78 (1997).
Kolkova, K., Novitskaya, V., Pedersen, N., Berezin, V. & Bock, E. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway. J. Neurosci. 20, 2238–2246 (2000).
Leshchyns'ka, I., Sytnyk, V., Morrow, J. S. & Schachner, M. Neural cell adhesion molecule (NCAM) association with PKC{β}2 via {β}I spectrin is implicated in NCAM-mediated neurite outgrowth. J. Cell Biol. 161, 625–639 (2003). References 123 and 124 give novel insights into the mechanisms of NCAM-mediated FGFR signal transduction.
Walsh, F. S. & Doherty, P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu. Rev. Cell Dev. Biol. 13, 425–456 (1997).
Ignelzi, M. A. Jr, Miller, D. R., Soriano, P. & Maness, P. F. Impaired neurite outgrowth of src-minus cerebellar neurons on the cell adhesion molecule L1. Neuron 12, 873–884 (1994).
Niethammer, P. et al. Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis. J. Cell Biol. 157, 521–532 (2002). Differential membrane localization of NCAM results in the activation of different signalling pathways.
Baloh, R. H., Enomoto, H., Johnson, J., Eugene, M & Milbrandt, J. The GDNF family ligands and receptors: implications for neural development. Curr. Opin. Neurobiol. 10, 103–110 (2000).
Paratcha, G., Ledda, F. & Ibanez, C. F. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113, 867–879 (2003).
Conacci-Sorrell, M., Zhurinsky, J. & Ben-Ze'ev, A. The cadherin–catenin adhesion system in signaling and cancer. J. Clin. Invest. 109, 987–991 (2002).
Joo, M., Lee, H. K. & Kang, Y. K. Expression of E-cadherin, β-catenin, CD44s and CD44v6 in gastric adenocarcinoma: relationship with lymph node metastasis. AntiCancer Res. 23, 1581–1588 (2003).
Kinsella, A. R. et al. The role of the cell–cell adhesion molecule E-cadherin in large bowel tumour cell invasion and metastasis. Br. J. Cancer 67, 904–909 (1993).
Kanazawa, N. et al. E-cadherin expression in the primary tumors and metastatic lymph nodes of poorly differentiated types of rectal cancer. Surg. Today 32, 123–128 (2002).
Byrne, R. R. et al. E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup. J. Urol. 165, 1473–1479 (2001).
Hartveit, E. Attenuated cells in breast stroma: the missing lymphatic system of the breast. Histopathology 16, 533–543 (1990).
Mandriota, S. J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20, 672–682 (2001).
Stacker, S. A., Achen, M. G., Jussila, L., Baldwin, M. E. & Alitalo, K. Lymphangiogenesis and cancer metastasis. Nature Rev. Cancer 2, 573–583 (2002).