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N-cadherin is a member of the cadherin gene family encode proteins that mediate calcium-ion-dependent adhesion (Takeichi, 1988). In the nomenclature of CD antigens the new designation for this protein is CD325. N-cadherin is known also as Neural cadherin or Cadherin-2 and has been identified originally as the cell adhesion molecule A-CAM, which is localized to the adherens junction. The protein has been referred to also as CDHN [neural calcium-dependent adhesion protein].
N-cadherin has been identified by Grunwald et al (1982) as a 130 kDa protein in the chicken neural retina that is protected by calcium from proteolysis. Volk and Geiger (1984) have referred to the protein as A-CAM [adherens junction cell adhesion molecule]. A 90 kDa N-terminal ectodomain fragment of N-cadherin is being referred to as soluble N-cadherin (abbr. N-Cad90) (Paradies and Grunwald, 1993).
The human gene sequence has been described by Reid and Hemperly (1990). Wallis et al (1994) have reported the structure of the human N-cadherin gene and described sequence homologies between human and mouse N-cadherin and other cadherins.
N-cadherin is a cell adhesion molecule that typically interacts with other N-cadherin molecules in a homotypic homophilic manner. N-cadherin can engage also in heterotypic homophilic and heterophilic interactions with other caherins (Shan et al, 2000).
N-cadherin interacts directly with FGF receptors (Williams et al, 2001). Neurite outgrowth stimulated by N-cadherin can be inhibited by blocking the functions of this receptor (Williams et al, 1994). Interactions with FGF receptors are required also for the contact-dependent survival of ovarian granulosa cells mediated by N-cadherin (Trolice et al, 1997). FGF receptors also participate in regulating N-cadherin mediated cell motility and metastasis in cancer cells, whichy may involve ligand-dependent and ligand-independent processes (Suyama et al, 2002; Wheelock and Johnson, 2003). N-cadherin and FGF receptor interactions have been shown to be involved in the control of axonal growth, guidance to synapse formation, and synaptic plasticity (Doherty and Walsh, 1996). Full length and soluble N-cadherin have been shown to promote cell-matrix adhesion and neurite outgrowth (Paradies and Grunwald, 1993; Bixby et al, 1994; Utton et al, 2001).
N-cadherin is expressed early during embryonic development in different tissues (Hatta et al, 1987; Takeichi, 1988) and has been implicated in many different biological processes. It is required during gastrulation for a proper establisment of the left-right axis (Garcia-Castro et al, 2000). Tanaka et al (2000) have reported that N-cadherin is involved in the formation of central nervous system synapses. Rubinek et al (2003) have demonstrated that N-cadherin homophilic interactions mediating cell-cell contacts between pituicytes regulates human growth hormone secretion.
N-cadherin expression in early CD34(+) CD19(+) hematopoietic cells points to an involvement in the development and retention of early hematopoietic cells in the bone marrow (Puch et al, 2001). N-cadherin also plays a role in the commitment, condensation and chondrogenic differentiation of mesenchymal cells and the production of cartilaginous matrix (Tuan, 2003; Tufan and Tuan, 2001; Tufan et al, 2002), and during osteogenic and myogenic differentiation (Charasse et al, 2002; Ferrari et al, 2000; George-Weinstein et al, 1997; Brand-Saberi et al, 1996). N-cadherin may play a role also in angiogenesis during neuroectoderm vascularization and in cancer angiogenesis, although its exact function remains to be elucidated (Gerhardt et al, 1999; Nakashima et al, 2003).
Knock-out mice lacking expression of N-cadherin have been shown to die early during gestation. These embryos display major heart defects and malformed neural tubes and somites. The defect can be rescued partially by re-expression of N-cadherin (Radice et al, 1997; Luo et al, 2001).
Epithelial cells engineered to express N-cadherin have been shown to change their morphology and behaviour. These cells acquire a motile phenotype similar to that observed in cells undergoing epithelial-mesenchymal transition (Tran et al, 1999). This phenotype is independent of cell-cell adhesion, depends on the presence of two discrete N-cadherin protein domains that suppress or modulate movement, and also depends on the expression of other proteins interacting with these domains (Fedor-Chaiken et al, 2003; Kashima et al, 2003; Islam et al, 1996; Hazan et al, 1997; Kim et al, 2000). Thus varying effects may be observed in different cell types. Aberrant expression of N-cadherin by cancer cells can contribute to invasiveness and metastasis by making the cells more motile (Nieman et al, 1999; Hazan et al, 2000; Van Aken et al, 2003).
Breast carcinoma cells expressing N-cadherin have been shown to be more motile and invasive (Hazan et al, 1997, 2000), but there is no correlation with grade (Paredes et al, 2002) or patient survival (Peralta Soler et al, 1999). De novo expression of N-cadherin has been found in a high percentage of prostate carcinomas (Tomita et al, 2000). N-cadherin has been shown also to be re-expressed in metastasising melanomas (Matsuyoshi et al, 1997; Sanders et al, 1999). T-cell leukemia cell lines express N-cadherin and this is thought to facilitate invasion in mesenchymal tissues of the skin and nervous system (Kawamura-Kodama et al, 1999). Gastric carcinomas have been found to express N-cadherin (Yanagimoto et al, 2001; Rosivatz et al, 2002). Upregulated expression of N-cadherin has been observed in pleural mesothelioma (Han et al, 1997; Ord—nez, 2003).
Unaltered or downregulated expression has been shown to occur in osteosarcoma, where N-cadherin inhibits cell migration and the formation of metastasis (Kashima et al, 2003). Decreased N-cadherin expression correlates with the dissemination of malignant astrocytic tumors (Asano et al, 2000). In these cases N-cadherin may play a role as a tumor suppressor.
For additional information on CD antigens see also: CD antigens MiniCOPE Dictionary.
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ENTRY LAST MODIFIED: February 2007
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