Ycatenin

y-Catenin and ß-catenin are closely related and are members of the gene family that includes the Drosophila protein armadillo (Kodama et al., 1999; McCrea et al., 1991). y-Catenin is identical to plakoglobin (Peifer et al., 1992; Knudsen and Wheelock, 1992). y-Catenin and ß-catenin share 80% sequence identity in the twelve arm repeat domains (Huber and Weis, 2001), but only share 29% and 41% sequence identity in the N- and C-terminal regions, respectively. There are two types of cell-cell junctions: adherens junctions and desmosomes (Takeichi, 1991; Cowin and Burke, 1996). While adherens junctions have one transmembrane component, E-cadherin, desmosomes have two transmembrane components, desmoglein and desmocollin (Buxton et al., 1993). Similar to ß-catenin, y-catenin binds directly to E-cadherin and a-catenin at adherens junctions (Aberle et al., 1994; Hulsken et al., 1994). y-Catenin is the only component of both des-mosome and adherens junctions, suggesting a pivotal role in cell-cell adhesion. In addition to forming a complex with E-cadherin, y-catenin interacts with the cytoplasmic regions of desmoglein and desmocolin (Kowalczyk et al., 1994; Mathur et al., 1994; Troyanovsky et al., 1994a; Troyanovsky et al., 1994b; Wahl et al., 1996; Witcher et al., 1996). Arm repeats 1-4 of y-catenin specifically interact with desmoglein. In contrast, y-catenin arm repeats 11-12 are required for binding desmocolins, but not desmogleins (Witcher et al., 1996). A recent model proposes that the amino- and carboxy-terminal domains of y-catenin form intramolecular interactions with the armadillo domain, inhibiting its association with desmoglein (Wahl, 2000). Classical cadherins, which include E-and N-cadherin, bind to the same site on y-catenin as desmocolin (Hulsken et al., 1994; Sacco et al., 1995). Therefore, complexes consisting of E-cadherin, y- and a-catenins are formed at adherens junctions, while y-catenin, desmoglein and desmocolin complexes are formed at desmosomes in a mutually exclusive manner. y-Catenin in adherens junctions and desmosomes may have a potential role in organizing cadherins into an adhesive zipper between two adjacent cells, thereby tightening the association between two cells. y-Catenin is also found in the cytoplasm, where it forms a homodimer of unknown function (Cowin et al., 1986). The a-catenin binding region maps to the first repeat of y-catenin, while N-cadherin binding region maps within repeats 7 and 8 (Sacco et al., 1995). y-Catenin, like ß-catenin (Ben Ze'ev and Geiger, 1998), interacts with several proteins, such as classical cadherins (Sacco et al., 1995), a-catenin (Nieset et al., 1997), fascin (Tao et al., 1996), axin (Ikeda et al., 1998; Behrens et al., 1998; Hart et al., 1999; Itoh et al., 1998), APC (Hulsken et al., 1994), and LEF/TCF transcription factors (Simcha et al., 1998; Huber et al., 1996). Tcf-4, however, contains two different sites for binding ß- and y-catenin. Interaction with y-catenin inhibits transcription of downstream target genes (Miravet et al., 2002). ß-Catenin binds to amino acids 1-50 of Tcf-4, whereas y-catenin binds to residues 51-80. Tcf-4 specifically binds to y-catenin in the region of arm repeats 1-6. Furthermore, in vitro kinase assays have suggested that phosphorylation of Tcf-4 negatively affects its interaction with y-catenin without altering its association with ß-catenin. Therefore, y-catenin can contribute to homophilic cell-adhesion involving both adherens junctions and zonula adherens junctions.

3.5. p120ctn p120Catenin (p120ctn) was originally described as a tyrosine-phosphorylated protein in Src-transformed cells (Reynolds et al., 1992; Peifer et al., 1994; Mariner et al., 2000; Noren et al., 2000). Recent evidence suggests pleiotropic functions of p120ctn such as cadherin clustering (Yap, 1998a; Yap et al., 1998b), cell motility (Chen et al., 1997), cadherin turnover at the cell surface (Davis et al., 2004), as well as regulation of neuronal outgrowth and of cadherin-catenin complex stability (Aono et al., 1999; Ohkubo and Ozawa, 1999). While a-, ß- and y-cate-nins bind to the catenin-binding domain (CBD) of the cadherin cytoplasmic tail, p120ctn binds to the juxtamembrane domain (JMD). Unlike the other catenin proteins, p120ctndoes not interact with a-catenin, APC, or transcription factor Lef-1 (Daniel and Reynolds, 1995). Hence, p120ctn does not directly modulate the actin cytoskeleton, implying a distinct role of p120ctn in cadherin-catenin complex and downstream signaling.

p120ctn is thought to indirectly regulate assembly and disassembly of adherens junctions via the Rho family of GTPases (Anastasiadis and Reynolds, 2000; Mariner et al., 2001; Anastasia-dis et al, 2000; Grosheva et al., 2001). p120ctn mediates cadherin-dependent activation of RhoA at nascent cell-cell contacts, thereby regulating cadherin clustering and cell junction formation (Anastasiadis et al., 2000). RhoA-GDP forms a complex with p120ctn in the cytoplasm. Dissociation of GDP from RhoA is inhibited because of this trimer formation. In response to post-translational modification, such as tyrosine phosphorylation, p120ctn forms a tighter complex with cadherin-catenin complexes at the cell membrane. The cadherin-bound p120ctn dissociates from RhoA, resulting in the activation of RhoA by guanine nucleotide exchange factors (GEFs) such as Vav2. The exchange of GDP for GTP activates RhoA, which leads to downstream RhoA signaling events that promote cadherin clustering and junction formation. Therefore, cytoplasmic p120ctn regulates specific signaling events at the cell membrane, but this does not preclude the role of nuclear p120ctn in signal transduction.

In response to a putative external signal, p120ctn translocates to the nucleus where it binds Kaiso transcription factor, suggesting that p120ctn regulates transcriptional activity of unidentified target genes (Daniel and Reynolds, 1999; Van Hengel et al., 1999; Mariner et al., 2000). Kaiso interacts with p120, but does not form a complex with E-cadherin, a-catenin or ß-catenin, suggesting a mutually exclusive interaction of p120ctn with either Kaiso or E-cadherin. Kaiso is a DNA-binding protein that recognizes a specific consensus sequence and methylated CpG dinucleotides (Daniel et al., 2002; Prokhortchouk et al., 2001). Kaiso is ubiquitously expressed in a panel of cell lines that includes human breast cancer cell lines MCF-7 and MDA-MB-231. However, human prostate cancer cell lines have not yet been characterized with respect to Kaiso protein expression.

3.6. p120ctn isoforms

Most cell types express alternatively spliced isoforms of p120ctn (Anastasiadis and Reynolds, 2000; Thoreson and Reynolds, 2002; Staddon et al., 1995). The following nomenclature is used to distinguish the multiple isoforms of p120ctn (Figure 4). Four different ATG start sites at the N-terminal are used to generate p120 isoforms type 1, 2, 3 and 4. While all four isoforms contain a central armadillo domain with ten arm repeats, only p120 isoform 1 contains a putative coiled-coil domain. The significance of this domain in tumorigenesis is not completely understood. All p120ctn isoforms contain a loop in arm repeat 6, which is thought to act as a nuclear localization signal. C-terminal splicing of p120ctn, where exons A, B, C or none of the C-terminal exons are present adds to the complexity of p120ctn nomenclature. An additional A, B or C designation is included in p120ctn nomenclatrure, based on which C-terminal exon is present. For example, p120ctn 1BC refers to an isoform of p120ctn that is spliced at start site 1 in the N-terminus and contains exons B and C at the C-terminus. These four p120ctn isoforms are differentially expressed based on cell type, suggesting that each isoform may have a specific cellular function. For instance, macrophages and fibroblasts make N-cadherin and express the p120ctn 1A isoform, whereas epithelial cells make E-cadherin and express smaller isoforms such as p120ctn 3A (Anastasiadis and Reynolds, 2000). Based on alternative splicing, possible occurrence of up to 32 isoforms of p120ctn were found in human cells (Anastasiadis and Reynolds, 2000). As discussed above, it is well established that p120ctn interacts with E-cadherin, RhoA and the Kaiso transcription factor. However, the size and specific isoform(s) involved in these interactions remains to be determined. Delineation of the sub-cellular distribution (cytoplasmic vs nuclear) of p120ctn isoforms may provide some insight into the specific function of each.

Armadillo domain

ATGs

Armadillo domain

ATGs

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