p120 - Journal of Cell Science 113 1319-1334(2000 Printed...

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INTRODUCTION p120 (p120 ctn , hereafter p120) was originally identified as a prominent substrate of the Src oncoprotein (Reynolds et al., 1989). cDNA cloning revealed that it contains an Armadillo- repeat domain (Arm domain) that shares 22% identity with that of the catenin Armadillo/ β -catenin (Reynolds et al., 1992; Peifer et al., 1994) and led to experiments that demonstrated its direct interaction with cadherins (Reynolds et al., 1994; Daniel and Reynolds, 1995; Staddon et al., 1995; Shibamoto et al., 1995; see Fig. 1). Cadherins comprise a superfamily of transmembrane cell-cell adhesion receptors that link adjacent cells via calcium-dependent homophillic interactions between the cadherin extracellular domains. They regulate a variety of biological processes, including development, morphogenesis, and tumor metastasis (for review see Takeichi, 1995; Yap, 1998). During tumor progression to malignancy, the aberrant loss of expression of epithelial cadherin (E-cadherin), the major cell-cell adhesion molecule in epithelial cells, is widely believed to mediate the transition to metastasis (Perl et al., 1998; reviewed by Yap, 1998). Cadherin function is modulated by a group of cytoplasmic proteins called catenins (i.e. α - catenin, β -catenin, plakoglobin and p120), which interact with the cadherin intracellular domain. Defects in catenin expression or function have also been linked to metastasis. A major role of catenins is to anchor the cadherin complex to the actin cytoskeleton. β -Catenin and plakoglobin act as bridges connecting E-cadherin to α -catenin, which in turn associates with actin filaments either directly (Herrenknecht et al., 1991; Nagafuchi et al., 1991; Rimm et al., 1995) or indirectly (Knudsen et al., 1995; Nieset et al., 1997). β -Catenin also has signaling roles in the cytoplasm and nucleus that are important in development and cancer. For example, β -catenin/armadillo is a key player in the Wnt/Wg signaling pathway, directly mediating downstream events through transactivation of transcription factors of the Lef1/TCF family (Molenaar et al., 1996; Behrens et al., 1996; van de Wetering et al., 1997) . In addition, β -catenin interacts directly with the tumor suppressor adenomatous polyposis coli (APC; Su et al., 1993; Rubinfeld et al., 1993). Inactivating mutations in APC, or activating mutations in β -catenin, cause the accumulation of β -catenin in the cytoplasm and nucleus, leading to constitutive signaling through interaction with Lef1/TCF (Munemitsu et al., 1995; Korinek et al., 1997; Rubinfeld et al., 1997). Collectively, defects in APC or β -catenin function are thought to account for initiation of the majority of human colon cancer (Powell et al., 1992; Morin et al., 1997) and a smaller percentage of melanoma (Rubinfeld et al., 1997). The well-characterized dual roles of β -catenin in adhesion and signaling establish an important paradigm for other Arm proteins, many of which are known to function as adhesion molecules (e.g. p120).
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This note was uploaded on 05/28/2010 for the course BIOLOGY 03234 taught by Professor Sochacka during the Spring '10 term at Ghent University.

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p120 - Journal of Cell Science 113 1319-1334(2000 Printed...

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