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Signal Transducti Through [ -Catenin and Speclflcatlon°O Cell Fate During Embryogenesis

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Signal Transducti Through [ -Catenin and Speclflcatlon°O Cell Fate During Embryogenesis Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Signal transducti through [ -catenin and speclflcatlon°o cell fate during embryogenesis Jeffrey R. Miller and Randall T. Moon Howard Hughes Medical Institute and Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington 98195-7370 USA The development and maintenance of multicellular tis- sues requires that cells interact with their neighbors. These interactions include the adhesion of cells to one another, which induces the acquisition of cell polarity and promotes the assembly of cell-cell junctions. The S ..... modulation of these junctions is involved in the coordi- I nation of cell-shape changes and movements during GSK-3 ~f.~ degraded morphogenesis. In addition, cells interact with their neighbors via cell-surface and secreted signaling mole- ooo cules that may, among other things, specify responding CADHERIN /'~ cells to assume distinct developmental fates. The theo- MF MT retical synthesis of cell-junction function and signal transduction has increasingly focused on the product of the Drosophila segment polarity gene armadillo, and its vertebrate homolog 13-catenin, which are necessary for both cadherin-mediated cell-cell adhesion and for the transduction of signals involved in specifying cell fate (Gumbiner and McCrea 1993; Heasman et al. 1994; Gumbiner 1995; Haegel et al. 1995; Klymkowsky and Parr 1995; Peifer 1995). The roles of ~-catenin in both cell-cell adhesion and in signal transduction in embryos involve the association of ~3-catenin with different protein partners in distinct Figure 1. Relationships between the interaction of 13-catenin subcellular compartments (Fig. 1). Consistent with these with different protein partners, the intracellular localization of observations, endogenous Armadillo/~-catenin is O-catenin and the function of 13-catenin in cell adhesion, motil- present at the plasma membrane, in the cytoplasm, and ity, and signaling. Cytoplasmic ~-catenin (~) can interact with membrane-associated cadherin, a-catenin (a), and the adenom- in the nucleus (Riggleman et al. 1990; Fagotto and Gum- atous polyposis coli tumor suppressor protein (APC). In the cy- biner 1994; Peifer et al. 1994c; Schneider et al. 1996; toplasm ~3-catenin may interact with both glycogen synthase Yost et al. 1996). This review of f~-catenin emphasizes kinase-3 (GSK-3) and APC to regulate its stability, as well as the different protein partners with which it interacts, the downstream effectors of Wnt-1 signaling (X), resulting in trans- likely functions of ~-catenin in distinct subcellular com- location to the nucleus. As shown in greater detail in Fig. 3, the partments, and how dynamic regulatory processes, such accumulation of ~-catenin in the cytosol and nucleus is regu- as the responses to the Wnt-1 signal transduction path- lated by Wnt-1 signaling, which increases the steady-state lev- way, may lead to ~-catenin entering the nucleus and par- els of f~-catenin. (MF)Microfilaments; (MT)microtubules; (dsh) ticipating in regulating gene expression and cell fate. dishevelled. Adhesion roles of 13-catenin at the plasma membrane tinct types of junctions are present in vertebrate cells: Cell-cell junctions are specialized macromolecular tight junctions, adherens junctions, desmosomes, and structures that are essential for both intercellular adhe- gap junctions, each possessing a different array of protein sion and communication (Woods and Bryant 1993; Kirk- components with unique functional characteristics. patrick and Peifer 1995; Gumbiner 1996}. Several dis- Tight junctions form seals that prevent solutes from GENES & DEVELOPMENT 10:2527-2539 © 1996 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/96 $5.00 2527 Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Miller and Moon freely passing across epithelial tissues, whereas gap junc- Another catenin, p120, which was originally identified tions allow for transport of ions and small molecules as a substrate of Src and several receptor tyrosine kinases between cells. Adherens junctions and desmosomes play (Reynolds et al. 1989, 1992; Kanner et al. 1990, 1991; an adhesive as well as an architectural role in epithelia Downing and Reynolds 1991) and a related protein, pl00, by providing a link between cell-surface adhesion mole- also interact with the cadherin-f~-catenin complex cules and the cytoskeleton. In addition to a role in cell (Reynolds et al. 1994; Aghib and McCrea 1995; Shibam- adhesion, adherens junctions are also communication oto et al. 1995; Staddon et al. 1995) and may participate centers necessary for transducing signals from neighbor- in regulating the adhesive function of cadherins. Simi- ing cells and the environment (for review, see Gumbiner larly, a pl20-related protein (plakophilin)is associated 1996). The importance of cell-cell junctions, and espe- with desmosomes (Hatzfeld et al. 1994). cially adherens junctions, in regulating cellular physiol- That ~-catenin is important for the adhesive functions ogy is underscored by the high number of tumor suppres- of adherens junctions is evident from a range of studies. sor gene products that are components of these junctions For example, Armadillo/f~-catenin is required for adhe- (Tsukita et al. 1991; Woods and Bryant 1993; Kirkpatrick rens junction assembly during oogenesis (Peifer et al. and Peifer 1995). 1993) and normal embryonic development in Drosophila The adhesive function of adherens junctions is depen- (Cox et al. 1996). Second, the disruption of f~-catenin dent on members of the cadherin superfarnily and the genes in mouse embryos results in detachment of ecto- cytoplasmic adaptor proteins c~-, ~-, and ~/-catenin/pla- dermal cells in the embryo, consistent with reduced cell koglobin {Fig. 2; for review, see Kemler 1993; Gumbiner adhesion {Haegel et al. 1995). Moreover, expression of a 1996). Cadherins are Ca2+-dependent adhesion mole- truncated [3-catenin leads to a loss of cell adhesion in cules that bind homotypically to identical cadherin mol- human cancer cell lines (Oyama et al. 1994). ecules on apposing cells (Takeichi 1995). f~-Catenin in- In addition to the aforementioned interaction of [3-cat- teracts directly with the cytoplasmic domain of cadher- enin and ~/-catenin/plakoglobin with cadherins at the ins (Nagafuchi and Takeichi 1989; Ozawa and Kernler plasma membrane, it has been suggested that discrete 1992; Aberle et al. 1994; Jou et al. 1995) and forms a regions of the cell cortex may exhibit high levels of the complex with a-catenin, a cytoplasmic protein similar to adenomatous polyposis coli (APC) tumor suppressor pro- vinculin (Aberle et al. 1994; Hinck et al. 1994a; Jou et al. tein (Nathke et al. 1996), which binds ~-catenin (Mune- 1995), which links actin filaments to the adherens junc- mitsu et al. 1995), ~/-catenin/plakoglobin (Rubinfeld et tion (Hirano et al. 1987; Rirnm et al. 1995). ~/-Catenin/ al. 1995), and microtubules (Smith et al. 1994; Mune- plakoglobin is structurally related to B-catenin and is mitsu et al. 1994). These interactions with APC may likely to play a similar role to that of ~-catenin in regu- modulate catenin stability (Munemitsu et al. 1995)and, lating cadherin adhesive activity in adherens junctions, speculatively, reduce the availability of catenins for in- as well as modulating the activity of desmosomal cad- teraction with cadherins, thereby affecting cell adhesion herins (Klymkowsky and Parr 1995; Gumbiner 1996). and migration (Nathke et al. 1996). ,z CADHERIN Figure 2. f~-Catenin associates with cell- MT surface proteins involved in cell adhesion, signaling, and migration. Both f~-catenin and ~-catenin/plakoglobin bind cadherin and ~-catenin, linking transmembrane cad- herin cell adhesion molecules to the actin cytoskeleton (MF). Altered tyrosine phos- phorylation (Y-PO4)of f~-catenin often co- src, ras (/ incides with the disassembly of adherens junctions and diminished cell adhesion in response to growth factors and cell trans- formation, f~-Catenin also colocalizes with some membrane-associated APC in migrat- D --_2-2 ing cells (ruffled membrane on right)sug- gesting that localized degradation of B-cat- EGF-R enin could play a role in controlling the ....-~7:7 protrusive behavior of motile cells (Nathke et al. 1996). 2528 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Signal transduction through [3-catenin Phosphorylation of [3-catenin at the plasma membrane strate a correlation between altered tyrosine phosphory- lation of f~-catenin and the regulation of cell adhesion, Recent evidence demonstrates the importance of ~-cat- further studies are necessary to understand this relation- enin-cadherin interactions in modulating cell adhesion, ship. Finally, phosphorylation of Armadillo/f~-catenin at cell migration, and epithelial phenotype in embryonic the plasma membrane also occurs at non-tyrosine resi- development and tumorigenesis (Birchmeier et al. 1993; dues in Drosophila embryos. Specifically, membrane-as- Kirkpatrick and Peifer 1995; Klymkowsky and Parr sociated Armadillo is more highly phosphorylated on 1995; Drubin and Nelson 1996). These interactions of both Set/Thr and on Tyr residues than soluble Armadillo f~-catenin and cadherin, and consequently cell adhesion, (Peifer et al. 1994b), though it is somewhat unclear may be regulated in part through phosphorylation
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