Article |
Address correspondence to P.D. McCrea, Dept. of Biochemistry and Molecular Biology, Box 117, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030-4095. Tel.: (713) 792-8979. Fax: (713) 791-9478. email: pmccrea{at}odin.mdacc.tmc.edu
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: GTPase; actin cytoskeleton; cell adhesion; cell motility; morphogenesis
P.Z. Anastasiadis's present address is Mayo Clinic, Jacksonville, FL 32224.
Abbreviations used in this paper: ARVCF, armadillo repeat gene deleted in velo-cardio-facial syndrome; DA, dominant-active; DN, dominant-negative; EC, ectodomain; GDI, guanine nucleotide dissociation inhibitor; GEF, guanine nucleotide exchange factor; JMR, juxtamembrane; MO, morpholino oligonucleotide.
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The catenin proteins are distinguished by the various cellular compartments in which they function and the diversity of their protein associations, e.g., those occurring with the cytoplasmic domain of cadherins (plasma membrane; Gumbiner, 2000; Peifer and Polakis, 2000), Rho family GTPases (plasma membrane/cytoplasm; Anastasiadis and Reynolds, 2001), kinesin and microtubules (Chen et al., 2003; Yanagisawa et al., 2003; Franz and Ridley, 2004), and transcription factors (nucleus; Daniel and Reynolds, 1999; Kim et al., 2002; Bienz and Clevers, 2003). Certainly, the best characterized catenin family member is ß-catenin (McCrea et al., 1991), which transduces canonical Wnt signals in multiple developmental and pathological (cancer) contexts (Behrens, 2000; Sharpe et al., 2001).
The p120 catenin subfamily is lesser understood and exhibits functions distinct from ß-catenin (Sirotkin et al., 1997; Paulson et al., 1999; Anastasiadis and Reynolds, 2000). For example, at the plasma membrane, p120 and ARVCF competitively bind the membrane-proximal ("juxtamembrane") region of cadherin cytoplasmic domains (Mariner et al., 2000; Paulson et al., 2000), whereas ß-catenin and plakoglobin (-catenin) competitively bind the membrane-distal ("catenin-binding") domain and indirectly associate with the cortical actin cytoskeleton (Knudsen et al., 1995; Rimm et al., 1995). Recent papers further demonstrate the association of p120 with kinesin and microtubules (Chen et al., 2003; Franz and Ridley, 2004) and with the POZ/zinc finger transcription factor Kaiso (Daniel and Reynolds, 1999; Kim et al., 2002; Yanagisawa et al., 2003), whereas nuclear partners of ARVCF and
-catenin remain to be identified.
Arising from effects on cadherin stability and clustering (Ireton et al., 2002; Davis et al., 2003; Peifer and Yap, 2003; Xiao et al., 2003) or on small GTPases and the cell cytoskeleton, p120 is thought to positively or negatively regulate cell adhesion and motility (Brieher et al., 1996; Yap et al., 1998; Aono et al., 1999; Ohkubo and Ozawa, 1999; Paulson et al., 2000; Thoreson et al., 2000). For example, depending on p120's intracellular localization to cell junctions or the cytoplasm and free cell edges, p120 may promote cell adhesion versus motility via activation of Rac and Cdc42 and inhibition of RhoA (Anastasiadis et al., 2000; Anastasiadis and Reynolds, 2000, 2001; Noren et al., 2000; Grosheva et al., 2001; Magie et al., 2002). In this manner, p120 has been likened to a molecular switch contributing to both cell adhesion and motility.
The junctional organization and adhesive activity of cellcell contacts containing cadherins is further known to be responsive to Rho family GTPases (Braga, 2000; Fukata and Kaibuchi, 2001), which in turn are responsive to the levels and adhesive activity of cadherins (Kim et al., 2000; Nakagawa et al., 2001; Noren et al., 2001; Goodwin et al., 2003). Such functional interdependencies are believed to promote vertebrate gastrulation (Gumbiner, 2000; Tepass et al., 2000), wound healing, or pathologies, including a variety of human carcinomas (Behrens, 1999; Nollet et al., 1999; Anastasiadis and Reynolds, 2000; Van Aken et al., 2001; Thoreson and Reynolds, 2002).
At the biochemical level, the activation of Rac and Cdc42 by p120 appears to be mediated via its direct association with the guanine nucleotide exchange factor (GEF) Vav2 (Noren et al., 2000), which promotes the residence of GTP (as opposed to GDP) within the nucleotide binding pocket of Rho family GTPases such as Rac. In contrast, inhibition of RhoA is likely to occur as a consequence of direct p120RhoA complex formation in which p120 functions as a guanine nucleotide dissociation inhibitor (GDI; Anastasiadis et al., 2000; Magie et al., 2002), favoring the residence of GDP within RhoA's nucleotide binding pocket.
Because effectors of Rho family GTPases are numerous (Bishop and Hall, 2000), various outcomes likely follow p120 (or ARVCF) activation of Rac or Cdc42 or inhibition of RhoA. In addition to effects on the actin cell cytoskeleton, Rho family GTPases have roles in other essential biological processes, e.g., in transducing developmental signals within noncanonical Wnt pathways (Myers et al., 2002). Thus, although modulation of the actin cytoskeleton comprises a significant aspect of Rho family functions, each GTPase acts in additional cellular and developmental capacities.
Given cell line studies indicating that p120 modulates cadherin function and Rho family GTPases, we tested if p120 and/or ARVCF are required in early vertebrate development. Using early X. laevis embryos, we further assessed if ARVCF regulates Rac, Cdc42, and RhoA in a manner similar to that proposed for p120. Our work, conducted in X. laevis and using a depletion-rescue strategy in conjunction with biochemical and cell biological analyses, indicates that Xp120 and xARVCF are each developmentally essential, and that these two catenins share related functions in early embryogenesis via the stabilization of cadherin, activation of Rac, and inhibition of RhoA.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
Specificity of the xARVCF or Xp120 depletion phenotype indicated via self-rescue
To assess if the xARVCF or Xp120 depletion phenotype is specific, we tested the respective capacity of exogenous xARVCF or Xp120 to rescue their depletion in vivo. Indeed, morpholino-directed depletion of xARVCF was rescued upon expression of exogenous xARVCF (injection of in vitro transcribed mRNA), and likewise the depletion of Xp120 rescued upon expression of exogenous Xp120 (Fig. 3 and Tables I and II). Importantly, we used minimal rescuing doses of xARVCF or Xp120 mRNAs that had been titrated to exhibit no or very minimal effects when injected alone (Tables I and II). This process was required given that p120 perturbs development when expressed at higher doses (Geis et al., 1998; Paulson et al., 1999). Because nearly complete rescues followed minimal-dose injections of xARVCF or Xp120 mRNA, our depletion phenotypes likely resulted from the targeted reduction of xARVCF or Xp120. Furthermore, because our rescuing constructs lack any 5' UTR sequence, they did not complement (xARVCF-MOI and Xp120-MOI) or only partially complemented the morpholinos used (xARVCF-MOII and Xp120-MOII). Thus, the rescues are unlikely to have been successful as a consequence of morpholino sequestration, again suggesting the specificity of our observed phenotypes (see the following paragraph).
Depletion of xARVCF is partially rescued by exogenous Xp120 and vice versa
Because xARVCF and Xp120 are structurally similar members of the p120 sub-class of catenins, we assessed if depletion of one could be functionally compensated by increasing the level of the other. As in the aforementioned experiments, we assayed a range of Xp120 or xARVCF mRNA concentrations to optimize their potential effectiveness. We found that Xp120 largely cross-rescues depletion of xARVCF, and conversely, that xARVCF largely rescues codepletion of xARVCF and Xp120 (Fig. 4). Because the Xp120 and xARVCF mRNAs lack sequence complementarity in the regions targeted by their respective morpholinos, observed phenotypes likely resulted from selective xARVCF or Xp120 depletion (Figs. 1 and 2). However, complicating matters somewhat is that depletion of one catenin produced slight but measurable decreases of the other (not depicted), perhaps as an indirect consequence of lowered cadherin stability (Fig. 2) or an unknown indirect effect. In any case, given the cross-rescues, we propose that xARVCF and Xp120 share significant functional overlap in early vertebrate development (see following Results sections).
C-Cadherin partially rescues depletion of xARVCF or Xp120
Because the depletion of xARVCF or Xp120 resulted in slightly reduced C-cadherin levels (Figs. 1 and 2), we tested if exogenous C-cadherin would rescue embryogenesis in depleted embryos. We found that a carefully titrated level of C-cadherin mRNA rescued to a significant extent phenotypes arising from xARVCF or Xp120 depletion (Fig. 5), suggesting that reduced C-cadherin levels are contributory to our observed developmental phenotypes.
|
However, one functional strategy did suggest effects on C-cadherin adhesive function resulting from Xp120 depletion. A carefully titrated level of C-cadherin ectodomain (EC) construct partially rescued Xp120 depletion phenotypes (construct included the C-cadherin transmembrane domain but not cytoplasmic sequence; Fig. S5, available at http://www/jcb.org/cgi/content/full/jcb.200307109/DC1). C-Cadherin's juxtamembrane (JMR) domain also displayed partial rescuing activity in isolation (tethered to the inner plasma membrane via an engineered myristylation sequence), but to a lesser extent than the EC construct or native (full-length) C-cadherin (Fig. S5 and Fig. 5). Given that C-cadherin's EC reproducibly exhibited rescuing activity, we conjecture that the adhesive function of C-cadherin is reduced after Xp120 (or xARVCF) depletion, but to a subtle extent that is not readily detectable using accepted direct or indirect assays of cadherin function (Figs. S2S4).
xARVCF or Xp120 depletion inhibits morphogenic movements
To test depletion effects on cadherin-dependent morphogenic movements (convergent-extension), we used an ex vivo explant assay in which activin-induced naive ectoderm (animal caps) reflect aspects of the more elaborate in vivo process, wherein dorsal mesoderm cells polarize and converge toward the dorsal midline during gastrulation to drive mesoderm involution as well as subsequent embryo elongation along the anteriorposterior axis.
Naive ectoderm (animal caps) were excised from late blastula embryos (stage 9), and convergent-extension responses were scored after the addition (versus not) of activin, a member of the TGF-ß family of morphogenic factors. Consistent with our embryonic phenotypes (Fig. 3 and Tables I and II), animal caps depleted for xARVCF or Xp120 exhibited a significantly reduced ability to converge and extend (Fig. 6), suggesting that xARVCF and Xp120 contribute to the directed interdigitation of cells in vivo.
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Prior studies conducted in mammalian cell lines are consistent with a number of these observations (Anastasiadis et al., 2000; Noren et al., 2000; Anastasiadis and Reynolds, 2001; Grosheva et al., 2001). Interestingly, the neural cell-specific -catenin was also shown to functionally interact with RhoA (and cortactin), suggesting that multiple members of the p120 subfamily may interact with small GTPases (Martinez et al., 2003). Thus, in both embryological and cell line contexts, it appears that ARVCF and p120 inhibit RhoA while activating Rac. A question that arises is if xARVCF and Xp120 are redundant with respect to functional interactions with Rho family GTPases or other molecular pathways. Certainly, each catenin's presence is required in the embryo given that xARVCF or Xp120 depletion results in perturbed gastrulation. Furthermore, because xARVCF or Xp120 depletion does not result in the complete absence of either protein product, the nondepleted (surviving) fraction of each catenin is likely to continue executing a subset of xARVCF- versus Xp120-specific functions, which will escape phenotypic detection. Thus, we propose that xARVCF or Xp120 have required and overlapping relationships with Rho family GTPases and cadherins during early X. laevis embryogenesis, while additional functions unique to one or the other catenin exist and likely play important biological roles.
In the mouse, ARVCF or p120 knockouts have not yet been published, although work in progress indicates that the functional inactivation of p120 is embryonic lethal (Reynolds, A., L. Elia, and L. Reichardt, personal communications). However, in Drosophila melanogaster or Caenorhabditis elegans, deletion or depletion (siRNA) of the single p120/ARVCF-like gene product surprisingly results in animals of wild-type appearance and fertility (Myster et al., 2003; Pettitt et al., 2003). However, genetic backgrounds sensitized for cadherin/junctional function reveal significant genetic interactions when crossed with p120-deficient animals, indicating their coupled contribution to invertebrate development. Furthermore, flies deficient in RhoA (D. melanogaster Rho1) display functional interactions with p120 (siRNA depletion), while biochemical tests demonstrated RhoA's direct physical association with p120 and -catenin (Magie et al., 2002). Thus, although both invertebrate and vertebrate p120/ARVCF appear to interact with Rho family GTPases and with cadherins, the respective impact of reducing p120/ARVCF function differs with vertebrates exhibiting the greater functional dependence.
In our work, effects arising from the morpholino-directed depletion of xARVCF or Xp120 were largely rescued by exogenous introduction of titrated levels of DN-RhoA, DA-Rac, or C-cadherin. Each of those embryonic rescues can be accounted for if endogenous xARVCF/Xp120 inhibits RhoA, activates Rac, and contributes to the function/stabilization of cadherins. We are uncertain as to why human ARVCF overexpression was earlier found to lack activity in producing a dendritic phenotype in mammalian cells (Anastasiadis et al., 2000), but the distinction may conceivably be due to a difference in construct expression levels or an isoform or mutational difference (indeed, upon sequencing the human ARVCF construct used in the other work, we detected a PL transition at amino acid 222). In any case, consistent with xARVCF acting as an inhibitor/GDI of RhoA in vivo, we find that xARVCF (and Xp120) coprecipitates with DN-RhoA from X. laevis extracts and that DA-RhoA rescues the dendritic phenotype of NIH-3T3 cells overexpressing xARVCF. Thus, we expect that xARVCF is an inhibitor/GDI of RhoA as demonstrated for p120 (Anastasiadis et al., 2000; Magie et al., 2002). In further likeness to p120 (Noren et al., 2000), we find that xARVCF biochemically associates with Vav2, an activator/GEF of Rac, and more impressively that the embryonic depletion of xARVCF (or Xp120) is rescued by DA-Rac. Finally, xARVCF or Xp120 depletion results in reduced C-cadherin levels, which when exogenously increased, rescues normal embryogenesis. As indicated in recent papers (Fujita et al., 2002; Ireton et al., 2002; Davis et al., 2003; Xiao et al., 2003), we expect that the mechanism by which xARVCF and Xp120 protein levels are coupled to that of C-cadherin involves the catenins' modulation of the complex's metabolic stability.
Given that DN-Rho, DA-Rac, and C-cadherin rescue xARVCF or Xp120 depletion in vivo, all five proteins likely have coupled functions in embryogenesis. For example, exogenous DA-Rac or DN-Rho have the capacity to compensate for reduced C-cadherin protein levels after xARVCF or Xp120 depletion, perhaps by enhancing the remaining cadherin adhesive (extracellular) and/or signaling (intracellular) function. As alluded to previously, a further possibility is that rescues mediated by DN-Rho and DA-Rac occur via effects on cadherin metabolic stability by way of modulating cadherin endocytosis/destruction or delivery to the plasma membrane (Akhtar and Hotchin, 2001; Fujita et al., 2002; Le et al., 2002; Paterson et al., 2003; Yanagisawa et al., 2003).
Developmental events such as gastrulation require cadherins to be organized in a fashion that is responsive to developmental cues (Gumbiner, 1996; Keller et al., 2000; Tepass et al., 2000). Given the partial reductions in C-cadherin levels observed after xARVCF or xp120 depletion, we were surprised that few effects were evident using various cellcell adhesion or tissue integrity assays. One possibility is that C-cadherin extracellular adhesive activity is indeed reduced but occurs too subtly to be detected in the assays used. This view is supported by our observation that of the partial C-cadherin constructs tested, the EC produced the largest fractional rescue of embryos depleted for xARVCF or Xp120. Further, it is possible that C-cadherin's intracellular signaling (Rac activation?) capacity is reduced upon xARVCF or Xp120 depletion as a simple consequence of lessened C-cadherin levels, perhaps accounting for the fractional capacity of C-cadherin's JMR domain to rescue Xp120 depletion. Interestingly, because JMR mutants incapable of direct associations with xARVCF or Xp120 continued to display fractional rescuing activities, unknown JMR associations are likely to play a significant role in C-cadherin's cytoplasmic rescuing activity (Fedor-Chaiken et al., 2003; Ozawa, 2003). In any case, various laboratories will undoubtedly continue to direct attention to the role of cadherin in activating or inhibiting Rho family members (outside-in signaling; Kim et al., 2000; Nakagawa et al., 2001; Noren et al., 2001; Goodwin et al., 2003) as well as the activity of Rho family GTPases on cadherin function (inside-out signaling; Wunnenberg-Stapleton et al., 1999; Braga, 2000; Fukata and Kaibuchi, 2001; Ehrlich et al., 2002; Magie et al., 2002). Our principal contribution here is in demonstrating that ARVCF and p120 are required for vertebrate development and that each catenin is closely functionally linked to cadherin, RhoA, and Rac in vivo.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
X. laevis embryos and microinjection
X. laevis females were induced to lay eggs, which were fertilized and microinjected using published procedures (Montross et al., 2000). MOs and mRNA constructs were microinjected into the animal hemisphere of one or two blastomeres in 1-, 2-, or 4-cell cleavage stage embryos. The embryos were placed within a solution of 5% ficoll in 1x MMR for culture at 18°C. The total volume of MOs and/or mRNA constructs injected was 20 nl, with the total doses of 20 or 40 ng for morpholinos, 0.02 ng for Xp120 or xARVCF mRNA, and 0.5 pg for RhoA or Rac mRNA. Embryonic phenotypes were observed and evaluated using a standard binocular dissecting microscope (model SMZ-U; Nikon).
RNA and in vitro transcription
The Xp120ctn isoform 1 (Xp120 iso1) construct was PCR generated using primers 5'-GAATTCGATGGATGAGCCAGAG-3' and 5'-GAATTCACACGCTGATCTTC-3' and subcloned into pCS2+MT (Myc epitope tag) at the EcoRI site (Kim et al., 2002). xARVCF isoform 1A (xARVCF-1A) construct was PCR generated using primers 5'-GCTCTAGAATGATGCAGGAACC-3' and 5'-GCTCTAGACCCAAAAAGGGTCACTGC-3' and subcloned into pCS2+HA (HA epitope tag) at the XbaI site (Kim et al., 2002).
RhoA and Rac (rat) constructs were a gift from M. Symons (North Shore Long Island Jewish Research Institute, Bronx, NY). They were moved from the original EXV vector by EcoRI digestion and subcloned into the EcoRI site of pCS2+.
Capped mRNAs encoding these constructs were generated in vitro using the SP6 mMessage mMachine kit (Ambion) according to the manufacturer's protocol. Unincorporated nucleotides were removed by filtration through Sephadex G-50 Quick Spin Columns (Roche Applied Science). The quantity and quality of transcribed mRNA products were evaluated on the basis of migration within 1% agarose formaldehyde gels and by optical density (OD 280/260).
Antibodies
Xp120 polyclonal antibodies were generated against the NH2- or COOH-terminal domains of Xp120 (corresponding to amino acids 43176 and 789860). Each fragment was subcloned into the pQE32 vector having an NH2-terminal 6x His tag (QIAexpress System; QIAGEN). The 6x His-Xp120 fusion proteins were expressed and purified using Ni-NTA matrices according to the manufacture's instructions (QIAGEN) and raised at the institutional antibody core facility (University of Texas M.D. Anderson Cancer Center). The xARVCF polyclonal antibody was generated as described previously (Paulson et al., 2000). The C-cadherin polyclonal antibody was generated against the EC of X. laevis C-cadherin protein purified in the same manner as Xp120 but was raised by Sigma-Genosys. Actin polyclonal antibody was purchased from Sigma-Aldrich.
Western blots
To evaluate endogenous or exogenous protein levels, embryos were harvested at the indicated developmental stages and lysates were prepared for SDS-PAGE/Western blotting according to published procedures (1:5,000 dilution of antibodies directed against xARVCF, Xp120 NH2 terminus, Xp120 COOH terminus, or C-cadherin; Kim et al., 2002).
Explant elongation assay
Morpholino oligos and/or mRNAs were injected at the 2-cell stage in the animal pole region of both blastomeres. Animal caps were dissected from injected embryos at stage 8 and incubated at 18°C overnight in 0.4x MMR with or without human activin A (R&D Systems) at a final concentration of 20 ng/ml. Elongations of the isolated animal caps were evaluated using a standard binocular dissecting microscope (model SMZ-U; Nikon).
Immunofluorescence of NIH-3T3 cells
Immunofluorescence localization procedures have been described previously (Anastasiadis et al., 2000). The primary antibodies used were directed against xARVCF (polyclonal, 1:20,000) or Myc (9E10 monoclonal, 1 µg/ml). Antimurine-p120 mAb 12F4 was used in positive control assays (1 µg/ml). The secondary antibodies used were cross-absorbed goat antimouse Alexa 488 (green; Molecular Probes) and goat antirabbit Alexa 596 (red; Molecular Probes; 1:600 dilutions). Coverslips were mounted on glass slides using PolyMount (Polysciences, Inc.) and visualized under a fluorescent microscope (model Optiphot 2; Nikon) with Plan Fluor (Nikon) 40x magnification (0.85 numerical aperture). Photos were acquired with the Metamorph program using a CCD camera (model CoolSnap Fx; Photometrics) and compiled in Photoshop and PowerPoint.
Image acquisition and manipulation
Image acquisition and manipulation procedures are described elsewhere in Materials and methods in accordance with the indicated assays.
Online supplemental material
Eight supplemental figures and legends indicate the following: (a) cellcell interactions or tissue integrity is not graphically altered upon xARVCF or Xp120 depletion (Figs. S1S4); (b) C-cadherin deletion or point mutants partially rescue Xp120 depletion (Fig. S5); (c) DA-Cdc42, DA-Rho, or DN-Rac do not rescue xARVCF or Xp120 depletion (Fig. S6); (d) xARVCF coimmunoprecipitates with Vav2 (Fig. S7); and (e) xARVCF and Xp120 coimmunoprecipitate with DN-RhoA from X. laevis embryo extracts (Fig. S8). Online supplemental material is available at http://www/jcb.org/cgi/content/full/jcb.200307109/DC1.
![]() |
Acknowledgments |
---|
X. Fang, S.-W. Kim, J.-I. Park, T.G. Vaught, H. Ji, and this work were supported by a grant from the National Institutes of Health (RO1 GM52112) to P.D. McCrea. T.G. Vaught was partially supported by a National Institutes of Health training grant (GM-5-T32-HD07325). DNA sequencing and other core facilities were supported by a University of Texas M.D. Anderson Cancer Center National Cancer Institute core grant (CA-16672).
Submitted: 16 July 2003
Accepted: 27 February 2004
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Akhtar, N., and N.A. Hotchin. 2001. RAC1 regulates adherens junctions through endocytosis of E-cadherin. Mol. Biol. Cell. 12:847862.
Anastasiadis, P.Z., and A.B. Reynolds. 2000. The p120 catenin family: complex roles in adhesion, signaling and cancer. J. Cell Sci. 113:13191334.
Anastasiadis, P.Z., and A.B. Reynolds. 2001. Regulation of Rho GTPases by p120-catenin. Curr. Opin. Cell Biol. 13:604610.[CrossRef][Medline]
Anastasiadis, P.Z., S.Y. Moon, M.A. Thoreson, D.J. Mariner, H.C. Crawford, Y. Zheng, and A.B. Reynolds. 2000. Inhibition of RhoA by p120 catenin. Nat. Cell Biol. 2:637644.[CrossRef][Medline]
Angres, B., A.H.J. Müller, J. Kellermann, and P. Hausen. 1991. Differential expression of two cadherins in Xenopus laevis. Development. 111:829844.[Abstract]
Aono, S., S. Nakagawa, A.B. Reynolds, and M. Takeichi. 1999. p120ctn acts as an inhibitory regulator of cadherin function in colon carcinoma cells. J. Cell Biol. 145:551562.
Behrens, J. 1999. Cadherins and catenins: role in signal transduction and tumor progression. Cancer Metastasis Rev. 18:1530.[CrossRef][Medline]
Behrens, J. 2000. Control of beta-catenin signaling in tumor development. Ann NY Acad Sci. 910:2133; discussion 3335.
Bienz, M., and H. Clevers. 2003. Armadillo/beta-catenin signals in the nucleusproof beyond a reasonable doubt? Nat. Cell Biol. 5:179182.[CrossRef][Medline]
Bishop, A.L., and A. Hall. 2000. Rho GTPases and their effector proteins. Biochem. J. 348(Pt 2):241255.[Medline]
Braga, V. 2000. Epithelial cell shape: cadherins and small GTPases. Exp. Cell Res. 261:8390.[CrossRef][Medline]
Brieher, W.M., A.S. Yap, and B.M. Gumbiner. 1996. Lateral dimerization is required for the homophilic binding activity of C-cadherin. J. Cell Biol. 135:487496.[Abstract]
Chen, X., S. Kojima, G.G. Borisy, and K.J. Green. 2003. p120 catenin associates with kinesin and facilitates the transport of cadherincatenin complexes to intercellular junctions. J. Cell Biol. 163:547557.
Choi, Y.S., R. Sehgal, P. McCrea, and B. Gumbiner. 1990. A cadherin-like protein in eggs and cleaving embryos of Xenopus laevis is expressed in oocytes in response to progesterone. J. Cell Biol. 110:15751582.[Abstract]
Daniel, J.M., and A.B. Reynolds. 1999. The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol. Cell. Biol. 19:36143623.
Davis, M.A., R.C. Ireton, and A.B. Reynolds. 2003. A core function for p120-catenin in cadherin turnover. J. Cell Biol. 163:525534.
Ehrlich, J.S., M.D. Hansen, and W.J. Nelson. 2002. Spatio-temporal regulation of Rac1 localization and lamellipodia dynamics during epithelial cell-cell adhesion. Dev. Cell. 3:259270.[Medline]
Fedor-Chaiken, M., T.E. Meigs, D.D. Kaplan, and R. Brackenbury. 2003. Two regions of cadherin cytoplasmic domains are involved in suppressing motility of a mammary carcinoma cell line. J. Biol. Chem. 278:5237152378.
Franz, C.M., and A.J. Ridley. 2004. p120 Catenin associates with microtubules: inverse relationship between microtubule binding and Rho GTPase regulation. J. Biol. Chem. 279:65886594.
Fujita, Y., G. Krause, M. Scheffner, D. Zechner, H.E. Leddy, J. Behrens, T. Sommer, and W. Birchmeier. 2002. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat. Cell Biol. 4:222231.[CrossRef][Medline]
Fukata, M., and K. Kaibuchi. 2001. Rho-family GTPases in cadherin-mediated cell-cell adhesion. Nat. Rev. Mol. Cell Biol. 2:887897.[CrossRef][Medline]
Geis, K., H. Aberle, M. Kuhl, R. Kemler, and D. Wedlich. 1998. Expression of the Armadillo family member p120cas1B in Xenopus embryos affects head differentiation but not axis formation. Dev. Genes Evol. 207:471481.[CrossRef][Medline]
Goodwin, M., E.M. Kovacs, M.A. Thoreson, A.B. Reynolds, and A.S. Yap. 2003. Minimal mutation of the cytoplasmic tail inhibits the ability of E-cadherin to activate rac but not PI3-kinase. Direct evidence of a role for cadherin-activated Rac signaling in adhesion and contact formation. J. Biol. Chem. 278:2053320539.
Grosheva, I., M. Shtutman, M. Elbaum, and A.D. Bershadsky. 2001. p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell-cell contact formation and regulation of cell locomotion. J. Cell Sci. 114:695707.
Gumbiner, B.M. 1996. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 84:345357.[Medline]
Gumbiner, B.M. 2000. Regulation of cadherin adhesive activity. J. Cell Biol. 148:399404.
Heasman, J., M. Kofron, and C. Wylie. 2000. Beta-catenin signaling activity dissected in the early Xenopus embryo: a novel antisense approach. Dev. Biol. 222:124134.[CrossRef][Medline]
Ireton, R.C., M.A. Davis, J. van Hengel, D.J. Mariner, K. Barnes, M.A. Thoreson, P.Z. Anastasiadis, L. Matrisian, L.M. Bundy, L. Sealy, et al. 2002. A novel role for p120 catenin in E-cadherin function. J. Cell Biol. 159:465476.
Keller, R., L. Davidson, A. Edlund, T. Elul, M. Ezin, D. Shook, and P. Skoglund. 2000. Mechanisms of convergence and extension by cell intercalation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 355:897922.[CrossRef][Medline]
Kim, S.H., Z. Li, and D.B. Sacks. 2000. E-cadherin-mediated cell-cell attachment activates Cdc42. J. Biol. Chem. 275:3699937005.
Kim, S.W., X. Fang, H. Ji, A.F. Paulson, J.M. Daniel, M. Ciesiolka, F. van Roy, and P.D. McCrea. 2002. Isolation and characterization of XKaiso, a transcriptional repressor that associates with the catenin Xp120(ctn) in Xenopus laevis. J. Biol. Chem. 277:82028208.
Knudsen, K.A., A.P. Soler, K.R. Johnson, and M.J. Wheelock. 1995. Interaction of -actinin with the cadherin/catenin cellcell adhesion complex via
-catenin. J. Cell Biol. 130:6777.[Abstract]
Le, T.L., S.R. Joseph, A.S. Yap, and J.L. Stow. 2002. Protein kinase C regulates endocytosis and recycling of E-cadherin. Am. J. Physiol. Cell Physiol. 283:C489C499.
Magie, C.R., D. Pinto-Santini, and S.M. Parkhurst. 2002. Rho1 interacts with p120ctn and alpha-catenin, and regulates cadherin-based adherens junction components in Drosophila. Development. 129:37713782.[Medline]
Mariner, D.J., J. Wang, and A.B. Reynolds. 2000. ARVCF localizes to the nucleus and adherens junction and is mutually exclusive with p120(ctn) in E-cadherin complexes. J. Cell Sci. 113:14811490.
Martinez, M.C., T. Ochiishi, M. Majewski, and K.S. Kosik. 2003. Dual regulation of neuronal morphogenesis by a -catenincortactin complex and Rho. J. Cell Biol. 162:99111.
McCrea, P.D., C.W. Turck, and B. Gumbiner. 1991. A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin. Science. 254:13591361.[Medline]
Montross, W.T., H. Ji, and P.D. McCrea. 2000. A beta-catenin/engrailed chimera selectively suppresses Wnt signaling. J. Cell Sci. 113:17591770.
Myers, D.C., D.S. Sepich, and L. Solnica-Krezel. 2002. Convergence and extension in vertebrate gastrulae: cell movements according to or in search of identity? Trends Genet. 18:447455.[CrossRef][Medline]
Myster, S.H., R. Cavallo, C.T. Anderson, D.T. Fox, and M. Peifer. 2003. Drosophila p120catenin plays a supporting role in cell adhesion but is not an essential adherens junction component. J. Cell Biol. 160:433449.
Nakagawa, M., M. Fukata, M. Yamaga, N. Itoh, and K. Kaibuchi. 2001. Recruitment and activation of Rac1 by the formation of E-cadherin-mediated cell-cell adhesion sites. J. Cell Sci. 114:18291838.
Nollet, F., G. Berx, and F. van Roy. 1999. The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. Mol. Cell Biol. Res. Commun. 2:7785.[CrossRef][Medline]
Noren, N.K., B.P. Liu, K. Burridge, and B. Kreft. 2000. p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J. Cell Biol. 150:567580.
Noren, N.K., C.M. Niessen, B.M. Gumbiner, and K. Burridge. 2001. Cadherin engagement regulates Rho family GTPases. J. Biol. Chem. 276:3330533308.
Ohkubo, T., and M. Ozawa. 1999. p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity. J. Biol. Chem. 274:2140921415.
Ozawa, M. 2003. p120-independent modulation of E-cadherin adhesion activity by the membrane-proximal region of the cytoplasmic domain. J. Biol. Chem. 278:4601446020.
Paterson, A.D., R.G. Parton, C. Ferguson, J.L. Stow, and A.S. Yap. 2003. Characterization of E-cadherin endocytosis in isolated MCF-7 and chinese hamster ovary cells: the initial fate of unbound E-cadherin. J. Biol. Chem. 278:2105021057.
Paulson, A.F., X. Fang, H. Ji, A.B. Reynolds, and P.D. McCrea. 1999. Misexpression of the catenin p120(ctn)1A perturbs Xenopus gastrulation but does not elicit Wnt-directed axis specification. Dev. Biol. 207:350363.[CrossRef][Medline]
Paulson, A.F., E. Mooney, X. Fang, H. Ji, and P.D. McCrea. 2000. Xarvcf, Xenopus member of the p120 catenin subfamily associating with cadherin juxtamembrane region. J. Biol. Chem. 275:3012430131.
Peifer, M., and P. Polakis. 2000. Wnt signaling in oncogenesis and embryogenesisa look outside the nucleus. Science. 287:16061609.
Peifer, M., and A.S. Yap. 2003. Traffic control: p120-catenin acts as a gatekeeper to control the fate of classical cadherins in mammalian cells. J. Cell Biol. 163:437440.
Pettitt, J., E.A. Cox, I.D. Broadbent, A. Flett, and J. Hardin. 2003. The Caenorhabditis elegans p120 catenin homologue, JAC-1, modulates cadherincatenin function during epidermal morphogenesis. J. Cell Biol. 162:1522.
Rimm, D.L., E.R. Koslov, P. Kebriaei, C.D. Cianci, and J.S. Morrow. 1995. Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc. Natl. Acad. Sci. USA. 92:88138817.[Abstract]
Sharpe, C., N. Lawrence, and A. Martinez Arias. 2001. Wnt signalling: a theme with nuclear variations. Bioessays. 23:311318.[CrossRef][Medline]
Sirotkin, H., H. O'Donnell, R. DasGupta, S. Halford, B. St Jore, A. Puech, S. Parimoo, B. Morrow, A. Skoultchi, S.M. Weissman, P. Scambler, and R. Kucherlapati. 1997. Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome. Genomics. 41:75-83.[CrossRef][Medline]
Tepass, U., K. Truong, D. Godt, M. Ikura, and M. Peifer. 2000. Cadherins in embryonic and neural morphogenesis. Nat. Rev. Mol. Cell Biol. 1:91100.[CrossRef][Medline]
Thoreson, M.A., and A.B. Reynolds. 2002. Altered expression of the catenin p120 in human cancer: implications for tumor progression. Differentiation. 70:583589.[CrossRef][Medline]
Thoreson, M.A., P.Z. Anastasiadis, J.M. Daniel, R.C. Ireton, M.J. Wheelock, K.R. Johnson, D.K. Hummingbird, and A.B. Reynolds. 2000. Selective uncoupling of p120ctn from E-cadherin disrupts strong adhesion. J. Cell Biol. 148:189202.
Van Aken, E., O. De Wever, A.S. Correia da Rocha, and M. Mareel. 2001. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch. 439:725751.[Medline]
Wunnenberg-Stapleton, K., I.L. Blitz, C. Hashimoto, and K.W. Cho. 1999. Involvement of the small GTPases XRhoA and XRnd1 in cell adhesion and head formation in early Xenopus development. Development. 126:53395351.
Xiao, K., D.F. Allison, K.M. Buckley, M.D. Kottke, P.A. Vincent, V. Faundez, and A.P. Kowalczyk. 2003. Cellular levels of p120 catenin function as a set point for cadherin expression levels in microvascular endothelial cells. J. Cell Biol. 163:535545.
Yanagisawa, M., I.N. Kaverina, A. Wang, Y. Fujita, A.B. Reynolds, and P.Z. Anastasiadis. 2003. A novel interaction between kinesin and p120 modulates p120 localization and function. J. Biol. Chem. 279:95129521.[Medline]
Yap, A.S., C.M. Niessen, and B.M. Gumbiner. 1998. The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. J. Cell Biol. 141:779789.