α-Catenin Can Form Asymmetric Homodimeric Complexes and/or Heterodimeric Complexes with ॆ-Catenin

Koslov, Erika R.; Maupin, Pam; Pradhan, Deepti; Morrow, Jon S.; Rimm, David L.

doi:10.1074/jbc.272.43.27301

Cited by 77 publications

(61 citation statements)

References 25 publications

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“…CTNNA1 encodes the protein -E-catenin, which functions in a complex with -catenin where it binds the cytoplasmic domain of E-cadherin to the cytoskeleton [36,37]. -E-catenin inhibition has been shown to destabilize adherens junctions, weakening the interaction between cells [38].…”

Section: Genetics Of Hdgcmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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Familial clustering is seen in 10% of gastric cancer cases and approximately 1-3% of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis.Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterised by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT>1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.6

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Section: Genetics Of Hdgcmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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“…5A), which interacts with a region of ␤-catenin partially encompassing its N-terminal domain and its first armadillo repeat (41,42). As seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

The first armadillo repeat is involved in the recognition and regulation of β-catenin phosphorylation by protein kinase CK1

Bustos

Ferrarese

Venerando

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Multiple phosphorylation of ␤-catenin by glycogen synthase kinase 3 (GSK3) in the Wnt pathway is primed by CK1 through phosphorylation of Ser-45, which lacks a typical CK1 canonical sequence. Synthetic peptides encompassing amino acids 38 -64 of ␤-catenin are phosphorylated by CK1 on Ser-45 with low affinity (Km Ϸ1 mM), whereas intact ␤-catenin is phosphorylated at Ser-45 with very high affinity (Km Ϸ200 nM). Peptides extended to include a putative CK1 docking motif (FXXXF) at 70 -74 positions or a F74AA mutation in full-length ␤-catenin had no significant effect on CK1 phosphorylation efficiency. ␤-Catenin C-terminal deletion mutants up to residue 181 maintained their high affinity, whereas removal of the 131-181 fragment, corresponding to the first armadillo repeat, was deleterious, resulting in a 50-fold increase in Km value. Implication of the first armadillo repeat in ␤-catenin targeting by CK1 is supported in that the Y142E mutation, which mimics phosphorylation of Tyr-142 by tyrosine kinases and promotes dissociation of ␤-catenin from ␣-catenin, further improves CK1 phosphorylation efficiency, lowering the Km value to <50 nM, approximating the physiological concentration of ␤-catenin. In contrast, ␣-catenin, which interacts with the N-terminal region of ␤-catenin, prevents Ser-45 phosphorylation of CK1 in a dosedependent manner. Our data show that the integrity of the N-terminal region and the first armadillo repeat are necessary and sufficient for high-affinity phosphorylation by CK1 of Ser-45. They also suggest that ␤-catenin association with ␣-catenin and ␤-catenin phosphorylation by CK1 at Ser-45 are mutually exclusive.casein kinase 1 ͉ Wnt pathway ͉ substrate recruitment ͉ ␣-catenin P rotein kinase CK1 (formerly casein kinase 1) makes up a separate subfamily within the superfamily of eukaryotic protein kinases (1). In vertebrates, there are genes encoding for seven CK1 isoforms (␣, ␤, ␥1, ␥2, ␥3, ␦, and ), which also generate different proteins through alternative splicing (2-5). All CK1 isoforms display a high degree of sequence identity within their kinase domains (Ͼ50%), but they differ significantly in their N-and C-terminal extensions.CK1 has been implicated in a wide variety of cellular processes, including chromosome segregation (6, 7), spindle formation (8-10), circadian rhythm (11), nuclear import (12), Wnt pathway (13-18), and apoptosis (19,20). Deregulation of CK1 isoforms has been observed in neurodegenerative and sleeping disorders (21-23) and in cancer (24-27).Implication in so many functions implies the ability to recognize specifically the physiologically relevant phosphoacceptor sites in its protein targets. Pertinent to target site recognition is the perplexing question concerning the consensus sequence(s) recognized by CK1. Early studies, mostly performed with artificial substrates (casein and synthetic peptides), revealed that CK1 is a ''phosphate-directed'' protein kinase able to phosphorylate with high efficiency Ser/Thr residues specified by a prephosphorylated side chain (eith...

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“…Cells were washed twice in Hanks' balanced saline solution and incubated at 3 ϫ 10 5 cells/well in 500 l of Hanks' balanced saline solution containing 1% bovine serum albumin and 100 g/ml DNase (Worthington) with or without 1 mM CaCl 2 in the presence or absence of 80 g/ml antibodies to E-cadherin, P-cadherin, or N-cadherin. Aggregation assays were performed at 37°C at 100 rpm for 20 min in triplicate wells on in Competitive Inhibition Studies-Glutathione S-transferase (GST)-␣-catenin and GST-␤-catenin fusion proteins as well as GST alone and GST-spectrin fusion proteins used as controls were prepared as described (53). The GST fusion proteins were isolated by affinity chromatography on glutathione-agarose (Sigma) and eluted with 5 mM glutathione in 10 mM Tris, pH 8.0, 150 mM NaCl, 1 mM EDTA, and 1 mM dithiothreitol, followed by dialysis in glutathione-free buffer.…”

Section: Methodsmentioning

confidence: 99%

Vinculin Is Associated with the E-cadherin Adhesion Complex

Hazan¹,

Kang²,

Roe³

et al. 1997

Journal of Biological Chemistry

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156

130

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Cadherins mediate calcium-dependent cell-cell adhesion, and this activity is regulated by cytoplasmic interactions between cadherins, catenins, and the actinbased cytoskeleton. ␣-Catenin plays a critical role in the transmembrane anchorage of cadherins, and deletion of ␣-catenin has been shown to inactivate cadherin-mediated adhesion, resulting in a nonadhesive phenotype. Here we show that serum starvation increases E-cadherin expression and induces E-cadherin-dependent adhesion in the MDA-MB-468 breast cancer cell line. This adhesion occurred despite a lack of ␣-catenin expression, which was caused by mutations in the ␣-catenin gene. Coprecipitation analysis suggests that this adhesion may be mediated by cytoplasmic connections from cadherins to the cytoskeleton involving vinculin. A high level of vinculin associated with E-cadherin immunoprecipitates was observed in MDA-MB-468 cells. In contrast, vinculin was not detected in E-cadherin complexes in the A431 and MCF-7 epithelial carcinoma cell lines, which express ␣-catenin. However, in reciprocal immunoprecipitations using anti-vinculin antibodies, Ecadherin associated strongly with vinculin in MDA-MB-468 cells and, to a lesser extent, in A431 and MCF-7 cells. These results suggest that both ␣-catenin and vinculin may be present in the adhesion complex. To test the hypothesis that vinculin associates with E-cadherin complexes via ␤-catenin, excess recombinant ␤-catenin or ␣-catenin fusion protein was added to MDA-MB-468 cell lysates. Both specifically inhibited the coprecipitation of E-cadherin with vinculin, suggesting competition for the same binding site. These results suggest that vinculin plays a role in the establishment or regulation of the cadherin-based cell adhesion complex by direct interaction with ␤-catenin.Cadherins are calcium-dependent cell-cell adhesion molecules that mediate homotypic interactions among cells and are essential for tissue morphogenesis (for review, see Refs. 1 and 2). Adhesion via cadherins involves the coordination of extracellular binding and intracellular anchorage to the actin-based cytoskeleton. The cytoplasmic domain of E-cadherin binds to either ␤-catenin or plakoglobin/␥-catenin (for review, see , and this complex is coupled to the actin cytoskeleton by ␣-catenin, which binds to both ␤-catenin and actin (6, 7). There is evidence that ␣-catenin also binds to ␣-actinin (8, 9) and spectrin (10), but the role of these interactions in adhesion is unknown. Disruption of ␣-catenin function by genetic deletion or mutation was shown to cause a loss of E-cadherin-dependent adhesion. PC-9 lung carcinoma cells, which lack detectable ␣-catenin expression, were shown to have aberrant cell-cell adhesion (11) that was restored by transfection of these cells with ␣-catenin cDNA (12). This resulted in the establishment of a polarized epithelium and inhibition of cell growth (13). This and other work suggest that the linkage of cadherin complexes to the cytoskeleton via ␣-catenin is essential for normal cell adhesion, morphogenesis, and ...

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α-Catenin Can Form Asymmetric Homodimeric Complexes and/or Heterodimeric Complexes with ॆ-Catenin

Cited by 77 publications

References 25 publications

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

The first armadillo repeat is involved in the recognition and regulation of β-catenin phosphorylation by protein kinase CK1

Vinculin Is Associated with the E-cadherin Adhesion Complex

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