Mechanistic insights from structural studies of β-catenin and its binding partners

Xu, Wenqing; Kimelman, David

doi:10.1242/jcs.013771

Cited by 220 publications

(229 citation statements)

References 88 publications

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“…It was previously shown that Vac8p interacts with Vac17p and Atg13p, and these interactions play essential roles in vacuole inheritance and the CVT pathway, respectively (13,14). Additionally, β-catenin, a structural homolog of Vac8p, shares the typical inner groove formed from the ARM repeats that serves as an interacting platform for their various binding partners (19). We therefore wondered whether Vac8p would also share Nvj1p-binding regions with Vac17p or Atg13p proteins.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic insight into the nucleus–vacuole junction based on the Vac8p–Nvj1p crystal structure

Jeong

Park

Kim

et al. 2017

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

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Formation of the nucleus-vacuole junction (NVJ) is mediated by direct interaction between the vacuolar protein Vac8p and the outer nuclear endoplasmic reticulum membrane protein Nvj1p. Herein we report the crystal structure of Vac8p bound to Nvj1p at 2.4-Å resolution. Vac8p comprises a flexibly connected N-terminal H1 helix followed by 12 armadillo repeats (ARMs) that form a right-handed superhelical structure. The extended 80-Å-long loop of Nvj1p specifically binds the highly conserved inner groove formed from ARM1−12 of Vac8p. Disruption of the Nvj1p-Vac8p interaction results in the loss of tight NVJs, which impairs piecemeal microautophagy of the nucleus in Saccharomyces cerevisiae. Vac8p cationic triad (Arg276, Arg317, and Arg359) motifs interacting with Nvj1p are also critical to the recognition of Atg13p, a key component of the cytoplasm-to-vacuole targeting (CVT) pathway, indicating competitive binding to Vac8p. Indeed, mutation of the cationic triad abolishes CVT of Ape1p in vivo. Combined with biochemical data, the crystal structure reveals a Vac8p homodimer formed from ARM1, and this self-association, likely regulated by the flexible H1 helix and the C terminus of Nvj1p, is critical for Vac8p cellular functions. M embrane contact sites (MCSs) between subcellular compartments play pivotal roles in cellular processes such as cooperative lipid biosynthesis, ion homeostasis, and interorganellar trafficking of molecules in eukaryotic cells (1-3). MCSs are physically formed through dynamic and direct interactions between proteins that are located in two distinct subcompartments. The nucleus-vacuole junction (NVJ), one of the best-characterized MCSs, is a physical contact site between perinuclear and vacuolar membranes and mediates essential cellular processes such as piecemeal microautophagy of the nucleus (PMN) and lipid biosynthesis in yeast (4, 5). PMN is a selective autophagic recycling process stimulated by carbon or nitrogen starvation through the target of rapamycin signaling pathway in Saccharomyces cerevisiae. Upon nutrient starvation, the region of the nucleus in the vicinity of NVJs invaginates into the vacuolar lumen and forms a bleb-like structure, which is released as a vesicle and eventually degraded by vacuolar hydrolases (5, 6). Because PMN occurs at the NVJ sites, their formation is essential for the initiation of the PMN process (7). NVJs are also involved in lipid metabolism by recruiting the two lipid-modifying enzymes, oxystereol-binding proteins homology (Osh1p) involved in nonvesicular lipid trafficking and the enoyl-CoA reductase Tsc13p that mediates the synthesis of verylong-chain fatty acids (8-11).Previous studies revealed that NVJs are generated by forming tight interactions between Vac8p, a vacuolar membrane protein, and Nvj1p, a nuclear membrane protein (12). Vac8p was initially found as a key player in vacuole inheritance by cooperating with Vac17p, actin, profilin, and Myo2p (13). In addition, Vac8p has a crucial role in mediating the processing of aminopeptidase I through in...

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Section: Resultsmentioning

confidence: 99%

Mechanistic insight into the nucleus–vacuole junction based on the Vac8p–Nvj1p crystal structure

Jeong

Park

Kim

et al. 2017

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

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“…This latter effect was primarily dependent on ␤-catenin binding to TCF4 and not to other possible-binding partners (49) because expression of dnTCF4 virtually negated the FGF9-mediated induction of HD5 mRNA expression. These results are consistent with prior studies showing that the canonical Wnt pathway regulates Paneth cell differentiation and, possibly, specification of the Paneth cell lineage in the intestine through Wnt/Frizzled-5 signaling and through regulation of Sox9, an HMG-box transcription factor expressed in intestinal crypt cells, including Paneth cells (10 -12).…”

Section: Discussionmentioning

confidence: 95%

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Brodrick

Vidrich

Porter

et al. 2011

Journal of Biological Chemistry

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Fibroblast growth factor receptor-3 (FGFR-3Despite the critical importance of Paneth cells in maintaining gut homeostasis, knowledge of the pathways regulating Paneth cell differentiation and function has only recently begun to emerge. Studies using transgenic mice or mice with targeted mutations in epithelial regulatory genes, including components of the Wnt signaling pathway (Tcf4, Fz5, Sox9, and Apc), FGFR-3, and PPAR␤/␦, have identified these genes as key regulators of Paneth cell differentiation and expression of defensin peptides in vivo (9 -14). However, the lack of an adequate intestinal epithelial cell culture system that can recapitulate features of Paneth cell differentiation and maturation has hampered direct investigation of how these signaling pathways may interact in regulating Paneth cell differentiation and functional maturation.We recently reported that signaling through FGFR-3 in crypt epithelial cells regulates both the number of epithelial stem cells and Paneth cell differentiation during postnatal gut development (13,15). FGFR-3 is highly expressed along the membranes of cells in the lower portion of the crypt in the developing mouse intestine (15). FGFRs are members of the receptor-tyrosine kinase family. Ligand binding induces dimerization, autophosphorylation, and initiation of a signal transduction cascade that ultimately results in modification of gene expression. Ligands for FGFR-3, FGF1, FGF2, and FGF9, are up-regulated in the postnatal murine small intestine from birth through the suckling weaning transition, when crypt mor-

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“…Recently, the biological function of some classical arm repeat proteins have been well clarified. Such as β-catenin , a classical member of ARM family plays important roles both at cells adherence junctions and in Wnt signaling through interaction with E-cadherin and T cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors (Xu et al, 2007;Bass-Zubek et al, 2009). Tumor suppressor adenomatous polyposis coli (APC) is also an ARM family member and acts with casein kinase Ι, glycogen synthase kinase-3β and AXIN to regulate Wnt signaling through β-catenin degradation (Munemitsu et al, 1995; Rubinfeld et al, 1996; Goss et al, 2000), APC promoter methylation was found to be significantly associated with a higher risk of developing CRC and the findings indicate that APC promoter methylation may be a potential biomarker for the carcinogenesis of CRC (Ding et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells

Gao

Wu²,

Zeng³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Arm protein lost in epithelial cancers, on chromosome X (ALEX) is a novel subgroup within the armadillo (ARM) family, which has one or two ARM repeat domains as opposed to more than six-thirteen repeats in the classical Armadillo family members. Materials and Methods: In the study, we explore the biological functions of ALEX1 in breast cancer cells. Overexpression of ALEX1 and silencing of ALEX1 were performed with SK-BR3 and MCF-7 cell lines. Cell proliferation and colony formation assays, along with flow cytometry, were carried out to evaluate the roles of ALEX1. Results: ALEX1 overexpression in SK-BR3 breast cancer cells inhibited proliferation and induced apoptosis. Furthermore, depletion of ALEX1 in MCF-7 breast cancer cells increased proliferation and inhibited apoptosis. Additional analyses demonstrated that the overexpression of ALEX1 activated the intrinsic apoptosis cascades through up-regulating the expression of Bax, cytosol cytochrome c, active caspase-9 and active caspase-3 and down-regulating the levels of Bcl-2 and mitochondria cytochrome c. Simultaneouly, silencing of ALEX1 inhibited intrinsic apoptosis cascades through down-regulating the expression of Bax, cytosol cytochrome c, active caspase-9, and active caspase-3 and up-regulating the level of Bcl-2 and mitochondria cytochrome c. Conclusions: Our data suggest that ALEX1 as a crucial tumor suppressor gene has been involved in cell proliferation and apoptosis in breast cancer, which may serve as a novel candidate therapeutic target.

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Mechanistic insights from structural studies of β-catenin and its binding partners

Cited by 220 publications

References 88 publications

Mechanistic insight into the nucleus–vacuole junction based on the Vac8p–Nvj1p crystal structure

Mechanistic insight into the nucleus–vacuole junction based on the Vac8p–Nvj1p crystal structure

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells

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