Dendrite-like Process Formation and Cytoskeletal Remodeling Regulated by δ-Catenin Expression

Biochemical and Biophysical Research Communications

et al. 2008

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Abstractδ-Catenin is upregulated in human carcinomas. However, little is known about the potential transcriptional factors that regulate δ-catenin expression in cancer. Using a human δ-catenin reporter system, we have screened several nuclear signaling modulators to test whether they can affect δ-catenin transcription. Among β-catenin/LEF-1, Notch1, and E2F1, E2F1 dramatically increased δ-catenin-luciferase activities while β-catenin/LEF-1 induced only a marginal increase. Rb suppressed the upregulation of δ-catenin-luciferase activities induced by E2F1 but did not interact with δ-catenin. RT-PCR and Western blot analyses in 4 different prostate cancer cell lines revealed that regulation of δ-catenin expression is controlled mainly at the transcriptional level. Interestingly, the effects of E2F1 on δ-catenin expression were observed only in human cancer cells expressing abundant endogenous δ-catenin. These studies identify E2F1 as a positive transcriptional regulator for δ-catenin, but further suggest the presence of strong negative regulator(s) for δ-catenin in prostate cancer cells with minimal endogenous δ-catenin expression.

Section: Plasmids and Antibodiesmentioning

confidence: 99%

“…Overexpressed δ-catenin promotes cellular processes with branching [3], and deletion of δ-catenin leads to severe cognitive and synaptic dysfunction [4]. In addition to presenilin-1, δ-catenin is known to associate with adhesive junction proteins such as Ecadherin [5].…”

Section: Introductionmentioning

confidence: 99%

Identification of E2F1 as a positive transcriptional regulator for δ-catenin

Biochemical and Biophysical Research Communications

et al. 2008

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Journal of Biological Chemistry

“…Established functions of p120 subfamily members include their binding to cadherin juxtamembrane regions (whereas ␤-catenin binds a more distal site), where they stabilize the larger adhesion complex by reducing its rate of internalization (31). In addition, ␦-catenin associates with small GTPases and/or their effectors, enabling the production or maintenance of discrete actin-dependent outgrowths, such as dendritic projections in neurons (32)(33)(34)(35). ␦-Catenin is further required in certain collective cell processes, apparently including amphibian gastrulation, via the modulation of Rho/Rac (36).…”

mentioning

confidence: 99%

Caspase-3 Cleavage Links δ-Catenin to the Novel Nuclear Protein ZIFCAT

Tonthat

Lee

et al. 2011

␦-Catenin is an Armadillo protein of the p120-catenin subfamily capable of modulating cadherin stability, small GTPase activity, and nuclear transcription. From yeast twohybrid screening of a human embryonic stem cell cDNA library, we identified ␦-catenin as a potential interacting partner of the caspase-3 protease, which plays essential roles in apoptotic as well as non-apoptotic processes. Interaction of ␦-catenin with caspase-3 was confirmed using cleavage assays conducted in vitro, in Xenopus apoptotic extracts, and in cell line chemically induced contexts. The cleavage site, a highly conserved caspase consensus motif (DELD) within Armadillo repeat 6 of ␦-catenin, was identified through peptide sequencing. Cleavage thus generates an amino-terminal (residues 1-816) and carboxyl-terminal (residues 817-1314) fragment, each containing about half of the central Armadillo domain. We found that cleavage of ␦-catenin both abolishes its association with cadherins and impairs its ability to modulate small GTPases. Interestingly, 817-1314 possesses a conserved putative nuclear localization signal that may facilitate the nuclear targeting of ␦-catenin in defined contexts. To probe for novel nuclear roles of ␦-catenin, we performed yeast two-hybrid screening of a mouse brain cDNA library, resolving and then validating interaction with an uncharacterized KRAB family zinc finger protein, ZIFCAT. Our results indicate that ZIFCAT is nuclear and suggest that it may associate with DNA as a transcriptional repressor. We further determined that other p120 subfamily catenins are similarly cleaved by caspase-3 and likewise bind ZIFCAT. Our findings potentially reveal a simple yet novel signaling pathway based upon caspase-3 cleavage of p120-catenin subfamily members, facilitating the coordinate modulation of cadherins, small GTPases, and nuclear functions.

“…Construction of full-length-δ-catenin constructs in pEGFP-C1 or pRFP-C1 has been described previously [11]. The wild-type PS-1 and mutant PS-1 in pEGFP-C1 were generated by PCR amplification of the desired PS-1 by using PS-1-specific oligonucleotides.…”

Section: Experimental Procedures Plasmid Constructionmentioning

confidence: 99%

“…and enhance dendritic morphogenesis in primary hippocampal neurons [11]. Some of the binding partners of δ-catenin include E-cadherin [14], S-SCAM [8], and PS-1 [13,19,21].…”

mentioning

confidence: 99%

Presenilin-1 inhibits δ-catenin-induced cellular branching and promotes δ-catenin processing and turnover

Bareiss

Biochemical and Biophysical Research Communications

et al. 2006

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Although δ-catenin/neural plakophilin-related armadillo protein (NPRAP) was reported to interact with presenilin-1 (PS-1), the effects of PS-1 on δ-catenin have not been established. In this study, we report that overexpression of PS-1 inhibits the δ-catenin-induced dendrite-like morphological changes in NIH 3T3 cells and promotes δ-catenin processing and turnover. The effects of PS-1 on endogenous δ-catenin processing were confirmed in hippocampal neurons overexpressing PS-1, as well as in the transgenic mice expressing the disease-causing mutant PS-1 (M146V). In addition, disease-causing mutant PS-1 (M146V and L286V) enhanced δ-catenin processing, whereas PS-1/γ-secretase inhibitors could block the formation of processed forms of δ-catenin. Together, our findings suggest that PS-1 can affect δ-catenin-induced morphogenesis possibly through the regulation of its processing and stability. KeywordsAlzheimer's disease; δ-Catenin/NPRAP; Presenilin/γ-secretase Alzheimer's disease (AD) is the most common type of senile dementia and is characterized by progressive loss of memory and cognitive dysfunction [16]. In familial Alzheimer's disease (FAD), over 70 mutations have been significantly associated with presenilin-1 (PS-1) and presenilin-2 (PS-2) [7]. Multiple lines of evidence indicate that PS contributes directly to the intramembranous "γ-secretase" processing of many proteins of diverse functions, including APP [3], the developmental signaling receptor Notch1 [4], and cell adhesion molecules N-and E-cadherin [15]. Interestingly, it is reported that PS-1 interacts with a member of the armadillo/ β-catenin family termed δ-catenin, a protein expressed mostly in the brain and encoded on chromosome 5 [21]. δ-Catenin, or neural plakophilin-related armadillo protein (NPRAP), is a member of the p120 ctn subfamily of armadillo/β-catenin proteins, which are defined as proteins with 10 armadillo (ARM) repeats in characteristic spacing and with diverse NH 2 -and COOH-terminal sequences that flank the ARM repeats [18]. δ-Catenin is a nervous system-specific adherens junction protein involved in cell motility and expressed early in neuronal development [14]. The overexpression of δ-catenin can induce the branching of cellular processes in 3T3 cells In this report, we investigated the effects of PS-1 on δ-catenin. The co-overexpressed PS-1 significantly impaired δ-catenin-induced cellular branching in NIH 3T3 fibroblasts. We also found that PS-1 expression promoted δ-catenin processing when they were co-transfected in 3T3 cells and when PS-1 was overexpressed in hippocampal neurons, which was sensitive to PS-1/γ-secretase inhibition and was facilitated by the Alzheimer's disease-causing PS-1 mutation. Our findings suggest that one function of PS-1 expression is to promote δ-catenin processing and, thereby, affect the function of δ-catenin in cells. Experimental procedures Plasmid constructionConstruction of full-length-δ-catenin constructs in pEGFP-C1 or pRFP-C1 has been described previously [11]. The wild-type PS-1 and...