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

Abstract

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...

C-Src-mediated phosphorylation of δ-catenin increases its protein stability and the ability of inducing nuclear distribution of β-catenin

“…The potential mechanism could be that c-Src-mediated phosphorylation decreases the binding affinity of δ-catenin to its negative regulators. Two negative regulators of δ-catenin have been identified: PS-1 and GSK3β [29, 39]. Therefore, there are three potential mechanisms underlying our observation that c-Src stabilizes δ-catenin: 1) c-Src decreases the turnover of δ-catenin induced by PS-1; 2) c-Src protects δ-catenin from being phosphorylated by GSK3β; and 3) c-Src affects the regulation controlled by both regulators.…”

δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming

“…δ-Catenin interacts with classical cadherins at their juxtermembrane domain, an association motif shared with that for p120 ctn which is another protein of the delta subfamily (p120 ctn : CTNND1 ) of β-catenin/armadillo superfamily (5, 10, 31). This interaction is critical for regulating E-cadherin stability and in brain it involves the regulation by presenilin (PS) of Alzheimer's disease (32, 33). While the roles of β-catenin and its mutations in development and cancer by effecting Wnt/wingless signaling are well established, recent evidence placed δ-catenin in the same pathway.…”

Xenopus δ-catenin is essential in early embryogenesis and is functionally linked to cadherins and small GTPases

“…-catenin associates with multiple proteins of the neural adherens or synaptic junction (Arikkath et al, 2008;Deguchi et al, 2000;Fujita et al, 2004;Ide et al, 1999;Izawa et al, 2002;Jones et al, 2002;Kim et al, 2006;Laura et al, 2002;Lu et al, 2002;Mackie and Aitken, 2005;Martinez et al, 2003;Munoz et al, 2007;Silverman et al, 2007). Most of these interactions occur through its central armadillo domain or its C-terminal PDZ (PSD-95/Discslarge/ZO-1) binding motif.…”