δ-Catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: Implications on human prostate cancer progression

Abstract

δ-Catenin binds the juxtamembrane domain of E-cadherin and is known to be overexpressed in some human tumors. However, the functions of δ-catenin in epithelial cells and carcinomas remain elusive. We found that prostate cancer cells overexpressing δ-catenin show an increase in multi-layer growth in culture. In these cells, δ-catenin colocalizes with E-cadherin at the plasma membrane, and the E-cadherin processing is noticeably elevated. E-Cadherin processing induced by δ-catenin is serum-dependent and requires MMP- and PS-1/γ-secretase-mediated activities. A deletion mutant of δ-catenin that deprives the ability of δ-catenin to bind E-cadherin or to recruit PS-1 to E-cadherin totally abolishes the δ-catenin-induced E-cadherin processing and the multilayer growth of the cells. In addition, prostate cancer cells overexpressing δ-catenin display an elevated total β-catenin level and increase nuclear distribution, resulting in the activation of β-catenin/LEF-1-mediated transcription and their downstream target genes as well as androgen receptor-mediated transcription. Indeed, human prostate tumor xenograft in nude mice, which is derived from cells overexpressing δ-catenin, shows increased β-catenin nuclear localization and more rapid growth rates. Moreover, the metastatic xenograft tumor weights positively correlate with the level of 29 kD E-cadherin fragment, and primary human prostate tumor tissues also show elevated levels of δ-catenin expression and the E-cadherin processing. Taken together, these results suggest that δ-catenin plays an important role in prostate cancer progression through inducing E-cadherin processing and thereby activating β-catenin-mediated oncogenic signals.

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

“…As expected, full-length δ-catenin was distributed at the cell-cell junction (Fig 4B, GFP: arrows, Rv/δ) (5, 10). However, the truncated δ-catenin was exclusively cytoplasmic (Fig 4B, GFP: arrowhead, Rv/M1) and did not co-localize with the cell-cell junction protein p120 ctn (Fig 4B, p120 ctn : arrows) (5).…”

“…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).…”

“…However, this initially described neural specific member of the β-catenin/armadillo superfamily is commonly overexpressed in cancers of peripheral tissues, including prostate, esophageal, breast, lung and ovarian cancers (6-9). While the mechanisms of δ-catenin regulation in neurologic disorders and cancer are beginning to emerge, studies show that δ-catenin promotes canonical Wnt/β-catenin/LEF-1-mediated transcription (10). δ-Catenin genelocus (5p15.2) is highly susceptible for generating single nucleotide polymorphism (SNP).…”

δ-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions

“…␦-Catenin promotes trafficking of N-cadherin to membrane (45), masks an endocytic signal in cadherin (46), recruits and tethers (47) the presenilin 1 complex to cadherin (48), recruits AMPA receptorbinding protein and glutamate receptor interacting protein to AMPA receptor and promotes stabilization of surface GluR2 (36). We propose a model (Fig.…”

p0071/PKP4, a multifunctional protein coordinating cell adhesion with cytoskeletal organization

“…Indeed, the stimulation of E-cadherin processing correlats with an elevated level and increased nuclear localization of β -catenin, resulting in the activation of β -catenin/LEF-1 target transcripts. This demonstrates the interdependence of β -catenin signaling and δ -catenin expression (Kim et al , 2012 ).…”