Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development

Abstract

Uncontrolled canonical Wnt signaling supports colon epithelial tumor expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, epsins’ involvement in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signaling effector, dishevelled (Dvl2), and impairing Wnt signaling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signaling in colon cancer cells to ensure robust colon cancer progression. Epsins’ pro-carcinogenic role suggests they are potential therapeutic targets to combat colon cancer.

Selective Targeting of a Novel Epsin–VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis

“…We used site-directed mutagenesis to create expression constructs with mutated versions of VEGFR2, and expressed these or wild-VEGFR2 in HUVEC cells as indicated (Figure 1D). Cells were subsequently stimulated with VEGF to induce VEGFR2 activation and ubiquitination, and processed for immunoprecipitation using epsin 1-specific antibody as previously described (Figure 1D) 9, 33 . We found that WT VEGFR2 co-immunoprecipitated with epsin1; however all of the VEGFR2 mutants impeded binding to epsin1 (Figure 1D).…”

The Dishevelled Protein Family

“…Strikingly, there are huge amounts of Dsh protein and RNA deposited in the egg during Drosophila oogenesis by the mother (Perrimon, Engstrom, & Mahowald, 1989; Perrimon & Mahowald, 1987) and hence the zygotic null dsh mutants, originating from a dsh +/− mother, survive and look largely normal all the way to third instar larval stages and some even beyond that. This suggests that either the Dsh protein is very stable which has not been addressed thoroughly yet, but seems unlikely as several ubiquitin-linked enzymes and associated proteasome degradation have been lined to Dsh regulation (for example, Chang et al, 2015; de Groot et al, 2014; Madrzak et al, 2015; Strutt, Searle, Thomas-Macarthur, Brookfield, & Strutt, 2013), or that the dsh RNA is particularly stable and maintained throughout embryogenesis to later developmental stages. As such, only maternal-zygotic double mutant dsh − embryos display the classical Wg/Wnt-signaling canonical defects comparable to wg itself or arm /β-catenin (Perrimon et al, 1989; Perrimon & Mahowald, 1987).…”

Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis

“…Epsins are reportedly overexpressed in several types of cancer, such as prostate, colon, breast, lung, and skin cancers [49]. A recent study using a genetic mouse model reveals that loss of intestinal epithelial epsins protect against colon cancer by significantly reducing the stability of the crucial Wnt signaling effector, dishevelled, and impairing Wnt signaling [50]. Further studies are needed to delineate the intrinsic roles of epsins.…”