The nucleo-junctional interplay of the cellular prion protein: A new partner in cancer-related signaling pathways?

Abstract

ABSTRACT. The cellular prion protein PrP c plays important roles in proliferation, cell death and survival, differentiation and adhesion. The participation of PrP c in tumor growth and metastasis was pointed out, but the underlying mechanisms were not deciphered completely. In the constantly renewing intestinal epithelium, our group demonstrated a dual localization of PrP c , which is targeted to cell-cell junctions in interaction with Src kinase and desmosomal proteins in differentiated enterocytes, but is predominantly nuclear in dividing cells. While the role of PrP c in the dynamics of intercellular junctions was confirmed in other biological systems, we unraveled its function in the nucleus only recently. We identified several nuclear PrP c partners, which comprise g-catenin, one of its desmosomal partners, b-catenin and TCF7L2, the main effectors of the canonical Wnt pathway, and YAP, one effector of the Hippo pathway. PrP c up-regulates the activity of the b-catenin/TCF7L2 complex and its invalidation impairs the proliferation of intestinal progenitors. We discuss how PrP c could participate to oncogenic processes through its interaction with Wnt and Hippo pathway effectors, which are controlled by cell-cell junctions and Src family kinases and dysregulated during tumorigenesis. This highlights new potential mechanisms that connect PrP c expression and subcellular redistribution to cancer.

Beyond cell-cell adhesion: Plakoglobin and the regulation of tumorigenesis and metastasis

“…c-Myc, cyclin D1, MMP7; [ 133 ]). The inhibition of β-catenin-TCF-4 transcriptional activity by plakoglobin was also demonstrated in a recent study that reported the interaction of both catenins with the cellular prion protein PrP(c) [ 83 , 134 , 135 ]. PrP(c) was shown to interact with actin, spectrin, annexin A2, plakoglobin, desmoglein 2, desmoplakin and c-Src in epithelial cells.…”

“…PrP(c) interacted not only with plakoglobin but also with β-catenin and TCF-4 in both the cytoplasm and nucleus. Futhermore, the interaction of PrP(c) with β-catenin-TCF-4 stimulated its transactivation, whereas PrP(c)-plakoglobin interactions decreased it [ 134 , 135 ].…”

Sporadic Creutzfeldt–Jakob disease with glial PrPRes nuclear and perinuclear immunoreactivity

“…In addition to truncated forms, PrP C can localize in the nucleus of different cell types including neural cells, and it interacts with structural chromatin components, principally histone H3; the interaction of PrP C with histone H3 suggests that PrP is involved in transcriptional regulation in the nucleus . Nuclear PrP interacts with distinct proteins involved in cell proliferation and cell junction in several cell types, and PrP participates in the process of DNA repair after genotoxic stress …”

Genetic effects of PRNP gene insertion/deletion (indel) on phenotypic traits in sheep

“…Because all of the all analyzed sheep were healthy, and previously reported pathogenic codons (such as codons 136, 141, 146, 154, and 171) were not located in the studied indels, the present study cannot provide results on the relationship between these indels and scrapie susceptibility. As well as being considered a pathogenic control, PRNP has also become an emerging target gene for cancer therapies, because PrPc participate in the processes of intercellular junctions, tumor growth, and metastasis [43][44]. Further cancer investigations revealed that PrPc contribute toward the self-renewal of embryonic, tissuespecific, and cancer stem cells [44], which provides a potential basis for researching the PRNP regulation of animal phenotypic traits.…”