The Prion Protein Controls Polysialylation of Neural Cell Adhesion Molecule 1 during Cellular Morphogenesis

Abstract

Despite its multi-faceted role in neurodegenerative diseases, the physiological function of the prion protein (PrP) has remained elusive. On the basis of its evolutionary relationship to ZIP metal ion transporters, we considered that PrP may contribute to the morphogenetic reprogramming of cells underlying epithelial-to-mesenchymal transitions (EMT). Consistent with this hypothesis, PrP transcription increased more than tenfold during EMT, and stable PrP-deficient cells failed to complete EMT in a mammalian cell model. A global comparative proteomics analysis identified the neural cell adhesion molecule 1 (NCAM1) as a candidate mediator of this impairment, which led to the observation that PrP-deficient cells fail to undergo NCAM1 polysialylation during EMT. Surprisingly, this defect was caused by a perturbed transcription of the polysialyltransferase ST8SIA2 gene. Proteomics data pointed toward β-catenin as a transcriptional regulator affected in PrP-deficient cells. Indeed, pharmacological blockade or siRNA-based knockdown of β-catenin mimicked PrP-deficiency in regards to NCAM1 polysialylation. Our data established the existence of a PrP-ST8SIA2-NCAM signaling loop, merged two mature fields of investigation and offer a simple model for explaining phenotypes linked to PrP.

The N Terminus of the Prion Protein Mediates Functional Interactions with the Neuronal Cell Adhesion Molecule (NCAM) Fibronectin Domain

“…However, PrP C -NCAM interacting surfaces have not been described at the structural and biophysical levels yet. Recently, it has been observed that PrP C controls polysialylation of NCAM during cellular morphogenesis (23). Current evidence strengthens the hypothesis that the FNIII1,2 domain plays a role for NCAM-mediated heterophilic interaction; therefore this domain may represent a useful model for structural studies aiming at understanding the molecular determinants of PrP C -NCAM interaction.…”

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

“…19 EMT is a key regulator of metastasis in some cancers, during which cells change their epithelial properties to adopt a more mesenchymal and invasive phenotype (for review see ref. 35).…”

“…Mehrabian and colleagues showed that stable PrP c -deficient mammary epithelial cells failed to complete EMT in response to TGF-b. 19 This was linked to a lack of polysialylation of neural cell adhesion molecule 1 (NCAM1) caused by a perturbed transcription of the polysialyltransferase ST8SIA2 gene. Interestingly, they demonstrated that PrP c regulates the transcription of the polysialyltransferase ST8SIA2 gene through a b-catenin-dependent mechanism.…”

“…Interestingly, they demonstrated that PrP c regulates the transcription of the polysialyltransferase ST8SIA2 gene through a b-catenin-dependent mechanism. 19 It thus appears that the links between PrP c and EMT could implicate not only PrP c capability to modulate the dynamics of cell-cell junctions but also a role of its nuclear pool in the regulation of Wnt target genes.…”

“…17,18 PrP c -deficient mammary epithelial cells fail to address properly E-cadherin at cell-cell contacts, but, interestingly, they were at the same time unable to rearrange adherens junctions and to accomplish epithelial-mesenchymal transition in response to TGF-b. 19 Therefore, accumulating evidences in different biological systems and organisms converge to identify PrP c as an important regulator of the dynamic assembly/disassembly of several junctional complexes involved in cell-cell adhesion.…”