Neuritogenesis: the prion protein controls β1 integrin signaling activity

Abstract

Cytoskeleton modifications are required for neuronal stem cells to acquire neuronal polarization. Little is known, however, about mechanisms that orchestrate cytoskeleton remodeling along neuritogenesis. Here, we show that the silencing of the cellular prion protein (PrP(C)) impairs the initial sprouting of neurites upon induction of differentiation of the 1C11 neuroectodermal cell line, indicating that PrP(C) is necessary to neuritogenesis. Such PrP(C) function relies on its capacity to negatively regulate the clustering, activation, and signaling activity of β1 integrins at the plasma membrane. β1 Integrin aggregation caused by PrP(C) depletion triggers overactivation of the RhoA-Rho kinase-LIMK-cofilin pathway, which, in turn, alters the turnover of focal adhesions, increases the stability of actin microfilaments, and in fine impairs neurite formation. Inhibition of Rho kinases is sufficient to compensate for the lack of PrP(C) and to restore neurite sprouting. We also observe an increased secretion of fibronectin in the surrounding milieu of PrP(C)-depleted 1C11 cells, which likely self-sustains β1 integrin signaling overactivation and contributes to neuritogenesis defect. Our overall data reveal that PrP(C) contributes to the acquisition of neuronal polarization by modulating β1 integrin activity, cell interaction with fibronectin, and cytoskeleton dynamics.

Induction of ligand-specific PrPCsignaling in human neuronal cells

“…While previous prion studies have pointed to laminin receptors as possible prion protein interaction receptors 36 we show that more specifically the integrin receptors may be linked to PrP C stimulation of neuronal cells, a result recently reported elsewhere. 33 Meanwhile, PrP C stimulation by the 6H4 antibody displayed a distinct signaling repertoire of which the strongest indicators pointed to insulin receptor/MAPK related signaling. While there is cross treatment signaling that is common to both, such as iNOS, the majority of signaling is unique to each treatment (Fig.…”

The prion protein inhibits monocytic cell migration by stimulating β1 integrin adhesion and uropod formation

“…Integrin binding to the actin cytoskeleton might impose constraints to the lateral mobility of integrins and reduce avidity. In addition, PrP-silencing has previously been shown to stabilize actin filaments in neuronal cells through a RhoA-dependent pathway (Loubet et al, 2012). Therefore, we explored RhoA activation in shCtrl-and shPrP-U937 cells stimulated with CXCL12 or PMA.…”

“…It has been shown previously that the RhoA-regulated actinsevering protein cofilin 1 is involved in the regulation of actin microfilament stability by PrP in neurons (Loubet et al, 2012). To determine whether this pathway is operational in monocytes, we determined the levels of phosphorylated (inactive) cofilin 1 in cells adhering to immobilized Fc-VCAM.…”

“…Although the basis for this phenotype was not investigated, one possibility is that PrP has an intrinsic role in leukocyte migration out of the circulation and/or into the peritoneum. In addition, several in vivo and in vitro studies have shown that PrP participates in the regulation of cell-cell (Málaga-Trillo et al, 2009;Mangé et al, 2002;Morel et al, 2008) and cellmatrix adhesion (Loubet et al, 2012;Schrock et al, 2009).…”

Investigation of the role of prion protein in protection against transition metal induced toxicity

“…The prion protein's role in a particular cellular process, including those that are concerned with metal-PrP interrelations in ex-vivo and in-vivo systems are generally studied by either genetically ablating (Büeler et al, 1992;Haigh and Brown, 2006;Kim et al, 2005;Kuwahara et al, 1999;Rossi et al, 2001;Sakaguchi et al, 1996) or siRNA silencing (Loubet et al, 2012) while working on HeLa cells (Molnár et al, 2013)., and have used here similarly. The bright red immunofluorescence-staining pattern in the ZW 13-2 cells revealed that the prion protein was distributed on the surface of the cells, whereas no immunoreactivity was detected in the Zpl 2-1 cells.…”