Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth

Abstract

In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor.

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

“…2). Because hemin can interact with many proteins, we investigated the selectivity of the effects of hemin on the aggregation of PrP C compared with other cell surface proteins such as NCAM (neural cell adhesion molecule), which interacts with PrP C (31,32), and GFP-GPI protein, which follows default trafficking pathways of GPI anchored, lipid-raft-associated proteins (26). No hemin-induced alteration of NCAM or GFP-GPI solubility was observed, indicating a degree of specificity for the effects of hemin on PrP C solubility ( Fig.…”

“…Laminin (an extracellular matrix protein) (56), NCAM (a transmembrane adhesion molecule) (31,32), and STI-1 (a co-chaperone) (57) are important partners that assist in this function of PrP C . Interestingly, these ligands have distinct binding sites on the PrP C molecule and interact with PrP C on the cell surface suggesting that a formation of the macromolecular complex may occur on the plasma membrane in PrP C -dependent neuritogenesis.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…However, only a small proportion of these related pathways are functional in a physiological context (see (Lee et al, 2003) or (Westergard et al, 2007) and (Linden et al, 2008) for reviews). Two in vitro studies demonstrate that PrP c binds to the laminin receptor 67K (Gauczynski et al, 2001) and the adhesion molecule N-CAM (Santuccione et al, 2005;Schmitt-Ulms et al, 2001), both transducing survival signals or promoting neurite outgrowth. In addition, PrP c mediates neuritogenesis in a laminin-mediated manner (Graner et al, 2000), thereby suggesting that the PrP c -laminin interaction is relevant for neuronal development and further plasticity-related mechanisms.…”

“…In this sense, we would like to remark two sets of studies with opens the notion of PrP c as a signaling molecule. In the first, using PrP c aggregation strategies, Mouillet-Richard and coworkers reported that PrP c -mediated signaling by P59Fyn kinase modulates cell survival in 1C11 cell line (Mouillet-Richard et al, 2000;Santuccione et al, 2005). This data is crucial since it linked the survival properties of PrP c to a specific signaling pathway.…”

Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes

“…PrP Sc but not PrP C accumulation stimulates the Notch and Hes pathways, resulting in the loss of dendritic processes (34,35). PrP C seems to function in signal transduction and neurite outgrowth in conjunction with the neural cell adhesion molecule, N-CAM (36,37). Moreover, PrP C -deficient mice exhibit defects in spatial memory tasks (38).…”