PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells. (28th May 2013)

• Record Type: Journal Article
• Authors: Llorens, Franc; Carulla, Patricia; Villa, Ana; Torres, Juan M.; Fortes, Puri; Ferrer, Isidre; del Río, José A.
• Is Part Of: Journal of neurochemistry. Volume 127:Number 1(2013:Oct.)
• Page Start: 124
• Page End: 138
• Publication Date: 2013-05-28
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12283
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12283-abs-0001"> <title>Abstract</title> <p>The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP<sup>SC</sup>) has been studied in depth, the physiological role of PrP<sup>C</sup> remains elusive and controversial. PrP<sup>C</sup> is a cell‐surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP<sup>C</sup> in animals and in cellular models. In this article, we present PrP<sup>C</sup>‐dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP<sup>C</sup> over‐expression enhances cell proliferation and cell cycle re‐entrance after serum stimulation, while PrP<sup>C</sup> silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP<sup>C</sup> in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP<sup>C</sup> in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP<sup>C</sup> over‐expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT‐Cdc42‐N‐WASP‐dependent pathway.</p> <p> <boxed-text content-type="graphic" id="jnc12283-blkfxd-0001" position="anchor" orientation="portrait"> <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg3hrdfxws" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> </boxed-text> </p> <p>In this study, we analyzed the PrP<sup>C</sup>‐dependent gene expression signature of neuroblastoma (N2a) cells after transient acute up‐regulation and down‐regulation of PrP<sup>C</sup>. We demonstrate that PrP<sup>C</sup> plays roles in proliferation and neuritogenesis through modulation of EGFR activity. This approach will give new insights into the molecular mechanisms by which PrP<sup>C</sup> regulates key cellular functions in cell physiology.</p> </abstract>