Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival

Induction of ligand-specific PrPCsignaling in human neuronal cells

“…Specifically, the dual requirement for conversion to PrP Sc , as well as the association with lipid rafts suggest a subversion of the normal function of PrP C upon misfolding to PrP Sc that involves distortion of signaling events. 12 Subsequent investigations of PrP C and PrP Sc from the perspective of signaling analysis have implicated a number of intracellular kinases and signaling pathways including: Sarcoma (Src), 13 mitogen activated protein kinase (MAPK), 14,15 phosphoinositide-3 kinase (PI3K)/RAC-α series/threonine protein kinase (Akt), 16 c-Jun N-terminal kinase (JNK), 17 and extracellular signal-regulated kinase (Erk). 18 While these investigations strongly indicate that PrP influences the intracellular kinase environment there is no consensus on the specific mechanism and consequences.…”

Physiological role of the cellular prion protein

“…Moreover, both PI 3-kinase activation and cytoprotection by PrP C appear to rely on copper binding to the N-terminal octapeptide of PrP C . So the interaction of copper with the N-terminal domain of PrP C could enable transduction of a signal to PI 3-kinase which, in turn, mediates downstream regulation of cell survival [105]. Due to its plasma membrane-localization, copper bound PrP C that can act as a sensor for extracellular stress and transmit signals to the intracellular milieu, the PI 3-kinase cascade having a crucial role in activating neuroprotective mechanisms.…”

Serum Withdrawal‐Induced Apoptosis in ZrchI Prion Protein (PrP) Gene‐Deficient Neuronal Cell Line Is Suppressed by PrP, Independent of Doppel

“…Copper-binding to Dpl alone may not increase the SOD activity in neuronal cell lines, and the underlying mechanism(s) of the reaction remains unknown as yet. It must be clarified whether PrP has a neuroprotective role on the cell surface inducing antioxidant activity, or in an internal signaling pathway activating phosphatidylinositol 3-kinase (34).…”