title: Modulation of Rack-1/PKCβII signalling by soluble AβPPα in SH-SY5Y cells.
abstract: The soluble amyloid β precursor protein α (sAβPPα) released after α-secretase cleavage of the amyloid β precursor protein (AβPP) has several functions including modulation of neuronal excitability and synaptic plasticity; it has been suggested that some of these effects are mediated by activation of NF-κB via induction of PI3K/Akt signaling pathway. We have recently described the presence of several consensus binding sites of c-Rel transcription factor in the promoter region of the GNB2L1 gene, coding for the Receptor for Activated C Kinase -1 (RACK-1). We investigated whether sAβPPα could influence the expression of RACK-1 through NF-κB involvement. Our data demonstrate that sAβPPα regulates RACK-1 gene expression through PI3K/Akt-dependent pathway, inducing c-Rel nuclear translocation and NF-κB activation. Since RACK-1 is the scaffold of protein kinase C βII (PKCβII), we turned our attention to this kinase in order to evaluate whether sAβPPα could also influence PKCβII signalling demonstrating that sAβPPα induces PKCβII translocation and interaction with its scaffold with consequent RACK-1/PKCβII complex increase in membrane. Altogether these results suggest the existence of an interesting loop between the functions of the metabolic products of AβPP and the role of PKC and that the impact of a dysregulated AβPP metabolism occurring in several conditions (from physiological aging to injury response) may have consequences on the potential protective functions of the non amyloidogenic sAβPPα.
authors.affiliation: Department of Drug Sciences- Pharmacology Unit, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Buoso
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Biundo
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.forename: Stefania
authors.initials: S
authors.lastname: Aiello
authors.forename: Serena
authors.initials: S
authors.lastname: Grossi
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
authors.forename: Stefano
authors.initials: S
authors.lastname: Govoni
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011485:Protein Binding / Q000502:physiology; D064546:Protein Kinase C beta / Q000096:biosynthesis*; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D064546:Protein Kinase C beta; D019204:GTP-Binding Proteins