Modulation of Rack-1/PKCβII Signalling By Soluble AβPPα in SH-SY5Y Cells

The soluble amyloid beta precursor protein alpha (sA beta PP alpha) released after alpha-secretase cleavage of the amyloid beta precursor protein (A PP) 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-kappa B 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 sA beta PP alpha could influence the expression of RACK-1 through NF-kappa B involvement. Our data demonstrate that sA beta PP alpha regulates RACK-1 gene expression through PI3K/Akt-dependent pathway, inducing c-Rel nuclear translocation and NF-kappa B activation. Since RACK-1 is the scaffold of protein kinase C beta II (PKC beta II), we turned our attention to this kinase in order to evaluate whether sA beta PP alpha could also influence PKC beta II signalling demonstrating that sA beta PP alpha induces PKC beta II translocation and interaction with its scaffold with consequent RACK-1/PKC beta II complex increase in membrane. Altogether these results suggest the existence of an interesting loop between the functions of the metabolic products of A beta PP and the role of PKC and that the impact of a dysregulated A beta PP metabolism occurring in several conditions (from physiological aging to injury response) may have consequences on the potential protective functions of the non amyloidogenic sA beta PP alpha.