title: Fine-tuning the intensity of the PKB/Akt signal enables diverse physiological responses.
abstract: The PI3K/PDK1/PKB signaling pathway plays essential roles in regulating neuronal survival, differentiation and plasticity in response to neurotrophic factors, neurotransmitters and ion channels. Both PDK1 and PKB can interact at the plasma membrane with a phosphoinositide synthesized by PI3K, the second messenger PtdIns(3,4,5)P3, enabling PDK1 to phosphorylate and activate PKB. In the PDK1 K465E knock-in mice expressing a mutant form of PDK1 incapable of phosphoinositide binding, activation of PKB was markedly affected, but not totally abolished. It has been recently proposed that in the absence of PtdIns(3,4,5)P3 binding, PDK1 can still moderately activate PKB due to a docking site-mediated interaction of these 2 kinases. A recent report has uncovered that in the PDK1 K465E mice neurons, a PKB signal threshold was sufficient to support neuronal survival responses, whereas neuritogenesis, neuronal polarization and axon outgrowth were severely impaired. We propose here that the low-efficiency mechanism of PKB activation observed in the PDK1 K465E mice might represent the ancestral mechanism responsible for the essential functions of this pathway, while the phosphoinositide-dependent activation should be considered an evolutionary innovation that enabled the acquisition of novel functions.
authors.affiliation: a Institut de Neurociències & Departament de Bioquímica i Biologia Molecular ; Universitat Autònoma de Barcelona ; Barcelona , Spain.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhou
authors.forename: Lluis
authors.initials: L
authors.lastname: Cordon-Barris
authors.forename: Tinatin
authors.initials: T
authors.lastname: Zurashvili
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Bayascas
mesh_terms: D000818:Animals; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: PDK1; PH-domain; PKB/Akt; knock-in mice; neuronal morphogenesis; neuronal survival; phosphoinositides