title: Interaction of PDK1 with phosphoinositides is essential for neuronal differentiation but dispensable for neuronal survival.
abstract: 3-Phosphoinositide-dependent protein kinase 1 (PDK1) operates in cells in response to phosphoinositide 3-kinase activation and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] production by activating a number of AGC kinases, including protein kinase B (PKB)/Akt. Both PDK1 and PKB contain pleckstrin homology (PH) domains that interact with the PtdIns(3,4,5)P(3) second messenger. Disrupting the interaction of the PDK1 PH domain with phosphoinositides by expressing the PDK1 K465E knock-in mutation resulted in mice with reduced PKB activation. We explored the physiological consequences of this biochemical lesion in the central nervous system. The PDK1 knock-in mice displayed a reduced brain size due to a reduction in neuronal cell size rather than cell number. Reduced BDNF-induced phosphorylation of PKB at Thr308, the PDK1 site, was observed in the mutant neurons, which was not rate limiting for the phosphorylation of those PKB substrates governing neuronal survival and apoptosis, such as FOXO1 or glycogen synthase kinase 3 (GSK3). Accordingly, the integrity of the PDK1 PH domain was not essential to support the survival of different embryonic neuronal populations analyzed. In contrast, PKB-mediated phosphorylation of PRAS40 and TSC2, allowing optimal mTORC1 activation and brain-specific kinase (BRSK) protein synthesis, was markedly reduced in the mutant mice, leading to impaired neuronal growth and differentiation.
authors.affiliation: Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Tinatin
authors.initials: T
authors.lastname: Zurashvili
authors.forename: Lluís
authors.initials: L
authors.lastname: Cordón-Barris
authors.forename: Gerard
authors.initials: G
authors.lastname: Ruiz-Babot
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhou
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lizcano
authors.forename: Nestor
authors.initials: N
authors.lastname: Gómez
authors.forename: Lydia
authors.initials: L
authors.lastname: Giménez-Llort
authors.forename: Jose R
authors.initials: JR
authors.lastname: Bayascas
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D009154:Mutation; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009929:Organ Size; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases