Interaction of PDK 1 with phosphoinositides is essential for neuronal 1 differentiation , but dispensable for neuronal survival

نویسندگان

  • Tinatin Zurashvili
  • Lluís Cordón-Barris
  • Gerard Ruiz-Babot
  • Xiangyu Zhou
  • Nestor Gómez
  • Lydia Giménez-Llort
  • Jose R Bayascas
چکیده

23 The 3-phosphoinositide-dependent protein kinase-1 (PDK1) operates in cells in 24 response to phosphoinositide 3-kinase activation and PtdIns(3,4,5)P 3 production by 25 activating a number of AGC kinases, including protein kinase B (PKB)/Akt. Both 26 PDK1 and PKB contain pleckstrin homology domains that interact with the 27 PtdIns(3,4,5)P 3 second messenger. Disrupting the interaction of the PDK1 pleckstrin 28 homology domain with phosphoinositides by expressing the PDK1 K465E knock-in 29 mutation resulted in mice with reduced PKB activation. We explored the physiological 30 consequences of this biochemical lesion in the central nervous system. The PDK1 31 knock-in mice displayed reduced brain size due to a reduction in neuronal cell size 32 rather than cell number. Reduced BDNF-induced phosphorylation of PKB at Thr308, 33 the PDK1 site, was observed in the mutant neurons, which was not rate-limiting for the 34 phosphorylation of those PKB substrates governing neuronal survival and apoptosis, 35 such as FOXO1 or GSK3. Accordingly, the integrity of the PDK1 PH domain was not 36 essential to support the survival of different embryonic neuronal populations analyzed. 37 In contrast, PKB-mediated phosphorylation of PRAS40 and TSC2, allowing optimal 38 mTORC1 activation and BRSK protein synthesis, were markedly reduced in the mutant 39 mice, leading to impaired neuronal growth and differentiation. 40 3 Introduction 41

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Interaction of PDK1 with phosphoinositides is essential for neuronal differentiation but dispensable for neuronal survival.

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. Dis...

متن کامل

Correction for Zurashvili et al., Interaction of PDK1 with Phosphoinositides Is Essential for Neuronal Differentiation but Dispensable for Neuronal Survival.

Tinatin Zurashvili, Lluís Cordón-Barris, Gerard Ruiz-Babot, Xiangyu Zhou, Jose M. Lizcano, Nestor Gómez, Lydia Giménez-Llort, Jose R. Bayascas Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain; Institut de Neurociències and Departament de Psiquiatria i de Medicina Legal, Universitat Autònoma de Barcelona, Barcelona,...

متن کامل

Improving the neuronal differentiation efficiency of umbilical cord blood-derived mesenchymal stem cells cultivated under appropriate conditions

Objective(s): Umbilical cord blood-derived mesenchymal stromal cells (UCB-MSCs) are ideally suited for use in various cell-based therapies. We investigated a novel induction protocol (NIP) to improve the neuronal differentiation of human UCB-MSCs under appropriate conditions. Materials and Methods: This experimental study was performed in Iranian Blood Transfusion Organization (IBTO), Tehran, I...

متن کامل

Effect of Different Doses of Staurosporine For Neuronal Differentiation

Purpose: The present study was designed to investigate the effect of different doses of Staurosporine on differentiation of PC-12 cell line into differentiated neuronal cells. Materials and Methods: PC-12 cell line as a useful model system for neurobiological studies was maintained in RPMI 1640 supplemented with 10% FBS. Staurosporine were added to culture medium in different concentrations (1...

متن کامل

IGF-I regulated phosphorylation and translocation of PDK-1 in neurons.

3'-phosphoinositide-dependent protein kinase-1 (PDK-1) is a crucial serine/threonine kinase in the insulin-like growth factor-I (IGF-I)/AKT signaling pathway, but its function and localization in the nervous system has not been fully characterized. In this study, we compared the localization of PDK-1 in adult neurons and non-neuronal PC-3 cells. We showed that PC-3 cells expressed phosphorylate...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2012