Home LiteratureArticle Details
PMID: 19605683 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cell type specificity of PI3K signaling in Pdk1- and Pten-deficient brains.

Genes & development ·Vol. 23 ·No. 14 ·2009-07-15 ·Pages 1619-24

Chalhoub N, Zhu G, Zhu X, Baker SJ

Abstract

Loss of PTEN causes unregulated activation of downstream components of phosphatidylinositol 3-kinase (PI3K) signaling, including PDK1, and disrupts normal nervous system development and homeostasis. We tested the contribution of Pdk1 to the abnormalities induced by Pten deletion in the brain. Conditional deletion of Pdk1 caused microcephaly. Combined deletion of Pdk1 and Pten rescued hypertrophy, but not migration defects of Pten-deficient neurons. Pdk1 inactivation induced strikingly different effects on the regulation of phosphorylated Akt in glia versus neurons. Our results show Pdk1-dependent and Pdk1-independent abnormalities in Pten-deficient brains, and demonstrate cell type specific differences in feedback regulation of the ubiquitous PI3K pathway.

MeSH Terms
3-Phosphoinositide-Dependent Protein Kinases Animals Brain/metabolism Cell Movement Cell Nucleus/metabolism Cerebellum/metabolism Class I Phosphatidylinositol 3-Kinases Jacobsen Distal 11q Deletion Syndrome Mice Mice, Knockout Neurons/metabolism PTEN Phosphohydrolase/genetics Phosphatidylinositol 3-Kinases/genetics,metabolism Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins c-akt/metabolism Signal Transduction
Chemicals
Class I Phosphatidylinositol 3-Kinases Pik3cd protein, mouse 3-Phosphoinositide-Dependent Protein Kinases Akt1 protein, mouse Pdpk1 protein, mouse Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Chalhoub Nader
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Zhu Guo
Zhu Xiaoyan
Baker Suzanne J
References (40)
40 references, click to expand
  1. PTEN and the PI3-kinase pathway in cancer.
    Annu Rev Pathol. 2009;4:127-50 PMID: 18767981
  2. Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure.
    Biochem J. 2005 Feb 1;385(Pt 3):639-48 PMID: 15554902
  3. The regulation of cell motility and chemotaxis by phospholipid signaling.
    J Cell Sci. 2008 Mar 1;121(Pt 5):551-9 PMID: 18287584
  4. S6k1 is not required for Pten-deficient neuronal hypertrophy.
    Brain Res. 2006 Jul 19;1100(1):32-41 PMID: 16777079
  5. Pten is essential for embryonic development and tumour suppression.
    Nat Genet. 1998 Aug;19(4):348-55 PMID: 9697695
  6. Essential role of PDK1 in regulating cell size and development in mice.
    EMBO J. 2002 Jul 15;21(14):3728-38 PMID: 12110585
  7. Regulation of neuronal survival by the serine-threonine protein kinase Akt.
    Science. 1997 Jan 31;275(5300):661-5 PMID: 9005851
  8. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation.
    Mol Cell Biol. 2002 Jul;22(14):5100-13 PMID: 12077339
  9. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.
    Mol Cancer Ther. 2008 Jul;7(7):1851-63 PMID: 18606717
  10. PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization.
    Development. 2005 Jul;132(14):3281-91 PMID: 15944184
  11. PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation.
    Mol Cell Neurosci. 2002 May;20(1):21-9 PMID: 12056837
  12. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
    PLoS Med. 2008 Jan 22;5(1):e8 PMID: 18215105
  13. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo.
    Science. 2001 Dec 7;294(5549):2186-9 PMID: 11691952
  14. PDK1 regulates growth through Akt and S6K in Drosophila.
    Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15020-5 PMID: 11752451
  15. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo.
    Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12923-8 PMID: 14534328
  16. In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation.
    EMBO J. 2003 Aug 15;22(16):4202-11 PMID: 12912918
  17. Inducible Cre recombinase activity in mouse mature astrocytes and adult neural precursor cells.
    Transgenic Res. 2008 Oct;17(5):919-28 PMID: 18483774
  18. Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors.
    Development. 2004 Jan;131(1):217-28 PMID: 14660435
  19. Cerebellar granule cells: insights into proliferation, differentiation, and role in medulloblastoma pathogenesis.
    Int J Biochem Cell Biol. 2009 Mar;41(3):435-45 PMID: 18755286
  20. Regulation of cell migration by the C2 domain of the tumor suppressor PTEN.
    Science. 2004 Feb 20;303(5661):1179-81 PMID: 14976311
  21. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease.
    Nat Genet. 2001 Dec;29(4):404-11 PMID: 11726927
  22. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease.
    Nat Genet. 2001 Dec;29(4):396-403 PMID: 11726926
  23. Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice.
    Curr Biol. 2005 Oct 25;15(20):1839-46 PMID: 16243031
  24. Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass.
    Nat Genet. 2006 May;38(5):589-93 PMID: 16642023
  25. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems.
    Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1563-8 PMID: 9990064
  26. The survival pathways phosphatidylinositol-3 kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation.
    Hepatology. 2009 Jan;49(1):204-14 PMID: 19065678
  27. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
    Cancer Res. 2006 Feb 1;66(3):1500-8 PMID: 16452206
  28. PDK1, the master regulator of AGC kinase signal transduction.
    Semin Cell Dev Biol. 2004 Apr;15(2):161-70 PMID: 15209375
  29. Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo.
    Cancer Res. 2004 Nov 1;64(21):7773-9 PMID: 15520182
  30. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.
    Science. 1998 Jun 5;280(5369):1614-7 PMID: 9616126
  31. Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
    Neuroscience. 2008 Jan 24;151(2):476-88 PMID: 18082964
  32. Cell division in the CNS: protective response or lethal event in post-mitotic neurons?
    Biochim Biophys Acta. 2007 Apr;1772(4):457-66 PMID: 17158035
  33. Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia.
    EMBO J. 2003 Sep 15;22(18):4666-76 PMID: 12970179
  34. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.
    Nature. 2004 Sep 9;431(7005):200-5 PMID: 15306821
  35. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
    Science. 2005 Feb 18;307(5712):1098-101 PMID: 15718470
  36. Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke.
    Mol Neurobiol. 2006 Dec;34(3):249-70 PMID: 17308356
  37. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
    Nat Rev Genet. 2006 Aug;7(8):606-19 PMID: 16847462
  38. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells.
    Curr Biol. 2000 Apr 20;10(8):439-48 PMID: 10801415
  39. PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum.
    Development. 2002 Jul;129(14):3513-22 PMID: 12091320
  40. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice.
    Curr Biol. 1998 Oct 22;8(21):1169-78 PMID: 9799734
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1799609
Published
2009-07-15
Pages
1619-24
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2714713
Subset
IM
Grants
NCI NIH HHS · P01 CA096832 · United States
NCI NIH HHS · R01 CA135554 · United States
NCI NIH HHS · CA135554 · United States
NCI NIH HHS · CA096832 · United States
External Links
PubMed source DOI: 10.1101/gad.1799609 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2