Home LiteratureArticle Details
PMID: 9852579 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

p21 ras and phosphatidylinositol-3 kinase are required for survival of wild-type and NF1 mutant sensory neurons.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 18 ·No. 24 ·1998-12-15 ·Pages 10420-8

Klesse LJ, Parada LF

Abstract

Nerve growth factor (NGF) is a required differentiation and survival factor for sympathetic and a majority of neural crest-derived sensory neurons in the developing vertebrate peripheral nervous system. Although much is known about the function of NGF, the intracellular signaling cascade that it uses continues to be a subject of intense study. p21 ras signaling is considered necessary for sensory neuron survival. How additional intermediates downstream or in parallel may function has not been fully understood yet. Two intracellular signaling cascades, extra cellular regulated kinase (erk) and phosphatidylinositol-3 (PI 3) kinase, transduce NGF signaling in the pheochromocytoma cell line PC12. To elucidate the role these cascades play in survival and differentiation, we used a combination of recombinant adenoviruses and chemical inhibitors to perturb these pathways in sensory neurons from wild-type mice and mice deficient for neurofibromin in which the survival and differentiation pathway is constitutively active. We demonstrate that ras activity is both necessary and sufficient for the survival of embryonic sensory neurons. Downstream of ras, however, the erk cascade is neither required nor sufficient for neuron survival or overall differentiation. Instead, the activity of PI 3 kinase is necessary for the survival of the wild-type and neurofibromin-deficient neurons. Therefore, we conclude that in sensory neurons, NGF acts via a signaling pathway, which includes both ras and PI 3 kinase.

MeSH Terms
Adenoviridae/genetics Animals Cell Differentiation/drug effects Cell Survival/drug effects,genetics Cells, Cultured Chromones/pharmacology Embryo, Mammalian Enzyme Activation Gene Deletion MAP Kinase Kinase 1 Mice Mice, Neurologic Mutants Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases/metabolism Morpholines/pharmacology Nerve Tissue Proteins/genetics Neurofibromin 1 Neurons, Afferent/drug effects,metabolism,physiology Phosphatidylinositol 3-Kinases/physiology Phosphoinositide-3 Kinase Inhibitors Protein Serine-Threonine Kinases/genetics,physiology Protein-Tyrosine Kinases/genetics,physiology Proteins/genetics Proto-Oncogene Proteins c-raf/genetics,physiology Proto-Oncogene Proteins p21(ras)/genetics,physiology
Chemicals
Chromones Morpholines Nerve Tissue Proteins Neurofibromin 1 Phosphoinositide-3 Kinase Inhibitors Proteins 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Protein-Tyrosine Kinases Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-raf Mitogen-Activated Protein Kinases MAP Kinase Kinase 1 Map2k1 protein, mouse Mitogen-Activated Protein Kinase Kinases Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Klesse L J
Center for Developmental Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75235-9133, USA.
Parada L F
References (60)
60 references, click to expand
  1. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.
    Science. 1997 Oct 24;278(5338):687-9 PMID: 9381178
  2. Rescue of a Drosophila NF1 mutant phenotype by protein kinase A.
    Science. 1997 May 2;276(5313):791-4 PMID: 9115203
  3. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)
    Cell. 1996 Nov 15;87(4):619-28 PMID: 8929531
  4. Mitogen-activated protein kinase-independent pathways mediate the effects of nerve growth factor and cAMP on neuronal survival.
    J Biol Chem. 1996 Aug 23;271(34):20713-8 PMID: 8702822
  5. Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.
    Cell. 1995 Sep 8;82(5):733-42 PMID: 7671302
  6. Nerve growth factor-induced process formation by cultured rat pheochromocytoma cells.
    Nature. 1975 Nov 27;258(5533):341-2 PMID: 1196362
  7. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP.
    Mol Cell Biol. 1988 Aug;8(8):3235-43 PMID: 3145408
  8. Characterization of apoptosis in cultured rat sympathetic neurons after nerve growth factor withdrawal.
    J Cell Biol. 1994 Feb;124(4):537-46 PMID: 8106551
  9. Neurotrophin signal transduction by the Trk receptor.
    J Neurobiol. 1994 Nov;25(11):1404-17 PMID: 7852994
  10. Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons.
    J Cell Biol. 1993 May;121(3):665-72 PMID: 8486743
  11. Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene.
    Science. 1992 Oct 9;258(5080):302-4 PMID: 1411528
  12. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1.
    Nature. 1993 Jul 22;364(6435):308-13 PMID: 8332187
  13. ras p21 protein promotes survival and fiber outgrowth of cultured embryonic neurons.
    Neuron. 1989 Jan;2(1):1087-96 PMID: 2696501
  14. Active p21Ras is sufficient for rescue of NGF-dependent rat sympathetic neurons.
    Neuroscience. 1996 Feb;70(4):1067-79 PMID: 8848168
  15. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase.
    Genes Dev. 1992 Apr;6(4):545-56 PMID: 1313769
  16. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.
    Genes Dev. 1994 May 1;8(9):1019-29 PMID: 7926784
  17. Intracellular signaling pathways activated by neurotrophic factors.
    Annu Rev Neurosci. 1996;19:463-89 PMID: 8833451
  18. Neurotrophin regulation of the developing nervous system: analyses of knockout mice.
    Rev Neurosci. 1997 Jan-Mar;8(1):13-27 PMID: 9402642
  19. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells.
    Cell. 1994 Jun 17;77(6):841-52 PMID: 7911739
  20. Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells.
    Mol Cell Biol. 1990 Oct;10(10):5324-32 PMID: 2118994
  21. Inhibition of growth factor-induced differentiation of PC12 cells by microinjection of antibody to ras p21.
    Nature. 1986 Feb 20-26;319(6055):680-2 PMID: 3005866
  22. Multiple agents rescue PC12 cells from serum-free cell death by translation- and transcription-independent mechanisms.
    J Neurosci. 1991 Aug;11(8):2552-63 PMID: 1714494
  23. Neutralizing anti-p21ras Fabs suppress rat sympathetic neuron survival induced by NGF, LIF, CNTF and cAMP.
    Eur J Neurosci. 1995 Feb 1;7(2):344-50 PMID: 7757268
  24. Adenovirus-mediated transfer of the muscle glycogen phosphorylase gene into hepatocytes confers altered regulation of glycogen metabolism.
    J Biol Chem. 1992 Dec 15;267(35):25129-34 PMID: 1334082
  25. Neurite outgrowth of PC12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase.
    J Biol Chem. 1994 Jul 22;269(29):18961-7 PMID: 8034653
  26. Neurofibromin can inhibit Ras-dependent growth by a mechanism independent of its GTPase-accelerating function.
    Mol Cell Biol. 1994 Jan;14(1):641-5 PMID: 8264632
  27. Signal transduction by the neurotrophin receptors.
    Curr Opin Cell Biol. 1997 Apr;9(2):213-21 PMID: 9069267
  28. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
    Cell. 1997 Oct 17;91(2):231-41 PMID: 9346240
  29. Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides.
    Science. 1997 May 2;276(5313):795-8 PMID: 9115204
  30. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death.
    Cell. 1995 Jan 27;80(2):285-91 PMID: 7834748
  31. Regulators of cell death.
    Trends Genet. 1995 Mar;11(3):101-5 PMID: 7732571
  32. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75.
    Nature. 1996 Oct 24;383(6602):716-9 PMID: 8878481
  33. Mechanism of activation of a human oncogene.
    Nature. 1982 Nov 11;300(5888):143-9 PMID: 6290897
  34. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.
    EMBO J. 1996 May 15;15(10):2442-51 PMID: 8665852
  35. Ras p21 protein promotes survival and differentiation of human embryonic neural crest-derived cells.
    Neuroscience. 1996 Aug;73(4):1121-7 PMID: 8809829
  36. Akt is a direct target of the phosphatidylinositol 3-kinase. Activation by growth factors, v-src and v-Ha-ras, in Sf9 and mammalian cells.
    J Biol Chem. 1996 Nov 29;271(48):30835-9 PMID: 8940066
  37. Regulation of neuronal survival by the serine-threonine protein kinase Akt.
    Science. 1997 Jan 31;275(5300):661-5 PMID: 9005851
  38. Nerve growth factor prevents the death and stimulates the neuronal differentiation of clonal PC12 pheochromocytoma cells in serum-free medium.
    J Cell Biol. 1978 Sep;78(3):747-55 PMID: 701359
  39. Inhibition of p42 and p44 mitogen-activated protein kinase activity by PD98059 does not suppress nerve growth factor-induced survival of sympathetic neurones.
    J Neurochem. 1996 Nov;67(5):1801-5 PMID: 8863483
  40. Neurofibromatosis type 1 and Ras-mediated signaling: filling in the GAPs.
    Biochim Biophys Acta. 1995 Jul 28;1242(1):43-59 PMID: 7626654
  41. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor.
    Nature. 1998 Apr 9;392(6676):622-6 PMID: 9560161
  42. Neuronal precursor cells in chick dorsal root ganglia: differentiation and survival in vitro.
    Dev Biol. 1988 Apr;126(2):420-32 PMID: 2450797
  43. p75NTR and apoptosis: Trk-dependent and Trk-independent effects.
    Trends Neurosci. 1997 Jul;20(7):287-90 PMID: 9223218
  44. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.
    Science. 1995 Nov 24;270(5240):1326-31 PMID: 7481820
  45. Phosphatidylinositol-3-OH kinase as a direct target of Ras.
    Nature. 1994 Aug 18;370(6490):527-32 PMID: 8052307
  46. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.
    Cell. 1995 Jun 2;81(5):727-36 PMID: 7774014
  47. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae.
    Cell. 1990 Nov 16;63(4):835-41 PMID: 2121369
  48. Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation.
    Cell. 1985 Oct;42(3):841-8 PMID: 2996779
  49. Mutational activation of c-raf-1 and definition of the minimal transforming sequence.
    Mol Cell Biol. 1990 Jun;10(6):2503-12 PMID: 2188091
  50. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death.
    Neuron. 1995 May;14(5):927-39 PMID: 7748560
  51. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins.
    Cell. 1990 Nov 16;63(4):851-9 PMID: 2121371
  52. The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction.
    Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5016-20 PMID: 8389463
  53. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons.
    J Neurosci. 1998 Apr 15;18(8):2933-43 PMID: 9526010
  54. Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro.
    J Biol Chem. 1993 Mar 5;268(7):5097-106 PMID: 8444886
  55. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death.
    Semin Cancer Biol. 1993 Dec;4(6):327-32 PMID: 8142617
  56. Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells.
    Oncogene. 1999 Mar 25;18(12):2055-68 PMID: 10321730
  57. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor.
    Science. 1995 Mar 31;267(5206):2003-6 PMID: 7701324
  58. Initiation and maintenance of NGF-stimulated neurite outgrowth requires activation of a phosphoinositide 3-kinase.
    J Cell Sci. 1996 Feb;109 ( Pt 2):289-300 PMID: 8838652
  59. Induction of cell death by endogenous nerve growth factor through its p75 receptor.
    Nature. 1996 Sep 12;383(6596):166-8 PMID: 8774880
  60. Dorsal root ganglion neurons require functional neurotrophin receptors for survival during development.
    Philos Trans R Soc Lond B Biol Sci. 1996 Mar 29;351(1338):395-403 PMID: 8730777
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
0270-6474
Published
1998-12-15
Pages
10420-8
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6793354
Subset
IM
Grants
NINDS NIH HHS · R01 NS034296 · United States
NINDS NIH HHS · R01-NS34296 · United States
External Links
PubMed source 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: [email protected]

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