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Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2.

Abstract
Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, a negative regulator of Ras. Neurofibromin is implicated in the neuronal abnormality of NF1 patients; however, the precise cellular function of neurofibromin has yet to be clarified. Using proteomic strategies, we identified a set of neurofibromin-associating cellular proteins, including axon regulator CRMP-2 (Collapsin response mediator protein-2). CRMP-2 directly bound to the C-terminal domain of neurofibromin, and this association was regulated by the manner of CRMP-2 phosphorylation. In nerve growth factor-stimulated PC12 cells, neurofibromin and CRMP-2 co-localized particularly on the distal tips and branches of extended neurites. Suppression of neurofibromin using NF1 small interfering RNA significantly inhibited this neurite outgrowth and up-regulated a series of CRMP-2 phosphorylations by kinases identified as CDK5, GSK-3b, and Rho kinase. Overexpression of the NF1-RAS-GAP-related domain rescued these NF1 small interfering RNA-induced events. Our results suggest that neurofibromin regulates neuronal differentiation by performing one or more complementary roles. First, neurofibromin directly regulates CRMP-2 phosphorylation accessibility through the complex formation. Also, neurofibromin appears to indirectly regulate CRMP-2 activity by suppressing CRMP-2-phosphorylating kinase cascades via its Ras-GAP function. Our study demonstrates that the functional association of neurofibromin and CRMP-2 is essential for neuronal cell differentiation and that lack of expression or abnormal regulation of neurofibromin can result in impaired function of neuronal cells, which is likely a factor in NF1-related pathogenesis.
AuthorsSiriporn Patrakitkomjorn, Daiki Kobayashi, Takashi Morikawa, Masayo Morifuji Wilson, Nobuyuki Tsubota, Atsushi Irie, Tatsuya Ozawa, Masashi Aoki, Nariko Arimura, Kozo Kaibuchi, Hideyuki Saya, Norie Araki
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 14 Pg. 9399-413 (Apr 04 2008) ISSN: 0021-9258 [Print] United States
PMID18218617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • GTPase-Activating Proteins
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Neurofibromin 1
  • RNA, Small Interfering
  • collapsin response mediator protein-2
  • Nerve Growth Factor
  • Cyclin-Dependent Kinase 5
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Gsk3b protein, rat
  • rho-Associated Kinases
  • CDK5 protein, human
  • Cdk5 protein, mouse
  • Cdk5 protein, rat
  • Glycogen Synthase Kinase 3
  • Oncogene Protein p21(ras)
Topics
  • Animals
  • Cell Differentiation (drug effects, genetics)
  • Cyclin-Dependent Kinase 5 (genetics, metabolism)
  • GTPase-Activating Proteins (genetics, metabolism)
  • Glycogen Synthase Kinase 3 (genetics, metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Intercellular Signaling Peptides and Proteins (genetics, metabolism)
  • Mice
  • Nerve Growth Factor (pharmacology)
  • Nerve Tissue Proteins (genetics, metabolism)
  • Neurites (metabolism, pathology)
  • Neurofibromatosis 1 (genetics, metabolism, pathology)
  • Neurofibromin 1 (antagonists & inhibitors, genetics, metabolism)
  • Oncogene Protein p21(ras) (genetics, metabolism)
  • PC12 Cells
  • Phosphorylation (drug effects)
  • Protein Structure, Tertiary (genetics)
  • Proteomics (methods)
  • RNA, Small Interfering (genetics)
  • Rats
  • Up-Regulation (drug effects)
  • rho-Associated Kinases (genetics, metabolism)

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