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Nerve growth factor-mediated neurite outgrowth via regulation of Rab5.

Nerve growth factor (NGF) induces neurite outgrowth and differentiation in a process that involves NGF binding to its receptor TrkA and endocytosis of the NGF-TrkA complex into signaling endosomes. Here, we find that biogenesis of signaling endosomes requires inactivation of Rab5 to block early endosome fusion. Expression of dominant-negative Rab5 mutants enhanced NGF-mediated neurite outgrowth, whereas a constitutively active Rab5 mutant or Rabex-5 inhibited this process. Consistently, inactivation of Rab5 sustained TrkA activation on the endosomes. Furthermore, NGF treatment rapidly decreased cellular level of active Rab5-GTP, as shown by pull-down assays. This Rab5 down-regulation was mediated by RabGAP5, which was shown to associate with TrkA by coimmunoprecipitation assays. Importantly, RNA interference of RabGAP5 as well as a RabGAP5 truncation mutant containing the TrkA-binding domain blocked NGF-mediated neurite outgrowth, indicating a requirement for RabGAP5 in this process. Thus, NGF signaling down-regulates Rab5 activity via RabGAP5 to facilitate neurite outgrowth and differentiation.

Pubmed ID: 17267689

Authors

  • Liu J
  • Lamb D
  • Chou MM
  • Liu YJ
  • Li G

Journal

Molecular biology of the cell

Publication Data

April 29, 2007

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM074692

Mesh Terms

  • Animals
  • Down-Regulation
  • GTPase-Activating Proteins
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors
  • Guanosine Triphosphate
  • Mutation
  • Nerve Growth Factor
  • Neurites
  • PC12 Cells
  • Rats
  • Receptor, trkA
  • Signal Transduction
  • rab5 GTP-Binding Proteins