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MBC in Press, published online ahead of print January 31, 2007
Mol. Biol. Cell 10.1091/mbc.E06-08-0725

A more recent version of this article appeared on April 1, 2007
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Submitted on August 17, 2006
Revised on December 18, 2006
Accepted on January 24, 2007

NGF-mediated Neurite Outgrowth via Regulation of Rab5

Jay Liu,* Darija Lamb,* Margaret M. Chou, Yong-Jian Liu,{ddagger} and Guangpu Li*

*Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; {dagger}Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; {ddagger}Department of Neurology and Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

Monitoring Editor: Francis Barr

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, while a constitutive 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 RNAi 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.

Address correspondence to: Guangpu Li (guangpu-li{at}ouhsc.edu)






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