Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex

Kazuhiko Namekata, Chikako Harada, Choji Taya, Xiaoli Guo, Hideo Kimura, Luis F. Parada, Takayuki Harada

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Atypical Rho-guanine nucleotide exchange factors (Rho-GEFs) that contain Dock homology regions (DHR-1 and DHR-2) are expressed in a variety of tissues; however, their functions and mechanisms of action remain unclear. Weidentify key conserved amino acids in the DHR-2 domain that are critical for the catalytic activity of Dock-GEFs (Dock1-4). We further demonstrate that Dock-GEFs directly associate with WASP family verprolin-homologous (WAVE) proteins through the DHR-1 domain. Brain-derived neurotrophic factor (BDNF)-TrkB signaling recruits the Dock3/WAVE1 complex to the plasma membrane, whereupon Dock3 activates Rac and dissociates from the WAVE complex in a phosphorylation-dependent manner. BDNF induces axonal sprouting through Dock-dependent Rac activation, and adult transgenic mice overexpressing Dock3 exhibit enhanced optic nerve regeneration after injury without affecting WAVE expression levels. Our results highlight a unique mechanism through which Dock-GEFs achieve spatial and temporal restriction of WAVE signaling, and identify Dock-GEF activity as a potential therapeutic target for axonal regeneration.

Original languageEnglish (US)
Pages (from-to)7586-7591
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number16
DOIs
Publication statusPublished - Apr 20 2010

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Keywords

  • Axonal regeneration
  • Brain-derived neurotrophic factor
  • Dock family proteins
  • Fyn
  • Optic nerve

ASJC Scopus subject areas

  • General

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