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 Citations (Scopus)

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
StatePublished - Apr 20 2010

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PDZ Domains
Brain-Derived Neurotrophic Factor
Wiskott-Aldrich Syndrome Protein Family
Rho Guanine Nucleotide Exchange Factors
Nerve Regeneration
Membranes
Optic Nerve
Transgenic Mice
Regeneration
Phosphorylation
Cell Membrane
Amino Acids
Wounds and Injuries
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. / Namekata, Kazuhiko; Harada, Chikako; Taya, Choji; Guo, Xiaoli; Kimura, Hideo; Parada, Luis F.; Harada, Takayuki.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 16, 20.04.2010, p. 7586-7591.

Research output: Contribution to journalArticle

Namekata, Kazuhiko ; Harada, Chikako ; Taya, Choji ; Guo, Xiaoli ; Kimura, Hideo ; Parada, Luis F. ; Harada, Takayuki. / Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 16. pp. 7586-7591.
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