Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex.
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. We identify 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.
Namekata
Kazuhiko
K
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan.
Harada
Chikako
C
Taya
Choji
C
Guo
Xiaoli
X
Kimura
Hideo
H
Parada
Luis F
LF
Harada
Takayuki
T
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism* / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009900:Optic Nerve / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; C485840:DOCK3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D051300:Wiskott-Aldrich Syndrome Protein Family; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn