Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling.
Netrins are prototypical axon guidance cues whose attractive signaling requires the small GTPase Rac1. It remains unclear how Rac1 is regulated in the netrin pathway. DOCK180 is a member of a new family of guanine nucleotide exchange factors for Rho GTPases. Here we provide evidence implicating DOCK180 in netrin signal transduction. Netrin promoted the formation of a protein-protein interaction complex that included DOCK180 and the netrin receptor deleted in colorectal carcinoma (DCC). Inhibition of DOCK180 reduced activation of Rac1 by netrin. Both axon outgrowth and axon attraction induced by netrin were inhibited after DOCK180 knockdown in vertebrate neurons. The in vivo functional role of DOCK180 was demonstrated by its requirement for projection of commissural axons in the neural tube. These findings indicate that netrin stimulation recruits DOCK180 through DCC, which then activates small GTPases, suggesting an essential role for DOCK180 in mediating attractive responses by neurons to netrin-1.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Xiaoling
X
Li
Xue
X
Gao
Guofa
G
Liu
Wencheng
W
Xiong
Jane
J
Wu
Yi
Y
Rao
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D015179:Colorectal Neoplasms / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D005625:Frontal Lobe / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020439:Growth Cones / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D009154:Mutation / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein