title: Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons.
abstract: During neuronal development, axons navigate long distances, eventually forming precise connections with such targets as peripheral tissues. Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. We found that phosphorylation of Ser(1194) in Dock6 inhibited its GEF activity and suppressed axonal growth of embryonic sensory neurons and axon regeneration of postnatal sensory neurons in vitro and in vivo. At early developmental stages, when axons are growing, the protein phosphatase PP2A interacted with and dephosphorylated Dock6, thereby increasing the activity of Dock6. At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching. Thus, the phosphorylation status of Dock6 at Ser(1194) determines whether it promotes axon extension or branching in sensory neurons, revealing interplay between kinase and phosphatase action on a Rho-GEF during axon growth.
authors: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors: Yuki
authors: Y
authors: Miyamoto
authors: Tomohiro
authors: T
authors: Torii
authors: Natsuki
authors: N
authors: Yamamori
authors: Toru
authors: T
authors: Ogata
authors: Akito
authors: A
authors: Tanoue
authors: Junji
authors: J
authors: Yamauchi
mesh_terms: D000818:Animals; D001369:Axons; D001483:Base Sequence; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000166:cytology*; D012694:Serine / Q000378:metabolism
chemical_list: D017931:DNA Primers; C518736:Dock6 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2