Akt and PP2A Reciprocally Regulate the Guanine Nucleotide Exchange Factor Dock6 to Control Axon Growth of Sensory Neurons

Yuki Miyamoto^1,2, Tomohiro Torii¹, Natsuki Yamamori^1,3, Toru Ogata⁴, Akito Tanoue¹, and Junji Yamauchi^1,2,3*

¹ Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
² The Japan Human Sciences Foundation, Chuo, Tokyo 103-0001, Japan.
³ Department of Biological Sciences, Tokyo Institute of Technology, Midori, Yokohama 226-8501, Japan.
⁴ Department of Rehabilitation for the Movement Functions, National Rehabilitation Center for Persons with Disabilities, Saitama 359-8555, Japan.

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 Ser¹¹⁹⁴ 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 Ser¹¹⁹⁴. 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 Ser¹¹⁹⁴ 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.

* To whom correspondence should be addressed. E-mail: yamauchi-j{at}ncchd.go.jp or jyamauchi{at}nch.go.jp

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