Sema4D/plexin-B1 activates GSK-3β through R-Ras GAP activity, inducing growth cone collapse

Yuri Ito, Izumi Oinuma, Hironori Katoh, Kozo Kaibuchi, Manabu Negishi

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

Abstract

Plexins are receptors for the axonal guidance molecules known as semaphorins, and the semaphorin 4D (Sema4D) receptor plexin-B1 induces repulsive responses by functioning as an R-Ras GTPase-activating protein (GAP). Here we characterized the downstream signalling of plexin-B1-mediated R-Ras GAP activity, inducing growth cone collapse. Sema4D suppressed R-Ras activity in hippocampal neurons, in parallel with dephosphorylation of Akt and activation of glycogen synthase kinase (GSK)-3β. Ectopic expression of the constitutively active mutant of Akt or treatment with GSK-3 inhibitors suppressed the Sema4D-induced growth cone collapse. Constitutive activation of phosphatidylinositol-3-OH kinase (PI(3)K), an upstream kinase of Akt and GSK-3β, also blocked the growth cone collapse. The R-Ras GAP activity was necessary for plexin-B1-induced dephosphorylation of Akt and activation of GSK-3β and was also required for phosphorylation of a downstream kinase of GSK-3β, collapsin response mediator protein-2. Plexin-A1 also induced dephosphorylation of Akt and GSK-3β through its R-Ras GAP activity. We conclude that plexin-B1 inactivates PI(3)K and dephosphorylates Akt and GSK-3β through R-Ras GAP activity, inducing growth cone collapse.

Original languageEnglish
Pages (from-to)704-709
Number of pages6
JournalEMBO Reports
Volume7
Issue number7
DOIs
Publication statusPublished - 07-2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics

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