TY - JOUR
T1 - Sema4D/plexin-B1 activates GSK-3β through R-Ras GAP activity, inducing growth cone collapse
AU - Ito, Yuri
AU - Oinuma, Izumi
AU - Katoh, Hironori
AU - Kaibuchi, Kozo
AU - Negishi, Manabu
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.embor.7400737
DO - 10.1038/sj.embor.7400737
M3 - Article
C2 - 16799460
AN - SCOPUS:33745603987
VL - 7
SP - 704
EP - 709
JO - EMBO Reports
JF - EMBO Reports
SN - 1469-221X
IS - 7
ER -