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

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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.