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Vol. 17, Issue 8, 3369-3377, August 2006

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Activation of Casein Kinase II and Inhibition of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Phosphatase by Nerve Growth Factor/p75^NTR Inhibit Glycogen Synthase Kinase-3 and Stimulate Axonal Growth

Instituto Cajal de Neurobiología, Consejo Superior de Investigaciones Cientificas, E28002 Madrid, Spain

Submitted December 16, 2005; Revised May 1, 2006; Accepted May 11, 2006
Monitoring Editor: Richard Assoian

Axonal elongation and guidance are controlled by extracellular factors such as the neurotrophins. Indeed, nerve growth factor (NGF) seems to promote axon growth through binding to its p75^NTR receptor and inactivating RhoA. Furthermore, the local inhibition of glycogen synthase kinase (GSK)-3 by NGF also favors microtubule polymerization and axon extension. Inactivation of GSK-3 may be due to the NGF/TrkA-mediated activation of phosphatidylinositol-3 kinase (PI-3 kinase), which increases the levels of phosphatydilinositol 3-phosphate [PI(3)P]. However, we show here that NGF may inactivate GSK-3 through an alternative mechanism. In cultured hippocampal neurons, the capacity of NGF to promote axon elongation is mostly mediated by p75^NTR, and the activation of this pathway leads to the inactivation of GSK-3. However, the signaling pathway triggered by NGF/p75^NTR acts through casein kinase II (CK2). NGF/p75^NTR-activated CK2 phosphorylates the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), thus rendering this phosphatase inactive. Like activation of the PI-3 kinase, PTEN inactivation allows PI(3)P levels to increase, thus favoring GSK-3 inactivation and axon outgrowth. This newly disclosed mechanism may help to extend the repertoire of pharmacological agents that activate CK2 or that inhibit PTEN to stimulate axon regeneration after trauma or disease.

Address correspondence to: A. Rodríguez-Tébar ( rodriguez{at}cajal.csic.es)

Abbreviations used: bpV(pic), dipotassium bisperoxo(picolinato) oxovanadate (V); DMAT, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole.