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MBC in Press, published online ahead of print May 24, 2006
Mol. Biol. Cell 10.1091/mbc.E05-12-1144

A more recent version of this article appeared on August 1, 2006
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Submitted on December 16, 2005
Revised on May 1, 2006
Accepted on May 11, 2006

Activation of CK2 and Inhibition of PTEN Phosphatase by NGF/p75NTR Inhibits GSK-3{beta} and Stimulates Axonal Growth

María-Angeles Arevalo and Alfredo Rodríguez-Tébar

Instituto Cajal de Neurobiología, CSIC, E28002 Madrid, Spain

Monitoring Editor: Richard Assoian

Axonal elongation and guidance are controlled by extracellular factors such as the neurotrophins. Indeed, NGF appears to promote axon growth through binding to its p75NTR receptor and inactivating RhoA. Furthermore, the local inhibition of GSK-3{beta} by NGF also favors microtubule polymerization and axon extension. Inactivation of GSK-3{beta} may be due to the NGF/TrkA mediated activation of phosphatydilinositol 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{beta} through an alternative mechanism. In cultured hippocampal neurons, the capacity of NGF to promote axon elongation is mostly mediated by p75NTR and the activation of this pathway leads to the inactivation of GSK-3{beta}. However, the signaling pathway triggered by NGF/p75NTR acts through casein kinase II (CK2). NGF/p75NTR-activated CK2 phosphorylates PTEN (the phosphatase and tensin homologue deleted on chromosome 10), 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{beta} 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: Alfredo Rodríguez-Tébar (rodriguez{at}cajal.csic.es)






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