The TrkB-Shc Site Signals Neuronal Survival and Local Axon Growth via MEK and PI3-Kinase

The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilitates Akt activation and stimulates GSK-3β inactivation, promoting microtubule polymerization and axon elongation. However, the molecular mechanisms that govern the spatial down-regulation of PtdIns(3,4,5)P3 signaling at the growth cone remain undetermined. The inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze the 5-position phosphate from phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and/or PtdIns(3,4,5)P3. We demonstrate here that PIPP, an uncharacterized 5-phosphatase, hydrolyzes PtdIns(3,4,5)P3 forming PtdIns(3,4)P2, decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to the plasma membrane of undifferentiated cells and the neurite shaft and growth cone of NGF-differentiated neurites. Overexpression of wild-type, but not catalytically inactive PIPP, in PC12 cells inhibited neurite elongation. Targeted depletion of PIPP using RNA interference (RNAi) resulted in enhanced neurite differentiation, associated with neurite hyperelongation. Inhibition of PI3-kinase activity prevented neurite hyperelongation in PIPP-deficient cells. PIPP targeted-depletion resulted in increased phospho-Ser473-Akt and phospho-Ser9-GSK-3β, specifically at the neurite growth cone, and accumulation of PtdIns(3,4,5)P3 at this site, associated with enhanced microtubule polymerization in the neurite shaft. PIPP therefore inhibits PI3-kinase-dependent neurite elongation in PC12 cells, via regulation of the spatial distribution of phospho-Ser473-Akt and phospho-Ser9-GSK-3β signaling.

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Rac1 plays an essential role in axon growth and guidance and in neuronal survival in the central and peripheral nervous systems

Neural Development ◽

10.1186/s13064-015-0049-3 ◽

2015 ◽

Vol 10 (1) ◽

Cited By ~ 22

Author(s):

Zhong L. Hua ◽

Francesco E. Emiliani ◽

Jeremy Nathans

Keyword(s):

Essential Role ◽

Neuronal Survival ◽

Axon Growth ◽

Nervous Systems ◽

Peripheral Nervous Systems

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Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

eNeuro ◽

10.1523/eneuro.0325-20.2020 ◽

2020 ◽

Vol 7 (6) ◽

pp. ENEURO.0325-20.2020

Author(s):

Márcio Ribeiro ◽

Konstantin Levay ◽

Benito Yon ◽

Ana C. Ayupe ◽

Yadira Salgueiro ◽

...

Keyword(s):

Neuronal Survival ◽

Axon Growth ◽

Neural Cadherin

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Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons

Neuropharmacology ◽

10.1016/s0028-3908(03)00273-9 ◽

2003 ◽

Vol 45 (7) ◽

pp. 995-1010 ◽

Cited By ~ 25

Author(s):

B MacInnis

Keyword(s):

Kinase Activity ◽

Neuronal Survival ◽

Sympathetic Neurons ◽

Axon Growth

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Depolarization and Neurotrophins Converge on the Phosphatidylinositol 3-Kinase–Akt Pathway to Synergistically Regulate Neuronal Survival

The Journal of Cell Biology ◽

10.1083/jcb.146.5.955 ◽

1999 ◽

Vol 146 (5) ◽

pp. 955-966 ◽

Cited By ~ 177

Author(s):

A.R. Vaillant ◽

I. Mazzoni ◽

C. Tudan ◽

M. Boudreau ◽

D.R. Kaplan ◽

...

Keyword(s):

Neural Activity ◽

Recombinant Adenovirus ◽

Neuronal Survival ◽

Sympathetic Neurons ◽

Pi3 Kinase ◽

General Mechanism ◽

Akt Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Akt Phosphorylation ◽

Phosphatidylinositol 3

In this report, we have examined the mechanisms whereby neurotrophins and neural activity coordinately regulate neuronal survival, focussing on sympathetic neurons, which require target-derived NGF and neural activity for survival during development. When sympathetic neurons were maintained in suboptimal concentrations of NGF, coincident depolarization with concentrations of KCl that on their own had no survival effect, synergistically enhanced survival. Biochemical analysis revealed that depolarization was sufficient to activate a Ras-phosphatidylinositol 3-kinase–Akt pathway (Ras–PI3-kinase–Akt), and function-blocking experiments using recombinant adenovirus indicated that this pathway was essential for ∼50% of depolarization-mediated neuronal survival. At concentrations of NGF and KCl that promoted synergistic survival, these two stimuli converged to promote increased PI3-kinase–dependent Akt phosphorylation. This convergent PI3-kinase–Akt pathway was essential for synergistic survival. In contrast, inhibition of calcium/calmodulin-dependent protein kinase II revealed that, while this molecule was essential for depolarization-induced survival, it had no role in KCl- induced Akt phosphorylation, nor was it important for synergistic survival by NGF and KCl. Thus, NGF and depolarization together mediate survival of sympathetic neurons via intracellular convergence on a Ras–PI3-kinase–Akt pathway. This convergent regulation of Akt may provide a general mechanism for coordinating the effects of growth factors and neural activity on neuronal survival throughout the nervous system.

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