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The Journal of Neuroscience, October 29, 2008, 28(44):11409-11420; doi:10.1523/JNEUROSCI.2135-08.2008

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Development/Plasticity/Repair
Requirement of 3-Phosphoinositide-Dependent Protein Kinase-1 for BDNF-Mediated Neuronal Survival

Giorgi Kharebava,^1,2 Denys Makonchuk,^1,2 Katarzyna B. Kalita,^1,2,4 Jing-Juan Zheng,^1,2 and Michal Hetman^1,2,3

¹Kentucky Spinal Cord Injury Research Center and Departments of ²Neurological Surgery and ³Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292, and ⁴Nencki Institute, 02-093 Warsaw, Poland

Correspondence should be addressed to Michal Hetman, Kentucky Spinal Cord Injury Research Center, University of Louisville, 511 South Floyd Street, MDR616, Louisville, KY 40292. Email: michal.hetman{at}louisville.edu

Although PDK1 regulates several signaling pathways that respond to neurotrophins, direct evidence for its involvement in neurotrophin-mediated survival has not yet been reported. Here we show high neuronal expression of active PDK1 in the rat cortex and hippocampus at the developmental stages with pronounced dependence on extracellular survival signals. Also, in cultured cortical neurons from newborn rats, BDNF resulted in PDK1- and extracellular signal-regulated kinase-1/2 (ERK1/2)-mediated activation of their direct target, the p90 ribosomal S6 kinase 1/2 (RSK1/2). In trophic-deprived cortical neurons, knockdown of endogenous PDK1 attenuated the antiapoptotic survival response to 10 ng/ml BDNF, whereas an overexpressed active mutant form of PDK1 reduced apoptosis. The neuroprotection by BDNF or active PDK1 required RSK1/2. Conversely, PDK1 knockdown reversed the survival effects of combining the overexpressed RSK1 with a low, subprotective BDNF concentration of 2 ng/ml. Likewise, the protection by the overexpressed, active PDK1 was enhanced by coexpression of an active RSK1 mutant. Consistent with the observations that in BDNF-stimulated neurons RSK1/2 activation required both PDK1 and ERK1/2, ERK1/2 knockdown removed BDNF-mediated survival. Selective activation of ERK1/2 with an overexpressed active mutant form of MKK1 resulted in RSK1/2- and PDK1-dependent neuroprotection. Finally, at subprotective plasmid DNA dosage, overexpression of the active MKK1 and PDK1 mutants produced synergistic effect on survival. Our findings indicate a critical role for PDK1-RSK1/2 signaling in BDNF-mediated neuronal survival. Thus, the PDK1 is indispensable for the antiapoptotic effects of the ERK1/2 pathway offering previously unrecognized layer of survival signal processing and integration.

Key words: neurotrophins; TrkB; p90RSK; MAP-kinase; protein kinase B; Akt; development; survival

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Received May 9, 2008; revised Sept. 11, 2008; accepted Sept. 24, 2008.

Correspondence should be addressed to Michal Hetman, Kentucky Spinal Cord Injury Research Center, University of Louisville, 511 South Floyd Street, MDR616, Louisville, KY 40292. Email: michal.hetman{at}louisville.edu

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