RGD Reference Report - Requirement of 3-phosphoinositide-dependent protein kinase-1 for BDNF-mediated neuronal survival. - Rat Genome Database

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Requirement of 3-phosphoinositide-dependent protein kinase-1 for BDNF-mediated neuronal survival.

Authors: Kharebava, G  Makonchuk, D  Kalita, KB  Zheng, JJ  Hetman, M 
Citation: Kharebava G, etal., J Neurosci. 2008 Oct 29;28(44):11409-20. doi: 10.1523/JNEUROSCI.2135-08.2008.
RGD ID: 10449508
Pubmed: PMID:18971483   (View Abstract at PubMed)
PMCID: PMC3383049   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.2135-08.2008   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to brain-derived neurotrophic factor stimulus  IEP 10449508 RGD 
negative regulation of neuron apoptotic process  IMP 10449508 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
perikaryon  IDA 10449508 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pdpk1  (3-phosphoinositide dependent protein kinase-1)


Additional Information