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The Journal of Neuroscience, October 17, 2007, 27(42):11389-11400; doi:10.1523/JNEUROSCI.3473-07.2007
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Development/Plasticity/Repair
Role of Kinase Suppressor of Ras-1 in Neuronal Survival Signaling by Extracellular Signal-Regulated Kinase 1/2
Erzsebet Szatmari,1,2 Katarzyna B. Kalita,1,2 Giorgi Kharebava,1,2 andMichal Hetman1,2,3 1Kentucky Spinal Cord Injury Research Center and Departments of 2Neurological Surgery and 3Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292
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
Scaffolding proteins including kinase suppressor of Ras-1 (KSR1) determine specificity of signaling by extracellular signal-regulated kinase 1/2 (ERK1/2), enabling it to couple diverse extracellular stimuli to various cellular responses. The scaffolding protein(s) that contributes to ERK1/2-mediated neuronal survival has not yet been identified. In cultured rat cortical neurons, BDNF activates ERK1/2 to enhance neuronal survival by suppressing DNA damage- or trophic deprivation-induced apoptosis. Here we report that in this system, BDNF increased KSR1 association with activated ERK1/2, whereas KSR1 knockdown with a short hairpin (sh) RNA reduced BDNF-mediated activation of ERK1/2 and protection against a DNA-damaging drug, camptothecin (CPT). In contrast, BDNF suppression of trophic deprivation-induced apoptosis was unaffected by shKSR1 although blocked by shERK1/2. Also, overexpression of KSR1 enhanced BDNF protection against CPT. Therefore, KSR1 is specifically involved in antigenotoxic activation of ERK1/2 by BDNF. To test whether KSR1 contributes to ERK1/2 activation by other neuroprotective stimuli, we used a cAMP-elevating drug, forskolin. In cortical neurons, ERK1/2 activation by forskolin was protein kinase A (PKA) dependent but TrkB (receptor tyrosine kinase B) independent and was accompanied by the increased association between KSR1 and active ERK1/2. Forskolin suppressed CPT-induced apoptosis in a KSR1 and ERK1/2-dependent manner. Inhibition of PKA abolished forskolin protection, whereas selective PKA activation resulted in an ERK1/2- and KSR1-mediated decrease in apoptosis. Hence, KSR1 is critical for the antiapoptotic activation of ERK1/2 by BDNF or cAMP/PKA signaling. In addition, these novel data indicate that stimulation of cAMP signaling is a candidate neuroprotective strategy to intervene against neurotoxicity of DNA-damaging agents.
Key words: BDNF; cAMP; ERK1/2; KSR1; DNA damage; apoptosis
Received Feb. 12, 2007; accepted Aug. 16, 2007.
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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