Spry2-mediated inhibition of the Ras/ERK pathway through interaction with Src kinase following cerebral ischemia.
OBJECTIVE
Global ischemia reportedly results in intense ERK activation followed by its inactivation and mild reactivation. This study examined the molecular mechanisms underlying inhibition of the ERK pathway following cerebral ischemia in the rat hippocampus.


METHODS
Forebrain ischemia was induced by four-vessel occlusion and protein activity was assessed using co-immunoprecipitation and immunoblotting analysis.


RESULTS
Reperfusion post-ischemia induced an up-regulation in Spry2 activity through Src-Spry2 interactions, contributing to suppression of the Ras/Raf/MEK/ERK signalling cascade. The NMDA receptor antagonist, ketamine, and the Src family protein kinase inhibitor, PP2, both potently blocked the ischemia-induced up-regulation of Spry2, indicating that NMDA receptors and Src family tyrosine kinases are essential for Spry2 activity.


CONCLUSIONS
Cerebral ischemia induces a Src-mediated up-regulation of Spry2 in a NMDA receptor-dependent manner, serving as an attenuation signal in the ERK cascade.
Wu
Huiwen
H
Morphological Laboratory, Nanjing Medical University, Nanjing, China.
Li
Hongfu
H
Guo
Jun
J
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D011905:Genes, ras / Q000502:physiology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018631:ras Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism*
D009419:Nerve Tissue Proteins; C404992:Spry2 protein, rat; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins