GRASP-1 is a neuronal scaffold protein for the JNK signaling pathway.
GRASP-1 is a neuronally enriched protein that interacts with the AMPA-type glutamate receptor/GRIP complex. GRASP-1 can be cleaved by Caspase-3 in both normal and ischemic brains although the functional significance of this cleavage remains elusive. We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. Furthermore, mutations that prevent Caspase 3-cleavage of GRASP-1 dramatically inhibit the JNK pathway activating activity of GRASP-1, suggesting a novel link between Caspase-3 activation and JNK pathway signaling. These results suggest that GRASP-1 serves as a scaffold protein to facilitate MEKK-1 activation of JNK signaling in neurons.
Ye
Bing
B
Solomon H Snyder Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yu
Wei-ping
WP
Thomas
Gareth M
GM
Huganir
Richard L
RL
D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D002352:Carrier Proteins; C485827:GRIPAP1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D053148:Caspase 3