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Inhibition of Aberrant and Constitutive Phosphorylation of the High‐Molecular‐Mass Neurofilament Subunit by CEP‐1347 (KT7515), an Inhibitor of the Stress‐Activated Protein Kinase Signaling Pathway
Author(s) -
O'Ferrall Erin K.,
Robertson Janice,
Mushynski Walter E.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0752358.x
Subject(s) - phosphorylation , neurofilament , protein subunit , microbiology and biotechnology , neurite , kinase , protein kinase a , signal transduction , chemistry , extracellular , biology , biochemistry , immunology , in vitro , immunohistochemistry , gene
Previous studies have implicated stress‐activated proteinkinases (SAPKs) in aberrant phosphorylation of the high‐molecular‐massneurofilament subunit (NFH). We now present direct evidence for thisinvolvement using CEP‐1347, a specific inhibitor of SAPK activation.Inhibition by this drug of stress‐induced phosphorylation of NFH and themiddle‐molecular‐mass neurofilament subunit in the perikaryon of dorsal rootganglion (DRG) neurons paralleled the decrease in levels of activated SAPKsand was essentially complete at 1 μ M CEP‐1347. In addition, a rolefor SAPKs in the constitutive phosphorylation of NFH was demonstrated.Longterm treatment of unstressed DRG neurons with CEP‐1347 lowered thesteady‐state phosphorylation level of NFH in neurites. No such effect was seenin neurons treated with PD 098059, which blocks activation of extracellularsignal‐regulated kinase 1/2. DRG neurites were shown to contain high basallevels of activated SAPKs. These included a 55‐kDa SAPK whose activation wascompletely abolished at 0.05 μ M CEP‐1347 and a 45‐kDa SAPK thatwas not affected by the drug. These results indicate that SAPKs are involvedin both stress‐induced and constitutive phosphorylation of NFH. The differingresponses of SAPKs in neurites and cell bodies to CEP‐1347 inhibition furthersuggest the presence of different signaling pathways in the two neuronalcompartments.