ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract: The stress-activated kinases c-Jun N-terminal kinase (JNK)and p38 are members of the mitogen-activated protein (MAP) kinase family andtake part in signalling cascades initiated by various forms of stress. Theirtargets include the microtubule-associated protein tau, which becomeshyperphosphorylated in Alzheimer's disease. It is necessary, as a forerunnerfor in vivo studies, to identify the protein kinases and phosphatases that areresponsible for phosphate turnover at individual sites. Using nanoelectrospraymass spectrometry, we have undertaken an extensive comparison ofphosphorylation in vitro by several candidate tau kinases, namely, JNK, p38,ERK2, and glycogen synthase kinase 3β (GSK3β). Between 10 and 15sites were identified for each kinase. The three MAP kinases phosphorylatedSer202 and Thr205 but not detectably Ser199,whereas conversely GSK3β phosphorylated Ser199 but notdetectably Ser202 or Thr205. PhosphorylatedSer404 was found with all of these kinases except JNK. The MAPkinases may not be strictly proline specific: p38 phosphorylated thenonproline sites Ser185, Thr245, Ser305, andSer356, whereas ERK2 was the most strict. All of the sites detectedexcept Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3β are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2000.0741587.x
