Wilhelm, Imola; Nagyoszi, Péter; Farkas, Attila E.; Couraud, Pierre-Olivier; Romero, Ignacio A.; Weksler, Babette; Fazakas, Csilla; Dung, Ngo Thi Khue; Bottka, Sándor; Bauer, Hannelore; Bauer, Hans-Christian and Krizbai, István A.
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|DOI (Digital Object Identifier) Link:||http://doi.org/10.1111/j.1471-4159.2008.05590.x|
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Due to the relative impermeability of the blood-brain barrier many drugs are unable to reach the CNS in therapeutically relevant concentration. One method to deliver drugs to the CNS is the osmotic opening of the blood-brain barrier using mannitol. Hyperosmotic mannitol induces a strong phosphorylation on tyrosine residues in a broad spectrum of proteins in cerebral endothelial cells, the principal components of the blood-brain barrier. Previously we have shown that among targets of tyrosine phosphorylation are ?-catenin, extracellular signal-regulated kinase 1/2 and the non-receptor tyrosine kinase Src. The aim of this study was to identify new signaling pathways activated by hypertonicity in cerebral endothelial cells. Using an antibody array and immunoprecipitation we identified the receptor tyrosine kinase Axl to become tyrosine phosphorylated in response to hyperosmotic mannitol. Besides activation, Axl was also cleaved in response to osmotic stress. Degradation of Axl proved to be metalloproteinase- and proteasome-dependent and resulted in 50-55 kDa C-terminal products which remained phosphorylated even after degradation. Specific knockdown of Axl increased the rate of apoptosis in hyperosmotic mannitol-treated cells, therefore we assume that activation of Axl may be a protective mechanism against hypertonicity-induced apoptosis. Our results identify Axl as an important element of osmotic stress-induced signaling.
|Item Type:||Journal Article|
|Extra Information:||The definitive version is available at www.blackwell-synergy.com.|
|Keywords:||blood-brain barrier, cerebral endothelial cells, mannitol, hyperosmosis, Axl|
|Academic Unit/Department:||Science > Life, Health and Chemical Sciences
|Interdisciplinary Research Centre:||Biomedical Research Network (BRN)|
|Depositing User:||Astrid Peterkin|
|Date Deposited:||12 Aug 2008 13:40|
|Last Modified:||23 Feb 2016 23:05|
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