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Hyperosmotic stress induces axl activation and cleavage in cerebral endothelial cells

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. (2008). Hyperosmotic stress induces axl activation and cleavage in cerebral endothelial cells. Journal of Neurochemistry, 107(1) pp. 116–126.

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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 Item
ISSN: 0022-3042
Extra Information: The definitive version is available at
Keywords: blood-brain barrier, cerebral endothelial cells, mannitol, hyperosmosis, Axl
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 11355
Depositing User: Astrid Peterkin
Date Deposited: 12 Aug 2008 13:40
Last Modified: 27 Jun 2020 06:03
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