Hyperosmotic stress induces Axl activation and cleavage in cerebral endothelial cells

Imola Wilhelm, Péter Nagyoszi, Attila E. Farkas, Pierre Olivier Couraud, Ignacio A. Romero, Babette Weksler, Csilla Fazakas, Ngo Thi Khue Dung, Sándor Bottka, Hannelore Bauer, Hans Christian Bauer, István A. Krizbai

Research output: Article

24 Citations (Scopus)

Abstract

Because of the relative impermeability of the blood-brain barrier (BBB), 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 BBB 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 BBB. Previously, we have shown that among targets of tyrosine phosphorylation are β-catenin, extracellular signal-regulated kinase 1/2 and the non-receptor tyrosine kinase Src. The aim of this study was to identify new signalling 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 signalling.

Original languageEnglish
Pages (from-to)116-126
Number of pages11
JournalJournal of neurochemistry
Volume107
Issue number1
DOIs
Publication statusPublished - okt. 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Wilhelm, I., Nagyoszi, P., Farkas, A. E., Couraud, P. O., Romero, I. A., Weksler, B., Fazakas, C., Dung, N. T. K., Bottka, S., Bauer, H., Bauer, H. C., & Krizbai, I. A. (2008). Hyperosmotic stress induces Axl activation and cleavage in cerebral endothelial cells. Journal of neurochemistry, 107(1), 116-126. https://doi.org/10.1111/j.1471-4159.2008.05590.x