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Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2002 Aug 30; Vol. 277 (35), pp. 31768-73. Date of Electronic Publication: 2002 Jun 24. - Publication Year :
- 2002
-
Abstract
- Tie2 is an endothelial receptor tyrosine kinase that is required for both embryonic vascular development and tumor angiogenesis. There is considerable interest in understanding the mechanisms of Tie2 activation for therapeutic purposes. The recent solution of the Tie2 crystal structure suggests that Tie2 activity is autoinhibited by its carboxyl terminus. Here we investigated the role of the C tail in Tie2 activation, signaling, and function both in vitro and in vivo by deleting the C terminus of Tie2 (Delta CT). Compared to wild type Tie2, in vitro autophosphorylation and kinase activity were significantly enhanced by the Delta CT mutation. In NIH 3T3 cells expressing chimeric Tie2 receptors, both basal and ligand-induced tyrosine phosphorylation were markedly enhanced compared to wild type in several independent clones of Tie2-Delta CT. Moreover, the Delta CT mutation enhanced basal and ligand-dependent activation of Akt and extracellular signal-regulated kinase. Enhanced Akt activation correlated with significant inhibition of staurosporine-induced apoptosis. These findings demonstrate that the Tie2 C tail performs a novel negative regulatory role in Tie2 signaling and function, and they provide important insights into the mechanisms by which the Tie2 kinase is activated.
- Subjects :
- 3T3 Cells
Animals
Base Sequence
Binding Sites
Cell Line
DNA Primers
Glutathione Transferase genetics
Kinetics
Mice
Phosphorylation
Protein Conformation
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor, TIE-2
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins metabolism
Sequence Deletion
Spodoptera
Transfection
Receptor Protein-Tyrosine Kinases genetics
Receptor Protein-Tyrosine Kinases metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 277
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12082108
- Full Text :
- https://doi.org/10.1074/jbc.M203995200