Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function
| Autor: | Christopher D. Kontos, Kevin G. Peters, Xi-Lin Niu |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Kinase
C-terminus Wild type Tyrosine phosphorylation Cell Biology Biology Biochemistry Molecular biology Receptor tyrosine kinase chemistry.chemical_compound surgical procedures operative chemistry embryonic structures cardiovascular system biology.protein sense organs Kinase activity Receptor tissues Molecular Biology Protein kinase B |
| Zdroj: | Journal of Biological Chemistry. 277:31768-31773 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m203995200 |
| Popis: | 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 (ΔCT). Compared to wild type Tie2, in vitroautophosphorylation and kinase activity were significantly enhanced by the ΔCT 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-ΔCT. Moreover, the ΔCT 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|