NDLI: Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function EVIDENCE FOR AN AUTOINHIBITORY MECHANISM

Content Provider	Journal of Biological Chemistry (JBC)
Author	Niu, Xi-Lin Peters, Kevin G. Kontos, Christopher D.
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 (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.
Related Links	http://www.jbc.org/content/277/35/31768.abstract
Ending Page	31773
Starting Page	31768
Page Count	6
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	35
Volume Number	277
DOI	10.1074/jbc.M203995200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2002-08-30
Access Restriction	Open
Subject Keyword	Receptor tyrosine kinase (RTK) Activation loop (A-loop) Angiopoietin (Ang) Alkaline phosphatase (AP) Glutathione S-transferase (GST) Phosphatidylinositol (PI) Wild type (WT) Fibroblast growth factor receptor (FGFR) Extracellular signal-regulated kinase (ERK) MECHANISMS OF SIGNAL TRANSDUCTION
Alternative Title	Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function EVIDENCE FOR AN AUTOINHIBITORY MECHANISM