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Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.

Publication ,  Journal Article
Niu, X-L; Peters, KG; Kontos, CD
Published in: J Biol Chem
August 30, 2002

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.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 30, 2002

Volume

277

Issue

35

Start / End Page

31768 / 31773

Location

United States

Related Subject Headings

  • Transfection
  • Spodoptera
  • Signal Transduction
  • Sequence Deletion
  • Recombinant Fusion Proteins
  • Receptor, TIE-2
  • Receptor Protein-Tyrosine Kinases
  • Protein Conformation
  • Phosphorylation
  • Mice
 

Citation

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Niu, X.-L., Peters, K. G., & Kontos, C. D. (2002). Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism. J Biol Chem, 277(35), 31768–31773. https://doi.org/10.1074/jbc.M203995200
Niu, Xi-Lin, Kevin G. Peters, and Christopher D. Kontos. “Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.J Biol Chem 277, no. 35 (August 30, 2002): 31768–73. https://doi.org/10.1074/jbc.M203995200.
Niu, Xi-Lin, et al. “Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.J Biol Chem, vol. 277, no. 35, Aug. 2002, pp. 31768–73. Pubmed, doi:10.1074/jbc.M203995200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 30, 2002

Volume

277

Issue

35

Start / End Page

31768 / 31773

Location

United States

Related Subject Headings

  • Transfection
  • Spodoptera
  • Signal Transduction
  • Sequence Deletion
  • Recombinant Fusion Proteins
  • Receptor, TIE-2
  • Receptor Protein-Tyrosine Kinases
  • Protein Conformation
  • Phosphorylation
  • Mice