Gln-362 of Angiopoietin-2 Mediates Migration of Tumor and Endothelial Cells through Association with alpha 5 beta 1 Integrin

초록

Angiopoietin-2 (Ang-2) not only regulates angiogenesis by binding to its well known receptor Tie2 on endothelial cells but also controls sprouting of Tie2-negative angiogenic endothelial cells and invasion of Tie2-negative non-endothelial cells by binding to integrins. However, the molecular mechanism of the Ang-2/ integrin association has been unclear. In this study, we found that the Gln-362 residue of Ang-2 was essential for binding to alpha 5 beta 1 integrin. A Q362E Ang-2 mutant, which still bound to Tie2, failed to associate with alpha 5 beta 1 integrin and was unable to activate the integrin downstream signaling of focal adhesion kinase. In addition, unlike wild-type Ang-2, the Q362E Ang-2 mutant was defective in mediating invasion of Tie2-negative glioma or Tie2-positive endothelial cells. Furthermore, the tailpiece domain of the alpha 5 subunit in alpha 5 beta 1 integrin was critical for binding to Ang-2. Taken together, these results provide a novel insight into the mechanism of integrin regulation by Ang-2, which contributes to tumor invasion and endothelial cell migration in a Tie2-independent manner.

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