Differential Akt Signaling Induced by Tumstatin and Endostatin in Human Endothelial Cells

Abstract

Tumstatin and Endostatin are endogenous extracellular matrix-derived inhibitors of angiogenesis generated from the non-collagenous domains of type IV and type XVIII collagens, respectively. Although both molecules suppress angiogenesis and tumor growth in vivo, previous studies demonstrated that they engage distinct endothelial integrin receptors and activate different intracellular signaling pathways. In particular, Tumstatin inhibits endothelial proliferation through suppression of the focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway, whereas Endostatin primarily inhibits endothelial migration through 5{beta}1 integrin-dependent signaling. Here we evaluated a key mechanistic distinction between these two angiogenesis inhibitors by examining Akt phosphorylation in human umbilical vein endothelial cells (HUVEC) cultured on fibronectin. Validating previous reports, recombinant human Tumstatin reduced Akt phosphorylation whereas recombinant human Endostatin did not alter Akt activation. These findings confirm a defining feature of Tumstatin signaling and reinforce the concept that collagen-derived angiogenesis inhibitors regulate endothelial cell behavior through distinct integrin-dependent mechanisms.