Endorepellin, the angiostatic module of perlecan, interacts with both the ?2?1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2): a dual receptor antagonism.

ABSTRACT: Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the ?2?1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the ?2?1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the ?2?1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express ?2?1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.

SUBMITTER: Goyal A 

PROVIDER: S-EPMC3138248 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature