Research ArticleCell Biology

Stabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development

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Science Signaling  06 Apr 2010:
Vol. 3, Issue 116, pp. ra26
DOI: 10.1126/scisignal.2000722

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Stability for Blood Vessel Formation

Cerebral cavernous malformations (CCMs) are commonly occurring, thin-walled dilations of the vasculature of the central nervous system. Although these defects can arise spontaneously, most cases are caused by mutations in the genes encoding the CCM proteins. How CCM3 contributes to these vascular defects is unknown. He et al. found that mice that were globally deficient for CCM3 or specifically deficient in endothelial cells died because of defects in angiogenesis during development. CCM3 deficiency reduced the activity of vascular endothelial growth factor receptor 2 (VEGFR2), which is required for hematopoiesis and vasculogenesis. VEGF stimulation promoted the interaction of CCM3 with VEGFR2, an association that prevented VEGF-induced internalization and degradation of VEGFR2. Three CCM3 mutant proteins associated with CCMs in humans were unstable and enhanced the degradation of VEGFR2. Thus, CCM3 is required to promote VEGFR2 signaling during vascular development.

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