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Sci Signal. 2010 Apr 6;3(116):ra26. doi: 10.1126/scisignal.2000722.

Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development.

Author information

1
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.

Erratum in

  • Sci Signal. 2010;3(121):er4.

Abstract

Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: CCM1, CCM2, and CCM3. CCM3, also known as PDCD10 (programmed cell death 10), was initially identified as a messenger RNA whose abundance was induced by apoptotic stimuli in vitro. However, the in vivo function of CCM3 has not been determined. Here, we describe mice with a deletion of the CCM3 gene either ubiquitously or specifically in the vascular endothelium, smooth muscle cells, or neurons. Mice with global or endothelial cell-specific deletion of CCM3 exhibited defects in embryonic angiogenesis and died at an early embryonic stage. CCM3 deletion reduced vascular endothelial growth factor receptor 2 (VEGFR2) signaling in embryos and endothelial cells. In response to VEGF stimulation, CCM3 was recruited to and stabilized VEGFR2, and the carboxyl-terminal domain of CCM3 was required for the stabilization of VEGFR2. Indeed, the CCM3 mutants found in human patients lacking the carboxyl-terminal domain were labile and were unable to stabilize and activate VEGFR2. These results demonstrate that CCM3 promotes VEGFR2 signaling during vascular development.

PMID:
20371769
PMCID:
PMC3052863
DOI:
10.1126/scisignal.2000722
[Indexed for MEDLINE]
Free PMC Article

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