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Sci. Signal., 6 April 2010
Vol. 3, Issue 116, p. ra26
[DOI: 10.1126/scisignal.2000722]

RESEARCH ARTICLES

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

Yun He1*, Haifeng Zhang1*, Luyang Yu1*, Murat Gunel1,2, Titus J. Boggon3, Hong Chen1,4{dagger}, and Wang Min1{dagger}

1 Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.
2 Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
3 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: hong-chen{at}omrf.org (H.C.); wang.min{at}yale.edu (W.M.)

Citation: Y. He, H. Zhang, L. Yu, M. Gunel, T. J. Boggon, H. Chen, W. Min, Stabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development. Sci. Signal. 3, ra26 (2010).

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