This project is focused on understanding the physiologic role of the adaptor protein CCM2 and on the basic mechanisms resulting in Cerebral Cavernous Malformations (CCMs) in the absence of CCM2. CCMs are sporadically acquired or inherited vascular anomalies of the CNS characterized by clusters of dilated thin-walled blood vessels that predispose individuals to seizures and strokes. CCM2 is an adaptor protein for the kinase MEKK3, a MAP3K that can activate MAPK. MEKK3 has also been reported to regulate the activity of the IkappaB Kinase, a kinase complex that activates the NF-kappaB transcription factors downstream of many signals. We originally cloned the genes for both MEKK3 and CCM2. The CCM2 gene was recently identified as one of three genetic loci mutated in patients with the inherited form of CCM. MAPK signaling pathways have been shown to be essential for cell growth, differentiation and apoptosis. Given the critical contributions of MAPKs and the clinical relevance of CCM2, it is important to fully understand the signaling pathways and targets of the CCM2-MEKK3 signaling module. To explore the in vivo roles of the adaptor protein CCM2 we have generated mice deficient in this protein. The homozygous loss of the adaptor results in early embryonic lethality, most likely due to a block in angiogenesis. PECAM staining revealed that the complex vessel structure that begins to develop around E8.5 is absent in mutant embryos. Furthermore, markers for arterial cell wells are lacking, suggesting that arterial angiogenesis is defective in mice deficient in CCM2. To investigate possible functions of CCM2 in endothelial cells, the most likely cell type responsible for the block in angiogenesis in CCM2-deficient mice, we silenced the CCM2 gene in human vein endothelial cells. The growth rate of these cells was significantly enhanced when CCM2 expression was suppressed, suggesting a role of CCM2 in controlling the expansion of endothelial cells. We will determine the mechanisms by which CCM2 may control growth and we will investigate the physiologic role of CCM2 with the help of conditionally deleted mice.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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Leonardi, A; Chariot, A; Claudio, E et al. (2000) CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Proc Natl Acad Sci U S A 97:10494-9
Ellinger-Ziegelbauer, H; Kelly, K; Siebenlist, U (1999) Cell cycle arrest and reversion of Ras-induced transformation by a conditionally activated form of mitogen-activated protein kinase kinase kinase 3. Mol Cell Biol 19:3857-68