Cerebral cavernous malformations are common vascular malformations with an unpredictable risk of hemorrhage which consequences range from headache to stroke or death. Three genes CCM1, 2, 3 have been linked to the disease. The encoded CCM proteins interact with each others within a large protein complex. Since less than two years, a plethora of new data has emerged on the signaling pathways in which they are involved. They regulate diverse aspects of endothelial cell morphogenesis and blood vessel stability such as cell-cell junctions, cell shape and polarity, or cell adhesion to extracellular matrix. Although fascinating, a global picture is hard yet to depict as little is known on how these pathways coordinate to orchestrate angiogenesis. We present here what is known on the structural domain organization of the CCM proteins, their association as a ternary complex and their subcellular localization. Numerous CCM partners have been identified by two-hybrid screens, genetic analyses or proteomic studies. We focus on the best characterized ones and we review data on the signaling pathways they regulate as a step toward better understanding the etiology of the disease.
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