Recent insights into cerebral cavernous malformations: a complex jigsaw puzzle under construction

Abstract

Cerebral cavernous malformations (CCM) are common vascular malformations with an unpredictable risk of hemorrhage, the consequences of which range from headache to stroke or death. Three genes, CCM1, CCM2 and CCM3, have been linked to the disease. The encoded CCM proteins interact with each other within a large protein complex. Within the past 2 years, a plethora of new data has emerged on the signaling pathways in which CCM proteins are involved. CCM proteins regulate diverse aspects of endothelial cell morphogenesis and blood vessel stability such as cell–cell junctions, cell shape and polarity, or cell adhesion to the extracellular matrix. Although fascinating, a global picture is hard to depict because little is known about how these pathways coordinate to orchestrate angiogenesis. Here we present what is known about the structural domain organization of CCM proteins, their association as a ternary complex and their subcellular localization. Numerous CCM partners have been identified using two‐hybrid screens, genetic analyses or proteomic studies. We focus on the best‐characterized partners and review data on the signaling pathways they regulate as a step towards a better understanding of the etiology of CCM disease.

STK25 Protein Mediates TrkA and CCM2 Protein-dependent Death in Pediatric Tumor Cells of Neural Origin

“…CCM2 is one of three genes mutated in patients with cerebral cavernous malformations (CCM), 3 a common class of vascular malformations in the central nervous system (5). The protein products of these three genes, CCM1, CCM2, and CCM3, interact with each other and with numerous other partners to form a diversity of complexes that may mediate diverse functions in different cell types (6). However, CCM2 was the only CCMrelated gene that could be linked to positive prognosis in neuroblastoma patients, in correlation with TrkA, suggesting that the signaling pathways mediating TrkA-CCM2 death signaling in cells of neural origin might be distinct from the pathways leading to CCM effects on the vasculature (2,4).…”

Arteriovenous Malformations and Other Vascular Malformation Syndromes

“…The three CCM disease genes are structurally unrelated intracellular proteins that lack catalytic domains and have been found to associate with one another, and influence a variety of signaling pathways. This topic was recently reviewed in greater detail by Faurobert (Faurobert and Albiges-Rizo 2009).…”

Cerebral cavernous malformation proteins at a glance

“…It is therefore possible that KRIT1, like other FERM proteins, adopts both open and closed conformations through a 'head-totail' interaction. The head-tail interaction probably occurs though the recognition of the KRIT1 NPxY/F motifs by the FERM domain, although the specificity of this interaction is still unclear (Faurobert and Albiges-Rizo, 2010). Changes in the conformation of KRIT1 are thought to regulate its localization; for example, microtubule binding is associated with a presumed 'closed' conformation (Francalanci et al, 2009) and ICAP1 binding is associated with a presumed 'open' conformation (Béraud-Dufour et al, 2007).…”