Signalling through cerebral cavernous malformation protein networks

Abstract

Cerebral cavernous malformations (CCMs) are neurovascular abnormalities characterized by thin, leaky blood vessels resulting in lesions that predispose to haemorrhages, stroke, epilepsy and focal neurological deficits. CCMs arise due to loss-of-function mutations in genes encoding one of three CCM complex proteins, KRIT1, CCM2 or CCM3. These widely expressed, multi-functional adaptor proteins can assemble into a CCM protein complex and (either alone or in complex) modulate signalling pathways that influence cell adhesion, cell contractility, cytoskeletal reorganization and gene expression. Recent advances, including analysis of the structures and interactions of CCM proteins, have allowed substantial progress towards understanding the molecular bases for CCM protein function and how their disruption leads to disease. Here, we review current knowledge of CCM protein signalling with a focus on three pathways which have generated the most interest—the RhoA–ROCK, MEKK3–MEK5–ERK5–KLF2/4 and cell junctional signalling pathways—but also consider ICAP1-β1 integrin and cdc42 signalling. We discuss emerging links between these pathways and the processes that drive disease pathology and highlight important open questions—key among them is the role of subcellular localization in the control of CCM protein activity.

Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells

“…However, the cellular type most strongly associated with cavernous malformations is the endothelial cell. The role played by CCM genes in other cellular models strictly associated with lesions localization (i.e., neuronal cells, astrocytes, pericytes, and smooth muscle cells) is unknown, and there is no evidence about their direct contributions to CCM pathology [ 45 ]. There is probably a tight interplay between endothelial cells and the glia in the central nervous system (CNS), which may explain why mutations in CCM-related genes are followed by the appearance of lesions predominantly localized in the brain and spinal cord [ 46 ].…”

“…In 2005, Zawistowski et al [ 60 ] reported that the subcellular localization of KRIT1 is differentially influenced by these two proteins—if ICAP1α induces nuclear translocation, CCM2 maintains KRIT1 into the cytosol. However, it has been recently suggested that the whole complex ICAP1α/KRIT1/CCM2 shuttles back and forth from cytoplasm to nucleus and plays different roles in different cellular compartments [ 45 ].…”

“…KRIT1 directly associates with β-catenin, HEG1, Rap1, and Ras effector protein 1 (Rasip1) in the junctional signaling, forming a larger complex for the stabilization of endothelial junctions [ 45 ]. This helps turn off RhoA activity, preventing downstream myosin light chain (MLC) phosphorylation by ROCK and excessive stress fiber formation, which has been linked to weakened junctions between cells and increased leakage from blood vessels.…”

Non-autonomous effects of CCM genes loss

“…The mutation rates for each gene range between 53% and 65% for KRIT1/CCM1, 15% and 19% for CCM2, and 10% and 16% for CCM3 [9,10] . However, genotype does not entirely explain the large clinical variability of CCM disease, even among family members carrying the same mutation, suggesting that genetic and environmental modifiers can contribute to CCM disease [11] . Despite the differences between families, some genotype-phenotype correlations are delineated.…”

“…The clinical approach to CCM disease depends on the position and size of the lesions and its association with hemorrhages or intractable seizures. When possible, the microsurgical resection of lesions is the eligible route [11,24] . Therefore, the development of new pharmacological strategies is necessary to prevent lesion formation and for treating patients with severe inoperable disease or with multiple lesions.…”