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.
Highlights
Cerebral cavernous malformations (CCMs) are vascular abnormalities found predominantly in the central nervous system, where they are the second most common type of vascular lesion, comprising 5–15% of all neurovascular malformations [1,2,3], and having a prevalence of 0.1–0.8% in the general population [3,4,5,6]
CCM proteins contribute to a series of interconnected signalling networks and are regulated in complex manners, including through control of CCM protein subcellular localization
How these pathways intersect with larger-scale physiological processes, leading to CCM pathogenesis in the absence of CCM proteins, is an important area of ongoing research and continued improvements in understanding CCM signalling pathways should help reveal how molecular changes occurring in the absence of CCM proteins lead to CCM lesion formation and growth
Summary
Cerebral cavernous malformations (CCMs) are vascular abnormalities found predominantly in the central nervous system, where they are the second most common type of vascular lesion, comprising 5–15% of all neurovascular malformations [1,2,3], and having a prevalence of 0.1–0.8% in the general population [3,4,5,6]. Within CCMs, endothelial cells lack intervening tight junctions, are surrounded by diminished lamina, collagen and elastic tissue, and have fewer neighbouring pericytes, astrocytes and vascular smooth muscle cells, all of which contribute to thin and leaky vascular walls that are prone to rupture [3,7,8,9] These lesions can occur anywhere in the body, those in the brain or spinal cord are the most clinically relevant [10] with approximately 40% producing symptoms which include seizures, focal neurological symptoms (e.g. double vision, nausea and mobility problems), haemorrhages or headaches [11,12,13,14]. Of key signalling pathways, as well as potential cross talk between these pathways
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