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.

脑海绵状血管畸形 (CCM) 是神经血管异常，其特征是血管薄而渗漏，导致易发生出血、中风、癫痫和局灶性神经功能缺损的病变。CCM 的出现是由于编码三种 CCM 复合蛋白 KRIT1、CCM2 或 CCM3 之一的基因发生功能丧失突变。这些广泛表达的多功能接头蛋白可以组装成 CCM 蛋白复合物，并（单独或以复合物形式）调节影响细胞粘附、细胞收缩性、细胞骨架重组和基因表达的信号通路。最近的进展，包括对 CCM 蛋白的结构和相互作用的分析，在理解 CCM 蛋白功能的分子基础以及它们的破坏如何导致疾病方面取得了实质性进展。这里，我们回顾了 CCM 蛋白信号传导的当前知识，重点关注三个最受关注的通路——RhoA-ROCK、MEKK3-MEK5-ERK5-KLF2/4 和细胞连接信号通路——但也考虑了 ICAP1-β1 整合素和 cdc42发信号。我们讨论了这些途径与驱动疾病病理的过程之间的新联系，并强调了重要的开放性问题——其中的关键是亚细胞定位在控制 CCM 蛋白活性中的作用。