Recent advances in cerebral cavernous malformation research

Abstract

Cerebral cavernous malformations (CCM) are manifested by microvascular lesions characterized by leaky endothelial cells with minimal intervening parenchyma predominantly in the central nervous system predisposed to hemorrhagic stroke, resulting in focal neurological defects. Till date, three proteins are implicated in this condition: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). These multi-domain proteins form a protein complex via CCM2 that function as a docking site for the CCM signaling complex, which modulates many signaling pathways. Defects in the formation of this signaling complex have been shown to affect a wide range of cellular processes including cell-cell contact stability, vascular angiogenesis, oxidative damage protection and multiple biogenic events. In this review we provide an update on recent advances in structure and function of these CCM proteins, especially focusing on the signaling cascades involved in CCM pathogenesis and the resultant CCM cellular phenotypes in the past decade.

Keywords: Cerebral cavernous malformation; angiogenesis; cellular function; cerebral cavernous malformation signaling complex; endothelial cells; function domain; microvessel lesions; motif; protein structure.

Figure 1

The cellular roles of the CSC complex. The schematic diagram summarizes the known CSC interaction protein partners (interactome), defined CSC-modulated signaling pathways (signalome), and distinct molecular and cellular functions of CSC complex (vasculome) with our current understanding of CSC cellular functions. CCM: cerebral cavernous malformations; CSC: CCM signaling complex; EC: endothelial cells