Concepts and hypothesis: integrin cytoplasmic domain-associated protein-1 (ICAP-1) as a potential player in cerebral cavernous malformation

Abstract

Cerebral cavernous malformation (CCM) is a common vascular disease in central nervous system that frequently predisposes to stroke, seizure, and cerebral hemorrhage. CCM lesions are characterized by dilated and leaky intracranial capillaries composed of a thin layer of vascular endothelial cells with abnormal subendothelial extracellular matrix. Despite the understanding that genetic mutation of three CCM genes (CCM1, CCM2, and CCM3) results in hereditary CCM, the molecular mechanism underlying vascular defects in CCM lesions remains poorly understood. Recent studies have shown that integrin cytoplasmic domain-associated protein-1 (ICAP-1, also known as integrin β1 binding protein1, ITGB1BP), a cytoplasmic protein interacting with both β1 integrin subunit and CCM1 protein (also known as Krit1), is implicated in vascular development. Analysis of data on the biochemistry and cellular biology of ICAP-1 highlights that bidirectional interaction of ICAP-1 with CCM1 and integrin might regulate diverse pathological processes of CCM disorder. Specifically, emerging evidence supports the hypothesized involvement of ICAP-1 in CCM pathogenesis through its significant effect in attenuating excessive vascular growth, its indispensable function in activating CCM1 protein, and its essential role in regulating integrin functions.

Review of familial cerebral cavernous malformations and report of seven additional families

“…There are gaps between adjacent endothelial cells where the blood is in direct contact with the basal lamina, which could be conducive to thrombus formation. The surrounding neural tissue is hemosiderin stained and strongly gliotic, suggested to be caused by recurrent hemorrhage due to the lesion's defective vascular integrity [Tomlinson et al, ; Zabramski et al, ; Del Curling et al, ; Clatterbuck et al, ; Chan et al, ; Glading and Ginsberg, ; Tanriover et al, ; Zheng et al, ]. It is thought that these hemorrhages, microscopic as well as macroscopic, are the main cause of symptomatic disease in 38–81% of patients [Rigamonti et al, ; Del Curling et al, ; Zabramski et al, ; Labauge et al, ].…”

“…Furthermore, DLL4‐NOTCH also stimulates cell survival and quiescence by activation of AKT1. In addition, DLL4‐NOTCH controls postangiogenic vessel remodeling and maturation [Serebriiskii et al, ; Zhang et al, , ; Gunel et al, ; Zawistowski et al, ; Fournier et al, ; Beraud‐Dufour et al, ; Ma et al, ; Crose et al, ; Francalanci et al, ; Whitehead et al, ; Borikova et al, ; Faurobert and Albiges‐Rizo, ; Glading and Ginsberg, ; Lampugnani et al, ; Lan et al, ; Stockton et al, ; Wustehube et al, ; Zheng et al, , ; Chan et al, ; Liu et al, ; Kim et al, ; McDonald et al, ; Corr et al, ; Haasdijk et al, ; Li et al, ; Faurobert et al, ; Richardson et al, ; You et al, ; Fisher and Boggon, ]. B: Disturbed CCM protein function in endothelial cells will disrupt the pathways depicted in ( A ).…”

“…Both disturbed β1 integrin activity and decreased DLL4‐NOTCH signaling lead to increased ERK–MAPK signaling. These processes lead to increased proliferation, migration and survival, lumen dilatation, disturbed vessel remodeling and maturation, defective attraction of mural cells, aberrant cell shape, and endothelial hyperpermeability, eventually resulting in lesion formation [Zhang et al, ; Crose et al, ; Whitehead et al, ; Borikova et al, ; Faurobert and Albiges‐Rizo, ; Glading and Ginsberg, ; Lampugnani et al, ; Stockton et al, ; Wustehube et al, ; Zheng et al, , ; Boulday et al, ; McDonald et al, ; Corr et al, ; Faurobert et al, ; Fischer et al, ; Richardson et al, ; You et al, ]. Δ, change; CDC42, cell division cycle 42; DLL4, delta‐like protein 4; ERK, extracellular signal‐regulated kinase; GCK‐III, germinal centre kinase III; ICAP‐1α, integrin cytoplasmic domain associated protein 1a; MAPK, mitogen‐activated protein kinase; NOTCH, neurogenic locus notch homolog protein; PAR, PAR polarity complex; PDCD10, programmed cell death 10; RhoA, ras homolog family member A; VE, vascular endothelial.…”

“…Beta1 integrin is a transmembrane protein localized at the cell surface and forms focal adhesions to the extracellular matrix (ECM) [Zhang et al, , ; Guzeloglu‐Kayisli et al, ; Beraud‐Dufour et al, ; Li et al, ; Faurobert et al, ; Zheng et al, ; Fisher and Boggon, ]. In endothelial cells, KRIT1 is recruited to the cell surface in a complex with CCM2, RAP1A (Ras‐related protein 1A) and ICAP‐1α (integrin cytoplasmic domain associated protein 1α).…”

“…Beta1 integrin activity controls pathways (including ERK/MAPK signaling and the PAR polarity complex, see Fig. A) that coordinate endothelial cell proliferation, migration, survival, and lumen formation [Serebriiskii et al, ; Zhang et al, , ; Zawistowski et al, ; Fournier et al, ; Beraud‐Dufour et al, ; Francalanci et al, ; Whitehead et al, ; Faurobert and Albiges‐Rizo, ; Haasdijk et al, ; Li et al, ; Faurobert et al, ; Zheng et al, ; Fisher and Boggon, ]. Beta1 integrin based cell‐ECM adhesion also stimulates the formation of cell–cell junctions, which stabilizes endothelial barrier function (see below and Fig.…”