Abstract
Cerebral cavernous malformations are fragile blood vessel conglomerates in the central nervous system that are caused by mutations in the CCM1/KRIT1, CCM2 or CCM3 genes. The gene products form a protein complex at adherens junctions and loss of either CCM protein disrupts endothelial cell quiescence leading to increased permeability and excessive angiogenesis. We performed a yeast 2-hybrid screen to identify novel proteins directly interacting with KRIT1. The ankyrin repeat and sterile alpha motif domain-containing protein 1B (ANKS1B) was identified as a novel binding partner of KRIT1. Silencing of ANKS1B or the related gene ANKS1A in primary human endothelial cells had no significant effects on cellular proliferation, migration and sprouting angiogenesis. However, silencing of ANKS1B expression disturbed endothelial cell barrier functions leading to increased permeability. Forced ANKS1B expression reduced permeability. This was independent of Rho kinase activity and the presence of KRIT1. Taken together, ANKS1B was identified as a novel KRIT1-interacting protein that selectively controls endothelial permeability but not angiogenesis.
Highlights
Cerebral cavernous malformations (CCMs) affect approximately 1 in 250 humans
The inherited form of the disease is caused by loss-of-function mutations in the KRIT1 (CCM1), CCM2 (Malcavernin) or CCM3
KRIT1 binds to the phosphotyrosine binding domain (PTB) domains of ICAP1 and CCM2 [23], suggesting that this is a common mode of KRIT1-mediated protein interactions
Summary
Cerebral cavernous malformations (CCMs) affect approximately 1 in 250 humans. CCMs can lead to a variety of clinical manifestations, most commonly headaches, seizures, and stroke, depending on size, growth rate and localisation [1]. CCM mutations primarily affect endothelial cells causing decreased endothelial junctional stability and excessive angiogenesis [4,5,6,7,8,9,10,11]. Most importantly a cluster of all three proteins is enriched at adherens junctions of endothelial cells [2,3]. This is essential to restrict vascular permeability via control of Rap, RhoA and Rho kinase signalling [9,10,12,13,14,15,16]. KRIT1 is needed to restrict endothelial-to-mesenchymal transition and Notch signalling [11,19] Both processes are integral to prevent uncontrolled angiogenesis
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