Determining the structure and endothelial signalling function of the CLEC14A-Multimerin2 complex

Angiogenesis plays a critical role during development, in physiological processes such as wound healing and in the pathogenesis of diseases including cancer and diabetic retinopathy. The CLEC14A-MMRN2-CD248 complex modulates angiogenesis and this project aims to characterise its structure and function. CLEC14A is a tumour endothelial marker expressed in the vasculature of multiple tumour types, and is being developed as a target for novel anti-cancer therapies aimed at destroying the vessels of solid tumours. We and others identified multimerin 2 (MMRN2) as a ligand for CLEC14A and subsequently discovered that CD93 and CD248 also bind MMRN2. Like CLEC14A, CD93 is expressed by endothelial cells and interacts with the same region of MMRN2 as CLEC14A, by contrast CD248 is expressed by pericytes and fibroblasts and interacts with a distinct region of MMRN2. The CLEC14A-MMRN2-CD248 complex thus forms a molecular bridge between the endothelial cells and adjacent mesenchymal cells such as pericytes and fibroblasts; this project will investigate its structure and signalling function using a range of state-of-art methodologies in molecular and cellular biology and biophysics. Understanding the structure of this complex will facilitate efficient therapeutic targeting of CLEC14A and may uncover new strategies to modulate angiogenesis in a variety of pathologies.