Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface

• Published in: Oncogene Vol. 36; no. 44; pp. 6097 - 6108
• Main Authors: Khan, K A, Naylor, A J, Khan, A, Noy, P J, Mambretti, M, Lodhia, P, Athwal, J, Korzystka, A, Buckley, C D, Willcox, B E, Mohammed, F, Bicknell, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-11-2017; Nature Publishing Group
• Subjects: 13/31; 14; 14/1; 14/63; 631/67/2328; 631/67/327; 631/80/79/750; 82; Analysis; Angiogenesis; Animal models; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antigens, Surface - genetics; Antigens, Surface - metabolism; Apoptosis; Care and treatment; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Biology; Cell surface; Diagnosis; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelium; Extracellular matrix; Fibroblasts; Human Genetics; Human Umbilical Vein Endothelial Cells; Humans; Internal Medicine; Lectins; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Ligands; Matrix protein; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Oncology; Original; original-article; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Peptides; Pericytes; Pericytes - metabolism; Pericytes - pathology; Protein Binding; Protein interaction; Protein-protein interactions; Receptors, Complement - genetics; Receptors, Complement - metabolism; Rodents; Thrombomodulin; Thrombomodulin - genetics; Thrombomodulin - metabolism; Tumors; Umbilical vein
• DOI: 10.1038/onc.2017.214
• EISSN: 1476-5594
• ISSN: 0950-9232

The C-type lectin domain containing group 14 family members CLEC14A and CD93 are proteins expressed by endothelium and are implicated in tumour angiogenesis. CD248 (alternatively known as endosialin or tumour endothelial marker-1) is also a member of this family and is expressed by tumour-associated fibroblasts and pericytes. Multimerin-2 (MMRN2) is a unique endothelial specific extracellular matrix protein that has been implicated in angiogenesis and tumour progression. We show that the group 14 C-type lectins CLEC14A, CD93 and CD248 directly bind to MMRN2 and only thrombomodulin of the family does not. Binding to MMRN2 is dependent on a predicted long-loop region in the C-type lectin domain and is abrogated by mutation within the domain. CLEC14A and CD93 bind to the same non-glycosylated coiled-coil region of MMRN2, but the binding of CD248 occurs on a distinct non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously and this occurs at the interface between endothelium and pericytes in human pancreatic cancer. A recombinant peptide of MMRN2 spanning the CLEC14A and CD93 binding region blocks CLEC14A extracellular domain binding to the endothelial cell surface as well as increasing adherence of human umbilical vein endothelial cells to the active peptide. This MMRN2 peptide is anti-angiogenic
in vitro
and reduces tumour growth in mouse models. These findings identify novel protein interactions involving CLEC14A, CD93 and CD248 with MMRN2 as targetable components of vessel formation.