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

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...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2017.214