MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth
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Roberta Colladel1,*, Rosanna Pellicani1,*, Eva Andreuzzi1, Alice Paulitti1, Giulia Tarticchio1, Federico Todaro1, Alfonso Colombatti1, Maurizio Mongiat1
1Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
*These two authors contributed equally to this work
Maurizio Mongiat, e-mail: email@example.com
Keywords: extracellular matrix (ECM), angiogenesis, tumor microenvironment, vascular endothelial growth factor (VEGF), endothelial cell sprouting
Received: August 18, 2015 Accepted: November 21, 2015 Published: December 09, 2015
Angiogenesis is a key process occurring under both physiological and pathological conditions and is a hallmark of cancer. We have recently demonstrated that the extracellular matrix (ECM) molecule MULTIMERIN2 exerts an angiostatic function through the binding to VEGF-A. In this study we identify the region of the molecule responsible for the binding and demonstrate that the interaction involves the carbohydrate chains. MULTIMERIN2 interacts with other VEGF-A isoforms and VEGF family members such as VEGF-B, -C, -D and PlGF-1 suggesting that the molecule may function as a reservoir for different cytokines. In response to VEGF-A165, we show that MULTIMERIN2 impairs the phosphorylation of VEGFR2 at both Y1175 and Y1214 residues, halts SAPK2/p38 activation and negatively affects endothelial cell motility. In addition, MULTIMERIN2 and its active deletion mutant decrease the availability of the VEGFR2 receptor at the EC plasma membrane. The ectopic expression of MULTIMERIN2 or its active deletion mutant led to a striking reduction of tumor-associated angiogenesis and tumor growth. In conclusion, these data pinpoint MULTIMERIN2 as a key angiostatic molecule and disclose the possibility to develop new prognostic tools and improve the management of cancer patients.
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