MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth

Roberta Colladel, Rosanna Pellicani, Eva Andreuzzi, Alice Paulitti, Giulia Tarticchio, Federico Todaro, Alfonso Colombatti, Maurizio Mongiat

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2022-2037
Number of pages16
JournalOncotarget
Volume7
Issue number2
DOIs
Publication statusPublished - 2016

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Keywords

  • Angiogenesis
  • Endothelial cell sprouting
  • Extracellular matrix (ECM)
  • Tumor microenvironment
  • Vascular endothelial growth factor (VEGF)

ASJC Scopus subject areas

  • Oncology

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