Requirements for efficient activation of vascular endothelial growth factor C

What is it about?

VEGF-C is a major lymphangiogenic growth factor. It is secreted as inactive proVEGF-C and requires cleavage of both it's N- and C-terminal domains for activation. ADAMTS3 and CCBE1 have been recently identified to activate VEGFC. However, complete mechanism of action remains partially unknown. In this paper, we show the roles of different domains in efficient activation of VEGFC. Our findings show that pro-VEGF-C becomes localized by virtue of its C-terminal domain to the extracellular matrix (ECM), notably fibronectin, and cell surfaces. Similarly, CCBE1 localizes to LEC surfaces via its N-terminal domain. Colocalization of CCBE1, ADAMTS3, and pro-VEGF-C at the cell surface largely increases the likelihood of VEGF-C activation.

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Why is it important?

Delineating VEGF-C activation is not only important in order to understand the development of the lymphatic system, but also to understand tumor angiogenesis, because mature VEGF-C is also able to activate the VEGFR-2 signaling pathway and because some tumors might escape antiangiogenic therapy by employing VEGF-C instead of VEGF-A. Inhibition of VEGF-C activation might provide a treatment strategy for such tumors.