Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1

• Published in: Blood 2013-02, Vol.121 (7), p.1229-1237
• Main Authors: Platonova, Natalia, Miquel, Geraldine, Regenfuss, Birgit, Taouji, Said, Cursiefen, Claus, Chevet, Eric, Bikfalvi, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - metabolism; Cell Line; CHO Cells; Cricetinae; Cricetulus; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Fibroblast Growth Factor 2 - administration & dosage; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Hyaluronan Receptors - metabolism; Lymphangiogenesis - drug effects; Lymphangiogenesis - physiology; Mice; Mice, Inbred BALB C; Protein Interaction Maps; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Small Interfering - genetics; Vesicular Transport Proteins - administration & dosage; Vesicular Transport Proteins - antagonists & inhibitors; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-450502

LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1) is a homolog of the hyaluronan receptor CD44, and one of the most widely used markers of lymphatic endothelial cells in normal and tumor tissues. However, the physiologic role of LYVE-1 in the lymphatic system still remains unclear. It is well established that fibroblast growth factor 2 (FGF2) induces lymphangiogenesis. Based on the known interaction between FGF2 and CD44 and based on the structural similarity of CD44 and LYVE-1, we investigated whether FGF2 might interact with LYVE-1. We found that FGF2 is able to bind LYVE-1 using AlphaScreen, or after surface-immobilization or in solution. FGF2 binds to LYVE-1 with a higher affinity than any other known LYVE-1–binding molecules, such as hyaluronan or PDGF-BB. Glycosylation of LYVE-1 is important for FGF2 binding. Furthermore, FGF2 interacts with LYVE-1 when overexpressed in CHO cells. Soluble LYVE-1 and knockdown of LYVE-1 in lymphatic endothelial cells impaired FGF2 signaling and functions. In addition, FGF2 but not VEGF-C-induced in vivo lymphangiogenesis, was also inhibited. Conversely, FGF2 also modulates LYVE-1 expression in cells and ex vivo. Thus, our data demonstrate a functional relationship to the interaction between FGF2 and LYVE-1. •FGF2 is able to directly interact with LYVE-1 and glycosylation of LYVE-1 is important for the interaction with FGF2.•LYVE-1 inhibits FGF2-dependent lymphangiogenesis and FGF2 modulates LYVE-1's endogenous expression and reverses the effect of TNFβ.