%0 Journal Article %J FASEB J %D 2006 %T Functional interaction of VEGF-C and VEGF-D with neuropilin receptors %A Kärpänen, Terhi %A Heckman, Caroline A %A Keskitalo, Salla %A Jeltsch, Michael %A Ollila, Hanna %A Neufeld, Gera %A Tamagnone, Luca %A Alitalo, Kari %X Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature. %B FASEB J %V 20 %P 1462 - 72 %8 2006/Jul/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/16816121 %N 9 %! The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology