TY - JOUR T1 - Functional interaction of VEGF-C and VEGF-D with neuropilin receptors JF - FASEB J Y1 - 2006 A1 - Kärpänen, Terhi A1 - Heckman, Caroline A A1 - Keskitalo, Salla A1 - Jeltsch, Michael A1 - Ollila, Hanna A1 - Neufeld, Gera A1 - Tamagnone, Luca A1 - Alitalo, Kari AB - 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. VL - 20 UR - http://view.ncbi.nlm.nih.gov/pubmed/16816121 IS - 9 JO - The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology ER -