Functional interaction of VEGF-C and VEGF-D with neuropilin receptors

Terhi Kärpänen, Caroline A. Heckman, Salla Keskitalo, Michael Jeltsch, Hanna Ollila, Gera Neufeld, Luca Tamagnone, Kari Alitalo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1462-1472
Number of pages11
JournalFASEB Journal
Issue number9
Publication statusPublished - Jul 2006


  • Lymphatic endothelial cell
  • NP2
  • VEGFR-3

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology


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