title: NRP1 presented in trans to the endothelium arrests VEGFR2 endocytosis, preventing angiogenic signaling and tumor initiation.
abstract: Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase Cγ (PLCγ) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Sina
authors.initials: S
authors.lastname: Koch
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Laurens A
authors.initials: LA
authors.lastname: van Meeteren
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Morin
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Chiara
authors.initials: C
authors.lastname: Testini
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Weström
authors.affiliation: Ridgeview Instruments, Skillsta 4, 740 20 Vänge, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Björkelund
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Le Jan
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Adler
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, Molecular Cell Biology, 5232 Villigen PSI, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Berger
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden. Electronic address: lena.welsh@igp.uu.se.
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: D000818:Animals; D002450:Cell Communication; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005354:Fibrosarcoma / Q000098:blood supply* / Q000378:metabolism / Q000517:prevention & control; D005455:Fluorescent Antibody Technique; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D039942:Neuropilin-1 / Q000502:physiology*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D013237:Stereoisomerism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D051966:Phospholipase C gamma