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uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis

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  • Tania Durré
  • Florent Morfoisse
  • Charlotte Erpicum
  • Marie Ebroin
  • Silvia Blacher
  • Melissa García-Caballero
  • Christophe Deroanne
  • Thomas Louis
  • Cédric Balsat
  • Maureen Van de Velde
  • Seppo Kaijalainen
  • Frédéric Kridelka
  • Lars Engelholm
  • Ingrid Struman
  • Kari Alitalo
  • Niels Behrendt
  • Jenny Paupert
  • Agnès Noel
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The development of new lymphatic vessels occurs in many cancerous and inflammatory diseases through the binding of VEGF-C to its receptors, VEGFR-2 and VEGFR-3. The regulation of VEGFR-2/VEGFR-3 heterodimerisation and its downstream signaling in lymphatic endothelial cells (LECs) remain poorly understood. Here, we identify the endocytic receptor, uPARAP, as a partner of VEGFR-2 and VEGFR-3 that regulates their heterodimerisation. Genetic ablation of uPARAP leads to hyperbranched lymphatic vasculatures in pathological conditions without affecting concomitant angiogenesis. In vitro, uPARAP controls LEC migration in response to VEGF-C but not VEGF-A or VEGF-CCys156Ser. uPARAP restricts VEGFR-2/VEGFR-3 heterodimerisation and subsequent VEGFR-2-mediated phosphorylation and inactivation of Crk-II adaptor. uPARAP promotes VEGFR-3 signaling through the Crk-II/JNK/paxillin/Rac1 pathway. Pharmacological Rac1 inhibition in uPARAP knockout mice restores the wild-type phenotype. In summary, our study identifies a molecular regulator of lymphangiogenesis, and uncovers novel molecular features of VEGFR-2/VEGFR-3 crosstalk and downstream signaling during VEGF-C-driven LEC sprouting in pathological conditions.

Original languageEnglish
JournalNature Communications
Volume9
Issue number1
Pages (from-to)5178
ISSN2041-1723
DOIs
Publication statusPublished - 5 Dec 2018

ID: 55803954