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

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 and Agnès Noel ()
Additional contact information
Tania Durré: Liege University
Florent Morfoisse: Liege University
Charlotte Erpicum: Liege University
Marie Ebroin: Liege University
Silvia Blacher: Liege University
Melissa García-Caballero: Liege University
Christophe Deroanne: Liege University
Thomas Louis: Liege University
Cédric Balsat: Liege University
Maureen Van de Velde: Liege University
Seppo Kaijalainen: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki
Frédéric Kridelka: Liege University
Lars Engelholm: Rigshospitalet/University of Copenhagen
Ingrid Struman: Liege University
Kari Alitalo: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki
Niels Behrendt: Rigshospitalet/University of Copenhagen
Jenny Paupert: Liege University
Agnès Noel: Liege University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07514-1

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