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; Agnès Noel

doi:10.1038/s41467-018-07514-1

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, Agnès Noel^*

^*Corresponding author for this work

Engelholm Group

5 Citations (Scopus)

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.

Original language	English
Article number	5178
Journal	Nature Communications
Volume	9
Issue number	1
Pages (from-to)	1-16
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-07514-1
Publication status	Published - 5 Dec 2018

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Durré, T., Morfoisse, F., Erpicum, C., Ebroin, M., Blacher, S., García-Caballero, M., Deroanne, C., Louis, T., Balsat, C., Van de Velde, M., Kaijalainen, S., Kridelka, F., Engelholm, L., Struman, I., Alitalo, K., Behrendt, N., Paupert, J., & Noel, A. (2018). uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis. Nature Communications, 9(1), 1-16. Article 5178. https://doi.org/10.1038/s41467-018-07514-1

Durré, T, Morfoisse, F, Erpicum, C, Ebroin, M, Blacher, S, García-Caballero, M, Deroanne, C, Louis, T, Balsat, C, Van de Velde, M, Kaijalainen, S, Kridelka, F, Engelholm, L, Struman, I, Alitalo, K, Behrendt, N, Paupert, J & Noel, A 2018, 'uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis', Nature Communications, vol. 9, no. 1, 5178, pp. 1-16. https://doi.org/10.1038/s41467-018-07514-1

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

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.",

author = "Tania Durr{\'e} and Florent Morfoisse and Charlotte Erpicum and Marie Ebroin and Silvia Blacher and Melissa Garc{\'i}a-Caballero and Christophe Deroanne and Thomas Louis and C{\'e}dric Balsat and {Van de Velde}, Maureen and Seppo Kaijalainen and Fr{\'e}d{\'e}ric Kridelka and Lars Engelholm and Ingrid Struman and Kari Alitalo and Niels Behrendt and Jenny Paupert and Agn{\`e}s Noel",

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AU - Durré, Tania

AU - Morfoisse, Florent

AU - Erpicum, Charlotte

AU - Ebroin, Marie

AU - Blacher, Silvia

AU - García-Caballero, Melissa

AU - Deroanne, Christophe

AU - Louis, Thomas

AU - Balsat, Cédric

AU - Van de Velde, Maureen

AU - Kaijalainen, Seppo

AU - Kridelka, Frédéric

AU - Engelholm, Lars

AU - Struman, Ingrid

AU - Alitalo, Kari

AU - Behrendt, Niels

AU - Paupert, Jenny

AU - Noel, Agnès

PY - 2018/12/5

Y1 - 2018/12/5

N2 - 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.

AB - 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.

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

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