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

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http://hdl.handle.net/10138/285185

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Durre , T , Morfoisse , F , Erpicum , C , Ebroin , M , Blacher , S , Garcia-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 , 5178 . https://doi.org/10.1038/s41467-018-07514-1

Title: uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis
Author: Durre, Tania; Morfoisse, Florent; Erpicum, Charlotte; Ebroin, Marie; Blacher, Silvia; Garcia-Caballero, Melissa; Deroanne, Christophe; Louis, Thomas; Balsat, Cedric; Van de Velde, Maureen; Kaijalainen, Seppo; Kridelka, Frederic; Engelholm, Lars; Struman, Ingrid; Alitalo, Kari; Behrendt, Niels; Paupert, Jenny; Noel, Agnes
Contributor: University of Helsinki, Translational Cancer Biology (TCB) Research Programme
University of Helsinki, Translational Cancer Biology (TCB) Research Programme
Date: 2018-12-05
Language: eng
Number of pages: 16
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/285185
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.
Subject: GROWTH FACTOR-C
ENDOTHELIAL-CELLS
VEGFR-2
COLLAGEN
ACTIVATION
MECHANISMS
ENDO180
TUMOR
ANGIOGENESIS
FIBROBLASTS
3111 Biomedicine
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