Laboratory of Tumor and Development Biology, GIGA (GIGA-Cancer), Liege University, B23, Avenue Hippocrate 13, 4000, Liege, Belgium.
Laboratory of Connective Tissues Biology, GIGA-Cancer, Liege University, B23, Avenue Hippocrate 13, 4000, Liege, Belgium.
Nat Commun. 2018 Dec 5;9(1):5178. doi: 10.1038/s41467-018-07514-1.
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.
新的淋巴管的发展发生在许多癌症和炎症性疾病中，通过 VEGF-C 与其受体 VEGFR-2 和 VEGFR-3 的结合。VEGFR-2/VEGFR-3 异二聚体的调节及其在淋巴管内皮细胞 (LEC) 中的下游信号仍然知之甚少。在这里，我们确定了内吞受体 uPARAP，作为 VEGFR-2 和 VEGFR-3 的伴侣，调节它们的异二聚体。uPARAP 的基因缺失导致病理性高分支淋巴管血管而不影响伴随的血管生成。在体外，uPARAP 控制 LEC 迁移对 VEGF-C 的反应，但不控制 VEGF-A 或 VEGF-CCys156Ser。uPARAP 限制 VEGFR-2/VEGFR-3 异二聚体化以及随后的 VEGFR-2 介导的 Crk-II 衔接子的磷酸化和失活。uPARAP 通过 Crk-II/JNK/paxillin/Rac1 通路促进 VEGFR-3 信号传导。在 uPARAP 敲除小鼠中使用 Rac1 药理学抑制剂可恢复野生型表型。总之，我们的研究确定了淋巴管生成的分子调节剂，并揭示了 VEGF-C 驱动的 LEC 发芽过程中 VEGFR-2/VEGFR-3 串扰和下游信号传导的新分子特征。
