Vascular Biology Program, Boston Children's Hospital, and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
Vascular Biology Program, Boston Children's Hospital, and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
Cold Spring Harb Perspect Med. 2024 Jan 2;14(1):a041165. doi: 10.1101/cshperspect.a041165.
Circulating vascular endothelial growth factor (VEGF) ligands and receptors are central regulators of vasculogenesis, angiogenesis, and lymphangiogenesis. In response to VEGF ligand binding, VEGF receptor tyrosine kinases initiate the chain of events that transduce extracellular signals into endothelial cell responses such as survival, proliferation, and migration. These events are controlled by intricate cellular processes that include the regulation of gene expression at multiple levels, interactions of numerous proteins, and intracellular trafficking of receptor-ligand complexes. Endocytic uptake and transport of macromolecular complexes through the endosome-lysosome system helps fine-tune endothelial cell responses to VEGF signals. Clathrin-dependent endocytosis remains the best understood means of macromolecular entry into cells, although the importance of non-clathrin-dependent pathways is increasingly recognized. Many of these endocytic events rely on adaptor proteins that coordinate internalization of activated cell-surface receptors. In the endothelium of both blood and lymphatic vessels, epsins 1 and 2 are functionally redundant adaptors involved in receptor endocytosis and intracellular sorting. These proteins are capable of binding both lipids and proteins and are important for promoting curvature of the plasma membrane as well as binding ubiquitinated cargo. Here, we discuss the role of epsin proteins and other endocytic adaptors in governing VEGF signaling in angiogenesis and lymphangiogenesis and discuss their therapeutic potential as molecular targets.
循环血管内皮生长因子 (VEGF) 配体和受体是血管生成、血管生成和淋巴管生成的核心调节剂。在 VEGF 配体结合后，VEGF 受体酪氨酸激酶启动一系列事件，将细胞外信号转导为内皮细胞反应，如存活、增殖和迁移。这些事件受到精细的细胞过程的控制，包括在多个水平上调节基因表达、多种蛋白质的相互作用以及受体-配体复合物的细胞内运输。内体-溶酶体系统中大分子复合物的内吞作用和运输有助于精细调节内皮细胞对 VEGF 信号的反应。网格蛋白依赖性内吞作用仍然是大分子进入细胞的最被理解的手段，尽管非网格蛋白依赖性途径的重要性越来越被认识到。许多这些内吞事件依赖于衔接蛋白，它们协调激活的细胞表面受体的内化。在血液和淋巴管内皮细胞中，epsin 1 和 2 是功能冗余的衔接蛋白，参与受体内吞和细胞内分拣。这些蛋白质既能结合脂质又能结合蛋白质，对于促进质膜的弯曲以及结合泛素化的货物非常重要。在这里，我们讨论了 epsin 蛋白和其他内吞衔接蛋白在调节血管生成和淋巴管生成中的 VEGF 信号转导中的作用，并讨论了它们作为分子靶点的治疗潜力。
