Epsins in vascular development, function and disease
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Cellular and Molecular Life Sciences
REVIEW
Epsins in vascular development, function and disease Sudarshan Bhattacharjee1 · Yang Lee1 · Bo Zhu1 · Hao Wu1 · Yabing Chen2 · Hong Chen1 Received: 12 June 2020 / Revised: 14 August 2020 / Accepted: 3 September 2020 © Springer Nature Switzerland AG 2020
Abstract Epsins are a family of adaptor proteins involved in clathrin-dependent endocytosis. In the vasculature, epsins 1 and 2 are functionally redundant members of this family that are expressed in the endothelial cells of blood vessels and the lymphatic system throughout development and adulthood. These proteins contain a number of peptide motifs that allow them to interact with lipid moieties and a variety of proteins. These interactions facilitate the regulation of a wide range of cell signaling pathways. In this review, we focus on the involvement of epsins 1 and 2 in controlling vascular endothelial growth factor receptor signaling in angiogenesis and lymphangiogenesis. We also discuss the therapeutic implications of understanding the molecular mechanisms of epsin-mediated regulation in diseases such as atherosclerosis and diabetes. Keywords Angiogenesis · Lymphangiogenesis · Vascular endothelial growth factor · Endocytosis · Endocytic adaptor proteins · Cell signaling · Receptor trafficking · Vasculogenesis · Diabetes · Atherosclerosis · Inflammatory signaling
Introduction Epsins are evolutionarily conserved proteins that are essential for fundamental cellular processes in embryos [1–3] and adults [4–6]. While working in Pietro De Camilli’s laboratory at the Yale University School of Medicine, one of us (Hong Chen) discovered that rat epsin 1 interacted with the endocytic accessory protein Eps15 [7] and helped to identify the epsin 2 isoform [8]. Epsins 1 and 2 are universally expressed and enriched in the brain, whereas epsin 3 expression is more restricted [9]. Structurally, epsins contain a conserved NH2-terminal homology (ENTH) domain, which anchors them to the plasma membrane, and ubiquitininteracting motifs (UIMs), which interact with ubiquitinated cargo. This region also contains less -structured clathrinbinding motifs and a number of amino acid repeats that Sudarshan Bhattacharjee, Yang Lee, and Bo Zhu have contributed equally to this work. * Hong Chen [email protected] 1
Vascular Biology Program, Harvard Medical School, Boston Children’s Hospital and Department of Surgery, Boston, MA 02115, USA
Department of Pathology, Birmingham Veterans Affairs Medical Center, University of Alabama at Birmingham and Research Department, Birmingham, AL 35294, USA
2
are upstream from the carboxyl terminus. Together, these domains help deliver cargo to coated vesicle formation sites for internalization and intracellular trafficking (Fig. 1) [7, 10]. The ENTH domain is approximately 150 amino acids in length, highly conserved, and responsible for binding inositol phospholipids such as phosphatidylinositol-4,5-bisphosphate (PI[4,5]P2) and proteins. This domain contributes to the nucleation and f
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