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Endocytic Adaptors in Cardiovascular Disease - PubMed

  • ️Wed Jan 01 2020

Review

Endocytic Adaptors in Cardiovascular Disease

Kui Cui et al. Front Cell Dev Biol. 2020.

Abstract

Endocytosis is the process of actively transporting materials into a cell by membrane engulfment. Traditionally, endocytosis was divided into three forms: phagocytosis (cell eating), pinocytosis (cell drinking), and the more selective receptor-mediated endocytosis (clathrin-mediated endocytosis); however, other important endocytic pathways (e.g., caveolin-dependent endocytosis) contribute to the uptake of extracellular substances. In each, the plasma membrane changes shape to allow the ingestion and internalization of materials, resulting in the formation of an intracellular vesicle. While receptor-mediated endocytosis remains the best understood pathway, mammalian cells utilize each form of endocytosis to respond to their environment. Receptor-mediated endocytosis permits the internalization of cell surface receptors and their ligands through a complex membrane invagination process that is facilitated by clathrin and adaptor proteins. Internalized vesicles containing these receptor-ligand cargoes fuse with early endosomes, which can then be recycled back to the plasma membrane, delivered to other cellular compartments, or destined for degradation by fusing with lysosomes. These intracellular fates are largely determined by the interaction of specific cargoes with adaptor proteins, such as the epsins, disabled-homolog 2 (Dab2), the stonin proteins, epidermal growth factor receptor substrate 15, and adaptor protein 2 (AP-2). In this review, we focus on the role of epsins and Dab2 in controlling these sorting processes in the context of cardiovascular disease. In particular, we will focus on the function of epsins and Dab2 in inflammation, cholesterol metabolism, and their fundamental contribution to atherogenicity.

Keywords: atherosclerosis; clathrin; diabetes; disabled-homolog 2; endocytic adaptor proteins; epsin; inflammation; receptor-mediated endocytosis.

Copyright © 2020 Cui, Dong, Wang, Cowan, Chan, Shyy and Chen.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Clathrin-mediated endocytosis. Extracellular ligands binding to cell surface receptors triggers the recruitment of the adaptor proteins, such as AP-2, Dab2, and/or members of the epsin family, which induces plasma membrane invagination and formation of clathrin-coated pits that are subsequently released via dynamin-mediated scission. Clathrin-coated vesicles undergo de-coating and sorting through fusion with early endosomes, late endosomes, and ultimately, lysosomes, leading to receptor degradation, or sorting back to the cell surface by recycling endosomes.

FIGURE 2
FIGURE 2

Epsin domain structure. Epsin interacting regions for binding partners. PIP2, phosphatidylinositol-4,5-bisphosphate; ENTH, epsin N-terminal homology; UIM, Ubiquitin-interacting motifs; AP-2, Adaptor protein 2; EH, Eps 15 homology domain.

FIGURE 3
FIGURE 3

Dab2 domain structure and isoforms. Dab2 has two splice variants called p96 and p67. The NH2-terminal phosphotyrosine-binding domain (PTB) or phosphotyrosine-interacting domain (PID) interacts with receptors, such as the LDL receptor or LDL receptor-related protein (LRP) via the NPXY (Asn-Pro-x-Tyr) motif. The middle region of p96 interacts with endocytic proteins clathrin and α-Adaptin. The COOH-terminal of Dab2 contains a Proline-Rich Domain (PRD) that can bind to Src homology 3 (SH3)-containing proteins. The Dab2 COOH-terminus can also bind myosin VI to mediate endocytic trafficking.

FIGURE 4
FIGURE 4

The role of endocytic adaptor proteins in physiological and pathophysiological processes. Physiological processes are depicted by words in black color. Pathological consequences of endocytic defects are depicted by words in red color.

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