Ehd2, or Eps15-homology domain containing protein 2, is a member of the EHD protein family. It is mainly located in the plasma membrane, cytoplasm, and endosomes, and acts as a nuclear-cytoplasmic shuttle protein. As a key regulator of endocytic transport, it is involved in endosomal tubule and vesicle formation and maintenance, which is crucial for intracellular protein and substance transport. It also connects to the actin cytoskeleton through its N-and C-termini, promoting cell endocytosis. Additionally, Ehd2 is associated with membrane protein trafficking, receptor signaling, and metabolism pathways like glucose and lipid metabolism [1].

In various disease-related studies, Ehd2 knockout models have provided insights. In zebrafish, Ehd2 knockout led to increased dysmorphic sprouts in intersomitic vessels during development and reduced downstream Notch activation, indicating its role in blood vessel development by modulating Dll4 endocytosis [2]. In C57BL6/N mice, Ehd2 deficiency under short-term high-fat diet conditions was associated with deteriorated insulin signal transduction and impaired insulin-stimulated GLUT4 translocation in adipocytes, highlighting its importance in insulin resistance and obesity [3]. In mice, global genetic ablation of Ehd2 led to increased lipid droplet size in fat tissue due to increased fatty acid uptake via a caveolae-and CD36-dependent pathway, suggesting a link between low Ehd2 expression and obesity [4]. In triple-negative breast cancer cell line models, Ehd2 knockdown and knockout (with mouse Ehd2 rescue) showed its positive role in promoting tumorigenesis and metastasis by regulating store-operated calcium entry [5]. In contrast, in lung adenocarcinoma, low Ehd2 expression was linked to lymph node metastasis and poor prognosis, and knockdown in A549 cells increased migration and invasion, while overexpression in H1299 cells suppressed these, indicating its anti-invasive role [6]. In colon cancer, Ehd2 overexpression suppressed cell invasion and proliferation in vitro [7].

In conclusion, Ehd2 plays essential roles in multiple biological processes, especially those related to endocytic transport, membrane dynamics, and metabolism. The use of gene knockout models in zebrafish and mice has revealed its significant implications in diseases such as blood vessel development disorders, insulin resistance, obesity, and various cancers, providing potential therapeutic targets for these conditions.

References:

1. Zhu, Guoqiang, Zhang, Hu, Xia, Min, Liu, Yiqi, Li, Mingyong. . EH domain-containing protein 2 (EHD2): Overview, biological function, and therapeutic potential. In Cell biochemistry and function, 42, e4016. doi:10.1002/cbf.4016. https://pubmed.ncbi.nlm.nih.gov/38613224/

2. Webb, Amelia M, Francis, Caitlin R, Judson, Rachael J, Meadows, Stryder M, Kushner, Erich J. 2021. EHD2 modulates Dll4 endocytosis during blood vessel development. In Microcirculation (New York, N.Y. : 1994), 29, e12740. doi:10.1111/micc.12740. https://pubmed.ncbi.nlm.nih.gov/34820962/

3. Neuhaus, Mathis, Fryklund, Claes, Taylor, Holly, Gould, Gwyn W, Stenkula, Karin G. 2023. EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events. In Molecular biology of the cell, 34, ar124. doi:10.1091/mbc.E23-03-0078. https://pubmed.ncbi.nlm.nih.gov/37703099/

4. Matthaeus, Claudia, Lahmann, Ines, Kunz, Séverine, Birchmeier, Carmen, Daumke, Oliver. 2020. EHD2-mediated restriction of caveolar dynamics regulates cellular fatty acid uptake. In Proceedings of the National Academy of Sciences of the United States of America, 117, 7471-7481. doi:10.1073/pnas.1918415117. https://pubmed.ncbi.nlm.nih.gov/32170013/

5. Luan, Haitao, Bielecki, Timothy A, Mohapatra, Bhopal C, Band, Vimla, Band, Hamid. 2023. EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry. In eLife, 12, . doi:10.7554/eLife.81288. https://pubmed.ncbi.nlm.nih.gov/36625722/

6. Wei, Sheng, Shao, Jingjing, Wang, Jinming, Chen, Haizhen, Wang, Gaoren. . EHD2 inhibits the invasive ability of lung adenocarcinoma and improves the prognosis of patients. In Journal of thoracic disease, 14, 2652-2664. doi:10.21037/jtd-22-842. https://pubmed.ncbi.nlm.nih.gov/35928621/

7. Guan, Chengqi, Lu, Cuihua, Xiao, Mingbing, Chen, Weichang. 2021. EHD2 Overexpression Suppresses the Proliferation, Migration, and Invasion in Human Colon Cancer. In Cancer investigation, 39, 297-309. doi:10.1080/07357907.2020.1870125. https://pubmed.ncbi.nlm.nih.gov/33356637/