EphB2, short for Eph receptor B2, is a significant member of the erythropoietin-producing hepatocellular carcinoma (Eph) receptor family. These receptors and their ephrin ligands form a crucial cell-communication system. EphB2 is involved in bidirectional signaling, with roles in diverse biological processes. It has been associated with multiple signaling pathways such as Notch, SRC/AKT/GSK3β/β-catenin, and is important for cell adhesion, migration, and synaptic plasticity [1,3,5].

In disease-related research, EphB2 has been studied extensively. In non-alcoholic steatohepatitis (NASH), EphB2-expressing hepatocytes contribute to disease progression. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH, indicating its role in NASH development [2]. In hepatocellular carcinoma (HCC), endogenous EPHB2 knockout in mice attenuated tumor development. EPHB2 was found to enhance cancer stem cell properties and drive sorafenib resistance through the SRC/AKT/GSK3β/β-catenin signaling cascade [3]. In systemic sclerosis, EphB2-knockout mice showed less dermal fibrosis. EphB2 expression was up-regulated in SSc skin tissue, and its forward signaling was a critical mediator of dermal fibrosis [4]. In the context of social isolation-induced memory forgetting, viral-mediated EphB2 knockdown in the hippocampal CA1 region mimicked memory defects in group-housed mice, while restoration of EphB2 reversed the memory decline in isolated mice [5].

In summary, EphB2 is essential for various biological processes and is involved in multiple diseases, including NASH, HCC, systemic sclerosis, and social-isolation-related memory deficits. Gene knockout mouse models have been instrumental in revealing its role in these disease conditions, providing potential therapeutic targets for treatment.

References:

1. Liu, Wei, Yu, Chengpeng, Li, Jianfeng, Fang, Jiwei. 2022. The Roles of EphB2 in Cancer. In Frontiers in cell and developmental biology, 10, 788587. doi:10.3389/fcell.2022.788587. https://pubmed.ncbi.nlm.nih.gov/35223830/

2. Xiao, Yang, Batmanov, Kirill, Hu, Wenxiang, Hill, David A, Lazar, Mitchell A. 2023. Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. In Science translational medicine, 15, eadc9653. doi:10.1126/scitranslmed.adc9653. https://pubmed.ncbi.nlm.nih.gov/36753562/

3. Leung, Hoi Wing, Leung, Carmen Oi Ning, Lau, Eunice Y, Ma, Stephanie, Lee, Terence K. 2021. EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma. In Cancer research, 81, 3229-3240. doi:10.1158/0008-5472.CAN-21-0184. https://pubmed.ncbi.nlm.nih.gov/33903122/

4. Egal, Erika S A, Kamdem, Severin Donald, Yoshigi, Masaaki, Frech, Tracy M, Mimche, Patrice N. 2024. EphB2 Receptor Promotes Dermal Fibrosis in Systemic Sclerosis. In Arthritis & rheumatology (Hoboken, N.J.), 76, 1303-1316. doi:10.1002/art.42858. https://pubmed.ncbi.nlm.nih.gov/38589317/

5. Wu, Xin-Rong, Zhang, Yu, Liu, Xian-Dong, Xu, Nan-Jie, Sun, Suya. 2020. EphB2 mediates social isolation-induced memory forgetting. In Translational psychiatry, 10, 389. doi:10.1038/s41398-020-01051-6. https://pubmed.ncbi.nlm.nih.gov/33168800/