EphB2, a receptor tyrosine kinase, is a key member of the erythropoietin-producing hepatocellular carcinoma (Eph) receptor family. It participates in cell-cell communication via bidirectional signaling with ephrin ligands, influencing diverse biological processes like cell adhesion, migration, and synaptic plasticity. EphB2 is involved in pathways such as Notch, SRC/AKT/GSK3β/β-catenin, and is crucial for normal development and tissue homeostasis [1,3]. Genetic models, especially KO mouse models, are valuable for studying EphB2 function.

In non-alcoholic steatohepatitis (NASH), EphB2-expressing hepatocytes, acting as a downstream effector of Notch signaling, contribute to disease progression. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model, suggesting its role in NASH [2]. In hepatocellular carcinoma, endogenous EPHB2 knockout attenuated tumor development in mice. EPHB2 drives sorafenib resistance by enhancing cancer stem cell properties through the SRC/AKT/GSK3β/β-catenin signaling cascade [3]. In systemic sclerosis, EphB2 is up-regulated in SSc skin tissue. EphB2-knockout mice had reduced dermal fibrosis in bleomycin-induced and tight skin (Tsk1/+) models, indicating its role in promoting dermal fibrosis [4]. In social isolation-induced memory forgetting, viral-mediated EphB2 knockdown in the hippocampal CA1 region mimicked memory defects, while restoration reversed the decline [5].

In conclusion, EphB2 plays essential roles in various biological processes and disease conditions. The use of KO mouse models has revealed its significance in NASH, hepatocellular carcinoma, dermal fibrosis in systemic sclerosis, and social isolation-related memory decline. Understanding EphB2 function through these models provides potential therapeutic targets for these diseases.

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/