Rabep2, or RAB GTPase-binding effector protein 2, is involved in several biological processes. It has been implicated in regulating endosomal trafficking, specifically modulating vascular endothelial growth factor receptor-2 (VEGFR2) trafficking, which is crucial for vascular development and normal vessel function [4]. It is also associated with the Hedgehog signaling pathway and ciliogenesis [5]. Additionally, it has been identified as a novel substrate for Glycogen Synthase kinase-3 (GSK3) [2].

In ischemic stroke research, gene knockout (KO) mouse models have been instrumental. Deletion of Rabep2 in mice led to decreased collateral vessel connections and increased infarct volume after ischemic stroke, indicating its role in modulating stroke outcomes [1]. Similar phenotypes were observed in hypoxemia-induced collateral formation, where Rabep2 deletion inhibited the process [3]. In large artery occlusion patients, the rs11645302 polymorphism of Rabep2 was linked to poorer collateral circulation [6]. Also, in a study comparing transient and permanent middle cerebral artery occlusion in mice with different Rabep2 genotypes, those lacking Rabep2 had different infarct volume responses, showing the impact of Rabep2 on stroke progression [7].

In conclusion, Rabep2 is essential for regulating endosomal trafficking related to VEGFR2-dependent signaling and plays a significant role in collateral vessel formation. The use of Rabep2 KO mouse models has provided valuable insights into its function in ischemic stroke, highlighting its potential as a target for stroke therapeutics development [1].

References:

1. Lee, Han Kyu, Kwon, Do Hoon, Aylor, David L, Marchuk, Douglas A. 2022. A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in human RABEP2 modulates ischemic stroke outcomes. In American journal of human genetics, 109, 1814-1827. doi:10.1016/j.ajhg.2022.09.003. https://pubmed.ncbi.nlm.nih.gov/36167069/

2. Logie, Lisa, Van Aalten, Lidy, Knebel, Axel, Fuller, Will, Sutherland, Calum. 2017. Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3). In Scientific reports, 7, 17682. doi:10.1038/s41598-017-17087-6. https://pubmed.ncbi.nlm.nih.gov/29247183/

3. Aghajanian, Amir, Zhang, Hua, Buckley, Brian K, Ma, Willa Y, Faber, James E. 2020. Decreased inspired oxygen stimulates de novo formation of coronary collaterals in adult heart. In Journal of molecular and cellular cardiology, 150, 1-11. doi:10.1016/j.yjmcc.2020.09.015. https://pubmed.ncbi.nlm.nih.gov/33038388/

4. Kofler, Natalie, Corti, Federico, Rivera-Molina, Felix, Toomre, Derek, Simons, Michael. 2018. The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. In The Journal of biological chemistry, 293, 4805-4817. doi:10.1074/jbc.M117.812172. https://pubmed.ncbi.nlm.nih.gov/29425100/

5. Airik, Rannar, Schueler, Markus, Airik, Merlin, Andersen, Jens S, Hildebrandt, Friedhelm. 2016. SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling. In PloS one, 11, e0156081. doi:10.1371/journal.pone.0156081. https://pubmed.ncbi.nlm.nih.gov/27224062/

6. Zhang, Kun, Liu, Luji, Li, Tong, Zhao, Pandi, Liu, Xiaoyun. 2025. Collateral Circulation and Rabep2 Polymorphisms in Large Artery Occlusion: Impacts on Short- and Long-Term Prognosis. In Journal of the American Heart Association, 14, e040032. doi:10.1161/JAHA.124.040032. https://pubmed.ncbi.nlm.nih.gov/40207533/

7. Zhang, Hua, Faber, James E. 2019. Transient versus Permanent MCA Occlusion in Mice Genetically Modified to Have Good versus Poor Collaterals. In Med one, 4, . doi:10.20900/mo.20190024. https://pubmed.ncbi.nlm.nih.gov/31840083/