Vps35, or vacuolar protein sorting-associated protein 35, is a core component of the retromer complex. This complex is crucial for mediating intracellular protein transport, specifically endosomal sorting and recycling of transmembrane cargo [1,2,3,6,7]. It is involved in pathways such as receptor trafficking, lysosomal and autophagy function, and mitochondrial homeostasis, which are vital for normal cellular function and are linked to various biological processes and diseases [2,4,6,7]. Genetic models are valuable for studying Vps35 as they can help uncover its role in these processes.

In gastric cancer, Vps35 promotes cell proliferation by recycling epidermal growth factor receptor (EGFR) to the cell surface, activating the ERK1/2 pathway. It also enhances the sensitivity of gastric cancer to EGFR inhibitors [1]. Additionally, in gastric cancer, Vps35 activates FAK-SRC kinases through integrin-mediated outside-in signalling, leading to YAP activation, IL-6 expression, and subsequent activation of the IL-6/STAT3 pathway. It also forms a positive regulatory feedback loop with STAT3, and knockdown of Vps35 sensitises GC cells to 5-FU and cisplatin [3]. In Parkinson's disease, Vps35 mutations (such as D620N) are associated with the disease. These mutations may lead to impaired lysosomal and autophagy function, mitochondrial dysfunction, and LRRK2 hyperactivation, as well as affect neurotransmitter receptor transport [2,4,5,6].

In conclusion, Vps35 has essential functions in receptor recycling, cell proliferation, and multiple signalling pathways in cancer. In Parkinson's disease, its mutations are linked to neurodegeneration through disrupted cellular functions. Model-based research, especially gene knockout and conditional knockout mouse models, can potentially further clarify these mechanisms, contributing to the understanding of related diseases and the development of targeted therapies.