Arf3, also known as ADP-ribosylation factor 3, is a key protein involved in diverse biological processes. It is a small GTPase that regulates Golgi dynamics, cargo sorting at the trans-Golgi network (TGN), and membrane trafficking, which are essential for normal cell function [3,5]. It is also associated with pathways like AKT and ERK, and its function impacts various biological processes and diseases [2].

In gastric cancer, Arf3 inhibits cell proliferation, induces cycle arrest, and promotes apoptosis by regulating the AKT and ERK pathways [2]. In prostate cancer, Arf3 controls the modality of invasion, acting as a switch between leader cell-led chains of invasion or collective sheet movement, and its levels can affect metastasis [1,4]. De novo missense variants in Arf3 can cause a developmental disease in humans, impairing nervous system and skeletal formation, with variants affecting Golgi morphology, vesicles assembly, and trafficking [3]. In zebrafish, disease modeling validates the dominant behavior of these mutants and their impact on brain and body plan formation [3]. Two de novo pathogenic variants in Arf3 in humans lead to a neurodevelopmental disorder with brain abnormalities, and these variants affect Golgi transport system differently, with one possibly a loss-of-function and the other a gain-of-function variant [5].

In conclusion, Arf3 plays crucial roles in multiple biological processes and disease conditions. Its functions in regulating cell proliferation, apoptosis, invasion, and metastasis in cancer, as well as its impact on neurodevelopment, are significant. The studies using model organisms like zebrafish and human cell-based functional analysis have provided insights into the roles of Arf3 in these disease areas, helping to understand the underlying mechanisms and potentially leading to new therapeutic strategies.

References:

1. Caswell, Patrick T. 2023. ARF3 weights the balance for prostate cancer metastasis. In The Journal of cell biology, 222, . doi:10.1083/jcb.202303037. https://pubmed.ncbi.nlm.nih.gov/36920439/

2. Liu, Jiayun, Liu, Shenlin, Wu, Maolin, Wu, Xiaoyu, Wu, Guannan. . ARF3 inhibits proliferation and promotes apoptosis in gastric cancer by regulating AKT and ERK pathway. In Acta biochimica Polonica, 68, 223-229. doi:10.18388/abp.2020_5519. https://pubmed.ncbi.nlm.nih.gov/33847108/

3. Fasano, Giulia, Muto, Valentina, Radio, Francesca Clementina, Lauri, Antonella, Tartaglia, Marco. 2022. Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish. In Nature communications, 13, 6841. doi:10.1038/s41467-022-34354-x. https://pubmed.ncbi.nlm.nih.gov/36369169/

4. Sandilands, Emma, Freckmann, Eva C, Cumming, Erin M, Blyth, Karen, Bryant, David M. 2023. The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels. In The Journal of cell biology, 222, . doi:10.1083/jcb.202206115. https://pubmed.ncbi.nlm.nih.gov/36880595/

5. Sakamoto, Masamune, Sasaki, Kazunori, Sugie, Atsushi, Miyake, Noriko, Matsumoto, Naomichi. . De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality. In Human molecular genetics, 31, 69-81. doi:10.1093/hmg/ddab224. https://pubmed.ncbi.nlm.nih.gov/34346499/