ATP9A, a lipid flippase of the class II P4-ATPases, is involved in cellular vesicle trafficking, specifically in the recycling pathway from endosomes to the plasma membrane [2,3]. It plays a role in several biological processes and is associated with various disease conditions.

In hepatocellular carcinoma, nutrient starvation-induced macropinocytosis was found to be regulated by ATP9A. High ATP9A levels predicted poor patient outcomes. ATP9A interacted with ATP6V1A, facilitating its transport to the plasma membrane, promoting cholesterol accumulation, and driving RAC1-dependent macropinocytosis [1]. In addition, ATP9A deficiency in humans and Atp9a null mice led to neurodevelopmental disorders such as autosomal recessive hypotonia, intellectual disability, and attention deficit hyperactivity disorder (ADHD). Atp9a null mice recapitulated these symptoms, with abnormal neurite morphology and impaired synaptic transmission. ATP9A was shown to be required for maintaining neuronal neurite morphology and neural cell viability in vitro, and it regulated endosomal recycling by modulating RAB5 and RAB11 activation [2].

In summary, ATP9A is crucial for vesicle trafficking and endosomal recycling. Its dysfunction in gene-knockout mouse models is associated with hepatocellular carcinoma and neurodevelopmental disorders, highlighting its significance in understanding these disease mechanisms. [1,2]

References:

1. Wang, Xiaoqing, Li, Yue, Xiao, Yunyun, Lin, Ye, Guan, Jian. 2023. The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma. In The Journal of pathology, 260, 17-31. doi:10.1002/path.6059. https://pubmed.ncbi.nlm.nih.gov/36715683/

2. Meng, Tian, Chen, Xiaoting, He, Zhengjie, Yan, Yousheng, Feng, Du. 2023. ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity. In Molecular psychiatry, 28, 1219-1231. doi:10.1038/s41380-022-01940-w. https://pubmed.ncbi.nlm.nih.gov/36604604/

3. Tanaka, Yoshiki, Ono, Natsuki, Shima, Takahiro, Takatsu, Hiroyuki, Shin, Hye-Won. 2016. The phospholipid flippase ATP9A is required for the recycling pathway from the endosomes to the plasma membrane. In Molecular biology of the cell, 27, 3883-3893. doi:. https://pubmed.ncbi.nlm.nih.gov/27733620/