Gpsm1, also known as activator of G-protein signaling 3, is an accessory protein that modulates G-protein signaling, which is crucial in various cellular processes [5]. It has been associated with multiple pathways including Gαi3/cAMP/PKA/CREB axis, PI3K/AKT/mTOR signaling, and is involved in processes like metabolic homeostasis, cell proliferation, apoptosis, and immune regulation [1,2,4].

In metabolic studies, myeloid-specific Gpsm1 ablation in mice protected against high-fat-diet-induced insulin resistance, glucose dysregulation, and liver steatosis by repressing adipose tissue pro-inflammatory states [1]. POMC neuron-specific Gpsm1 deficiency mice were protected against diet-induced obesity, glucose dysregulation, insulin resistance, and hepatic steatosis. Mechanistically, it enhanced autophagy and leptin sensitivity through PI3K/AKT/mTOR signaling [2]. In an ADPKD mouse model, complete loss of Gpsm1 increased cyst progression and reduced renal function [5]. In ovarian granulosa cells, silencing Gpsm1 increased apoptosis and decreased proliferation possibly through the cAMP-PKA-CREB pathway [3]. In B-cell acute lymphoblastic leukemia cells, knockdown of Gpsm1 inhibited proliferation and promoted apoptosis by suppressing the ADCY6-RAPGEF3-JNK signaling pathway [4].

In conclusion, Gpsm1 is involved in key biological functions such as metabolic regulation, cell growth, and apoptosis. Gene knockout and conditional knockout mouse models have been instrumental in revealing its role in diseases like type 2 diabetes, obesity, polycystic kidney disease, ovarian insufficiency, and leukemia, providing potential therapeutic targets for these conditions.

References:

1. Yan, Jing, Zhang, Yuemei, Yu, Hairong, Jia, Weiping, Hu, Cheng. 2022. GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages. In Nature communications, 13, 7260. doi:10.1038/s41467-022-34998-9. https://pubmed.ncbi.nlm.nih.gov/36434066/

2. Tang, Mengyang, Zhang, Yi, Zhang, Rong, Yan, Jing, Hu, Cheng. 2023. GPSM1 in POMC neurons impairs brown adipose tissue thermogenesis and provokes diet-induced obesity. In Molecular metabolism, 79, 101839. doi:10.1016/j.molmet.2023.101839. https://pubmed.ncbi.nlm.nih.gov/37979657/

3. Cai, Xuzi, Fu, Huijiao, Wang, Yan, Liu, Qiwen, Wang, Xuefeng. 2020. Depletion of GPSM1 enhances ovarian granulosa cell apoptosis via cAMP-PKA-CREB pathway in vitro. In Journal of ovarian research, 13, 136. doi:10.1186/s13048-020-00740-6. https://pubmed.ncbi.nlm.nih.gov/33220708/

4. Zhang, Ye, Zhou, Bo, Sun, Jingjing, He, Qun, Zhao, Yujie. 2021. Knockdown of GPSM1 Inhibits the Proliferation and Promotes the Apoptosis of B-Cell Acute Lymphoblastic Leukemia Cells by Suppressing the ADCY6-RAPGEF3-JNK Signaling Pathway. In Pathology oncology research : POR, 27, 643376. doi:10.3389/pore.2021.643376. https://pubmed.ncbi.nlm.nih.gov/34257610/

5. Kwon, Michelle, Pavlov, Tengis S, Nozu, Kandai, Staruschenko, Alexander, Park, Frank. 2012. G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. In Proceedings of the National Academy of Sciences of the United States of America, 109, 21462-7. doi:10.1073/pnas.1216830110. https://pubmed.ncbi.nlm.nih.gov/23236168/