Arrdc3, or arrestin domain-containing protein 3, is a member of the α-arrestin family. It functions as a multifunctional adaptor protein, regulating cellular signaling, particularly that of G protein-coupled receptors (GPCRs) [1]. It is also involved in various biological processes and is considered a tumor suppressor in some cancers [1,2,3].

In liver-specific knockout (L-Arrdc3 KO) mouse models, increased hepatic insulin sensitivity was observed, with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression, leading to reduced hepatic glucose production and increased hepatic glycogen accumulation. This indicates that Arrdc3 modulates insulin action and glucose metabolism in the liver [4]. In breast cancer, the loss of Arrdc3 causes overexpression of PAR1 (a GPCR) and aberrant signaling, and ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, affecting breast cancer metastasis [3]. In colorectal cancer, the expression of Arrdc3 is downregulated, and it suppresses cancer progression by promoting the degradation of the oncoprotein YAP [2].

In conclusion, Arrdc3 plays essential roles in regulating cellular signaling, glucose metabolism, and acts as a tumor suppressor in certain cancers. The use of gene knockout mouse models, like the L-Arrdc3 KO model, has been crucial in revealing its functions in these biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases such as diabetes-related liver metabolism disorders and specific cancers.

References:

1. Wedegaertner, Helen, Pan, Wen-An, Gonzalez, Carlos C, Gonzalez, David J, Trejo, JoAnn. 2022. The α-Arrestin ARRDC3 Is an Emerging Multifunctional Adaptor Protein in Cancer. In Antioxidants & redox signaling, 36, 1066-1079. doi:10.1089/ars.2021.0193. https://pubmed.ncbi.nlm.nih.gov/34465145/

2. Shen, Xu, Sun, Xiaohan, Sun, Bing, Cui, Meng, Zhou, Zizhang. 2018. ARRDC3 suppresses colorectal cancer progression through destabilizing the oncoprotein YAP. In FEBS letters, 592, 599-609. doi:10.1002/1873-3468.12986. https://pubmed.ncbi.nlm.nih.gov/29364502/

3. Arakaki, Aleena K S, Pan, Wen-An, Wedegaertner, Helen, Gujral, Taranjit S, Trejo, JoAnn. 2021. α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis. In Journal of cell science, 134, . doi:10.1242/jcs.254888. https://pubmed.ncbi.nlm.nih.gov/33722977/

4. Batista, Thiago M, Dagdeviren, Sezin, Carroll, Shannon H, Kahn, C Ronald, Lee, Richard T. 2020. Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver. In Proceedings of the National Academy of Sciences of the United States of America, 117, 6733-6740. doi:10.1073/pnas.1922370117. https://pubmed.ncbi.nlm.nih.gov/32156724/