Akt2, also known as Protein kinase B-β (Pkb-β), is a serine/threonine protein kinase central to multiple signaling pathways. It is involved in cell growth, proliferation, survival, and metabolism, and is part of the Phosphatidylinositol 3 kinase/Akt/Mammalian target of rapamycin (PI3K/mTOR) signaling axis [2,4]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in studying its functions.

In a study on non-neovascular AMD, overexpression of AKT2 in the retinal-pigmented epithelium (RPE) of aging Akt2 KI mice led to a dry AMD-like phenotype with a decline in retinal function. Inhibition of the AKT2/SIRT5/TFEB pathway in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function, and contributed to drusen formation [1]. In hepatosteatosis and cancer, hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice [3]. For nicotine responses, Akt2 cKO mice showed increased astrocyte morphological complexity during nicotine exposure, and astrocytic AKT2 deficiency reduced nicotine preference [5]. In the context of a Finnish-specific AKT2 gene variant, myotubes from variant carriers showed impaired insulin-stimulated glycolytic rate and reduced phosphorylation of related proteins, suggesting a role in insulin resistance [6].

In conclusion, Akt2 is essential in various biological processes and diseases. KO/CKO mouse models have revealed its role in non-neovascular AMD, hepatosteatosis-associated HCC, astrocytic nicotine responses, and insulin resistance. Understanding Akt2's functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Ghosh, Sayan, Sharma, Ruchi, Bammidi, Sridhar, Handa, James T, Sinha, Debasish. 2024. The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD. In Nature communications, 15, 6150. doi:10.1038/s41467-024-50500-z. https://pubmed.ncbi.nlm.nih.gov/39034314/

2. Honardoost, Maryam, Rad, Seyed Mohammad Ali Hosseini. 2017. Triangle of AKT2, miRNA, and Tumorigenesis in Different Cancers. In Applied biochemistry and biotechnology, 185, 524-540. doi:10.1007/s12010-017-2657-3. https://pubmed.ncbi.nlm.nih.gov/29199386/

3. Huang, Fuqiang, Zhao, Na, Cai, Pei, Liu, Fangming, Zhang, Hongbing. 2024. Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer. In Translational research : the journal of laboratory and clinical medicine, 268, 51-62. doi:10.1016/j.trsl.2024.01.005. https://pubmed.ncbi.nlm.nih.gov/38244769/

4. Pereira, Lucília, Horta, Sara, Mateus, Rita, Videira, Mafalda A. 2015. Implications of Akt2/Twist crosstalk on breast cancer metastatic outcome. In Drug discovery today, 20, 1152-8. doi:10.1016/j.drudis.2015.06.010. https://pubmed.ncbi.nlm.nih.gov/26136161/

5. Lombardi, Andrew M, Wong, Helen, Bower, Myra E, Stitzel, Jerry, Hoeffer, Charles A. 2024. AKT2 modulates astrocytic nicotine responses in vivo. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.05.31.596856. https://pubmed.ncbi.nlm.nih.gov/38854016/

6. Mäkinen, Selina, Datta, Neeta, Rangarajan, Savithri, Laakso, Markku, Koistinen, Heikki A. 2023. Finnish-specific AKT2 gene variant leads to impaired insulin signalling in myotubes. In Journal of molecular endocrinology, 70, . doi:10.1530/JME-21-0285. https://pubmed.ncbi.nlm.nih.gov/36409629/