APPL2, also known as adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2, is an adaptor protein involved in multiple signaling pathways. It plays roles in adiponectin signaling, neural stem cell fate determination, and is associated with pathways like PI3K/Akt. Genetic models such as KO mouse models are valuable for studying its functions [1,2].

In KO mouse models, Appl2 -/- mice are viable and grow normally, but Appl2 -null mouse embryonic fibroblasts show defects in HGF-induced Akt activation, migration, and invasion, indicating its importance in HGF cell signaling [3]. Appl2 KO mice also exhibit more severe endotoxin shock symptoms, with increased pro-inflammatory cytokine production and enhanced Akt and NF-κB phosphorylation, suggesting it is a negative regulator of the innate immune response via the PI3K/Akt/NF-κB pathway [4]. Conditional deletion of APPL2 in skeletal muscles enhances insulin sensitivity and glucose tolerance, as APPL2 overexpression impairs insulin-stimulated glucose uptake by interacting with TBC1D1 [5].

In conclusion, APPL2 is essential for multiple biological processes. Its study using KO mouse models has revealed its significance in cell signaling, the innate immune response, and glucose metabolism, contributing to our understanding of related disease mechanisms such as endotoxin shock and type 2 diabetes.

References:

1. Engin, Atilla. . Adiponectin-Resistance in Obesity. In Advances in experimental medicine and biology, 960, 415-441. doi:10.1007/978-3-319-48382-5_18. https://pubmed.ncbi.nlm.nih.gov/28585210/

2. Gao, Chong, Yan, Tingting, Chen, Xingmiao, Xu, Aimin, Shen, Jiangang. 2020. APPL2 Negatively Regulates Olfactory Functions by Switching Fate Commitments of Neural Stem Cells in Adult Olfactory Bulb via Interaction with Notch1 Signaling. In Neuroscience bulletin, 36, 997-1008. doi:10.1007/s12264-020-00514-6. https://pubmed.ncbi.nlm.nih.gov/32468397/

3. Tan, Yinfei, Xin, Xiaoban, Coffey, Francis J, Dong, Lily Q, Testa, Joseph R. 2015. Appl1 and Appl2 are Expendable for Mouse Development But Are Essential for HGF-Induced Akt Activation and Migration in Mouse Embryonic Fibroblasts. In Journal of cellular physiology, 231, 1142-50. doi:10.1002/jcp.25211. https://pubmed.ncbi.nlm.nih.gov/26445298/

4. Mao, Liufeng, Lin, Wanhua, Nie, Tao, Liu, Pentao, Wu, Donghai. 2014. Absence of Appl2 sensitizes endotoxin shock through activation of PI3K/Akt pathway. In Cell & bioscience, 4, 60. doi:10.1186/2045-3701-4-60. https://pubmed.ncbi.nlm.nih.gov/25328665/

5. Cheng, Kenneth K Y, Zhu, Weidong, Chen, Bin, Lam, Karen S L, Xu, Aimin. 2014. The adaptor protein APPL2 inhibits insulin-stimulated glucose uptake by interacting with TBC1D1 in skeletal muscle. In Diabetes, 63, 3748-58. doi:10.2337/db14-0337. https://pubmed.ncbi.nlm.nih.gov/24879834/