Doc2b-KO Mouse

Doc2b, a member of the double C2 protein family, is ubiquitously expressed and has multiple essential functions. It plays a key role in Ca(+2)-dependent exocytosis processes such as vesicle docking, priming, fusion, and recycling, which involve proper protein-protein and protein-lipid interactions [3]. It is also associated with pathways like insulin secretion, Wnt/β-catenin signaling, and epithelial-mesenchymal transition, and is of great biological importance in maintaining glucose homeostasis, neurotransmitter release, and normal cell behaviors [1,2,5]. Genetic models, especially knockout (KO) mouse models, have been crucial in studying its functions.

In β-cells, Doc2b knockout mice (Doc2b+/-) show a severe response to multiple-low-dose streptozotocin (MLD-STZ), with more apoptotic β-cells and a smaller β-cell mass [6]. Conversely, inducible β-cell-specific Doc2b-overexpressing transgenic (βDoc2b-dTg) mice show improved glucose tolerance and resist MLD-STZ-induced disruption of glucose tolerance, fasting hyperglycemia, β-cell apoptosis, and loss of β-cell mass [6]. In skeletal muscle, human donors with type 2 diabetes have reduced Doc2b levels, and inducible enrichment of Doc2b in skeletal muscle of transgenic mice enhances whole-body glucose tolerance and peripheral insulin sensitivity [4]. In cervical cancer, knockdown of Doc2b promotes cell proliferation, migration, invasion, and EMT, while its overexpression inhibits the Wnt/β-catenin signaling pathway [2,5].

In conclusion, Doc2b is essential for processes like insulin secretion, glucose homeostasis, and cell behavior regulation. KO and overexpression mouse models have revealed its protective role in β-cells against diabetogenic and pro-apoptotic stress, its impact on insulin sensitivity in skeletal muscle, and its tumor-suppressive function in cervical cancer. These findings provide potential therapeutic targets for diabetes and cervical cancer treatment [1,2,4,6].

References:

1. Chatterjee Bhowmick, Diti, Aslamy, Arianne, Bhattacharya, Supriyo, Ahn, Miwon, Thurmond, Debbie C. . DOC2b Enhances β-Cell Function via a Novel Tyrosine Phosphorylation-Dependent Mechanism. In Diabetes, 71, 1246-1260. doi:10.2337/db21-0681. https://pubmed.ncbi.nlm.nih.gov/35377441/

2. Adiga, Divya, Bhat, Samatha, Chakrabarty, Sanjiban, Kabekkodu, Shama Prasada. 2022. DOC2B is a negative regulator of Wnt/β-catenin signaling pathway in cervical cancer. In Pharmacological research, 180, 106239. doi:10.1016/j.phrs.2022.106239. https://pubmed.ncbi.nlm.nih.gov/35500882/

3. Friedrich, Reut, Yeheskel, Adva, Ashery, Uri. 2010. DOC2B, C2 domains, and calcium: A tale of intricate interactions. In Molecular neurobiology, 41, 42-51. doi:10.1007/s12035-009-8094-8. https://pubmed.ncbi.nlm.nih.gov/20052564/

4. Zhang, Jing, Oh, Eunjin, Merz, Karla E, Tunduguru, Ragadeepthi, Thurmond, Debbie C. 2019. DOC2B promotes insulin sensitivity in mice via a novel KLC1-dependent mechanism in skeletal muscle. In Diabetologia, 62, 845-859. doi:10.1007/s00125-019-4824-2. https://pubmed.ncbi.nlm.nih.gov/30707251/

5. Bhat, Samatha, Adiga, Divya, Shukla, Vaibhav, Kabekkodu, Shama Prasada, Satyamoorthy, Kapaettu. 2021. Metastatic suppression by DOC2B is mediated by inhibition of epithelial-mesenchymal transition and induction of senescence. In Cell biology and toxicology, 38, 237-258. doi:10.1007/s10565-021-09598-w. https://pubmed.ncbi.nlm.nih.gov/33758996/

6. Aslamy, Arianne, Oh, Eunjin, Olson, Erika M, Veluthakal, Rajakrishnan, Thurmond, Debbie C. 2018. Doc2b Protects β-Cells Against Inflammatory Damage and Enhances Function. In Diabetes, 67, 1332-1344. doi:10.2337/db17-1352. https://pubmed.ncbi.nlm.nih.gov/29661782/