Frat2-KO Mouse

Frat2, also known as frequently rearranged in advanced T-cell lymphomas 2, is a positive regulator of the WNT signaling pathway [3]. It binds to glycogen synthase kinase-3 (GSK-3) and Dishevelled, key proteins in Wnt signal transduction [4]. The WNT signaling pathway is crucial for maintaining the balance between cell proliferation and differentiation, both during tissue morphogenesis and in tissue maintenance throughout postnatal life [5]. Thus, Frat2 is of great biological importance in these processes. Genetic models, such as knockout mouse models, can be valuable for studying its functions.

In basal-like breast cancer (BLBC), knocking down Frat2 in cell lines T47D and MDA-MB-231 inhibits cell proliferation, arrests the cell cycle in the G2/M phase, and increases apoptosis, suggesting it is a potential treatment target [1]. In MLL-rearranged acute myeloid leukemia, modulation of FRAT2 leads to changes in Rac GTPases activation, and Frat knockout hematopoietic progenitor cells transformed by MLL fusions result in leukemias with reduced Rac activation and increased sensitivity to chemotherapeutic drugs [2].

In conclusion, Frat2 is essential in regulating the WNT signaling pathway. Studies using gene-knockout models have revealed its role in cancer-related processes, such as in BLBC and MLL-rearranged acute myeloid leukemia. These findings contribute to understanding the mechanisms of these diseases and may potentially lead to new therapeutic strategies.

References:

1. Zhou, Yao, Li, Can, Peng, Jie, Chen, Ge, Li, Taiyuan. . WNT signaling pathway regulator-FRAT2 affects oncogenesis and prognosis of basal-like breast cancer. In Journal of thoracic disease, 12, 3478-3487. doi:10.21037/jtd-20-1557A. https://pubmed.ncbi.nlm.nih.gov/32802426/

2. Walf-Vorderwülbecke, Vanessa, de Boer, Jasper, Horton, Sarah J, Berns, Anton, Williams, Owen. 2012. Frat2 mediates the oncogenic activation of Rac by MLL fusions. In Blood, 120, 4819-28. doi:10.1182/blood-2012-05-432534. https://pubmed.ncbi.nlm.nih.gov/23074275/

3. Saitoh, T, Moriwaki, J, Koike, J, Shiokawa, K, Katoh, M. . Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway. In Biochemical and biophysical research communications, 281, 815-20. doi:. https://pubmed.ncbi.nlm.nih.gov/11237732/

4. Freemantle, Sarah J, Portland, Holly B, Ewings, Katherine, Spinella, Michael J, Dmitrovsky, Ethan. . Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2. In Gene, 291, 17-27. doi:. https://pubmed.ncbi.nlm.nih.gov/12095675/

5. van der Wal, Tanne, Lambooij, Jan-Paul, van Amerongen, Renée. 2020. TMEM98 is a negative regulator of FRAT mediated Wnt/ß-catenin signalling. In PloS one, 15, e0227435. doi:10.1371/journal.pone.0227435. https://pubmed.ncbi.nlm.nih.gov/31961879/