RBFOX2, also known as RBM9, RTA, or HNRBP2, is an RNA-binding protein crucial for tissue-specific alternative splicing regulation and steroid receptors' transcriptional activity [5]. It has a wide-reaching impact on various cellular mechanisms from development to cell survival, and its dysregulation is associated with numerous diseases [5]. RBFOX2 can interact with other proteins and RNAs, playing a role in pathways like RHO GTPase, which is related to cytoskeletal organization and focal adhesion formation [1].

In pancreatic ductal adenocarcinoma (PDA), overexpression of RBFOX2 in a patient-derived xenograft metastatic PDA cell line reduced metastatic potential, while its depletion in primary pancreatic tumour cell lines increased it, suggesting it as a metastatic suppressor [1]. In myeloid leukaemia, down-regulation of RBFOX2 inhibited survival/proliferation of acute myeloid leukaemia cells and promoted their myeloid differentiation, and it was also required for self-renewal of leukaemia stem/initiation cells [2]. In pancreatic cancer, down-regulation of RBFOX2 promoted cancer progression and liver metastasis through regulating exon splicing events in cytoskeletal remodeling-related transcripts [3]. In glioblastoma, FBXO7 stabilized Rbfox2, which controlled the splicing of mesenchymal genes, contributing to mesenchymal transformation and chemoresistance [4]. In diabetes-induced cardiac hypertrophy, dysregulated Rbfox2 led to aberrant splicing of CaV1.2 calcium channel, increasing its alternative exon 9*-containing form and eventually inducing cardiomyocyte hypertrophy [6]. In the liver, decreased RBFOX2 function in diet-induced obesity caused a Scarb1 isoform switch and altered hepatocyte lipid homeostasis [7]. Conditional mutation of Rbfox2 in the mouse pancreas decreased insulin secretion and impaired blood glucose homeostasis [8].

In summary, RBFOX2 is a key splicing regulator involved in diverse biological processes. Model-based research, especially KO/CKO mouse models and other loss-of-function experiments, has revealed its role in various disease conditions such as cancer, leukaemia, diabetes-related cardiomyopathy, and metabolic diseases. Understanding RBFOX2 provides insights into disease mechanisms and potential therapeutic strategies.

References:

1. Jbara, Amina, Lin, Kuan-Ting, Stossel, Chani, Golan, Talia, Karni, Rotem. 2023. RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer. In Nature, 617, 147-153. doi:10.1038/s41586-023-05820-3. https://pubmed.ncbi.nlm.nih.gov/36949200/

2. Dou, Xiaoyang, Xiao, Yu, Shen, Chao, Chen, Jianjun, He, Chuan. 2023. RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation. In Nature cell biology, 25, 1359-1368. doi:10.1038/s41556-023-01213-w. https://pubmed.ncbi.nlm.nih.gov/37640841/

3. Maurin, Michelle, Ranjouri, Mohammadreza, Megino-Luque, Cristina, Black, Michael A, Mann, Karen M. 2023. RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing. In Nature communications, 14, 8444. doi:10.1038/s41467-023-44126-w. https://pubmed.ncbi.nlm.nih.gov/38114498/

4. Li, Shangbiao, Chen, Yanwen, Xie, Yuxin, Deng, Fan, Zhou, Aidong. 2023. FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2303561. doi:10.1002/advs.202303561. https://pubmed.ncbi.nlm.nih.gov/37822160/

5. Arya, Anurada D, Wilson, David I, Baralle, Diana, Raponi, Michaela. . RBFOX2 protein domains and cellular activities. In Biochemical Society transactions, 42, 1180-3. doi:10.1042/BST20140050. https://pubmed.ncbi.nlm.nih.gov/25110022/

6. Li, Pengpeng, Qin, Dongxia, Chen, Tiange, Sun, Yu, Wang, Juejin. 2023. Dysregulated Rbfox2 produces aberrant splicing of CaV1.2 calcium channel in diabetes-induced cardiac hypertrophy. In Cardiovascular diabetology, 22, 168. doi:10.1186/s12933-023-01894-5. https://pubmed.ncbi.nlm.nih.gov/37415128/

7. Paterson, Helen A B, Yu, Sijia, Artigas, Natalia, Sibley, Christopher R, Vernia, Santiago. 2022. Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice. In Nature metabolism, 4, 1812-1829. doi:10.1038/s42255-022-00681-y. https://pubmed.ncbi.nlm.nih.gov/36536133/

8. Moss, Nicole D, Wells, Kristen L, Theis, Alexandra, MacDonald, Patrick E, Sussel, Lori. 2023. Modulation of insulin secretion by RBFOX2-mediated alternative splicing. In Nature communications, 14, 7732. doi:10.1038/s41467-023-43605-4. https://pubmed.ncbi.nlm.nih.gov/38007492/