Tm9sf2, a member of the transmembrane 9 superfamily, is characterized by nine putative transmembrane domains [2,3,4]. It is involved in multiple biological processes. In Drosophila, it contributes to phagocytosis and controls the actin cytoskeleton, along with TM9SF4 [3]. In zebrafish, it is maternally expressed and present throughout embryogenesis [4]. It may play a regulatory role in innate immunity, as an evolutionary conserved immunoreceptor tyrosine-based inhibition motif and a conserved TRAF2 binding domain have been predicted in its cytoplasmic regions [4].

Functional studies have shown its significance in diseases. In colorectal cancer, transposon mutagenesis in mice identified Tm9sf2 as a novel oncogene. RNAi silencing and Nuclease technology knockout of Tm9sf2 reduced CRC cell growth in vitro and in vivo, suggesting its role in promoting tumor fitness [2]. In pancreatic adenocarcinoma, LINC01232, an up-regulated long intergenic non-protein coding RNA, was found to regulate Tm9sf2. LINC01232 recruited EIF4A3 to boost Tm9sf2 mRNA stability, and their transcriptional activation was mediated by SP1. Suppression of LINC01232 hindered PAAD deterioration by affecting cell proliferation and migration, indicating Tm9sf2's role in PAAD progression [1]. In addition, genome-wide CRISPR screens showed that Tm9sf2 is required for maintaining proper levels of glycosylation in the Golgi, as Tm9sf2 knockout cells had a reduction in glycosphingolipids like globotriaosylceramide (Gb3), and also had defective endosomal trafficking [5].

In conclusion, Tm9sf2 is involved in diverse biological functions such as phagocytosis, cytoskeleton control, and may have a role in innate immunity. Its dysregulation is associated with colorectal and pancreatic cancers. Gene knockout models in mice have been crucial in revealing its oncogenic role in these cancers, highlighting its potential as a therapeutic target. The findings from CRISPR-based knockout screens also provide insights into its role in glycosylation and endosomal trafficking, expanding our understanding of its cellular functions [1,2,5].

References:

1. Li, Qian, Lei, Chengbin, Lu, Changliang, Gao, Min, Gao, Wei. 2019. LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2. In Cell death & disease, 10, 698. doi:10.1038/s41419-019-1896-3. https://pubmed.ncbi.nlm.nih.gov/31541081/

2. Clark, Christopher R, Maile, Makayla, Blaney, Patrick, Abrahante, Juan E, Starr, Timothy K. 2018. Transposon mutagenesis screen in mice identifies TM9SF2 as a novel colorectal cancer oncogene. In Scientific reports, 8, 15327. doi:10.1038/s41598-018-33527-3. https://pubmed.ncbi.nlm.nih.gov/30333512/

3. Perrin, Jackie, Mortier, Magda, Jacomin, Anne-Claire, Thevenon, Dominique, Fauvarque, Marie-Odile. 2014. The nonaspanins TM9SF2 and TM9SF4 regulate the plasma membrane localization and signalling activity of the peptidoglycan recognition protein PGRP-LC in Drosophila. In Journal of innate immunity, 7, 37-46. doi:10.1159/000365112. https://pubmed.ncbi.nlm.nih.gov/25139117/

4. Pruvot, Benoist, Laurens, Véronique, Salvadori, Françoise, Pichon, Laurent, Chluba, Johanna. 2010. Comparative analysis of nonaspanin protein sequences and expression studies in zebrafish. In Immunogenetics, 62, 681-99. doi:10.1007/s00251-010-0472-x. https://pubmed.ncbi.nlm.nih.gov/20820770/

5. Tian, Songhai, Muneeruddin, Khaja, Choi, Mei Yuk, Adam, Rosalyn M, Dong, Min. 2018. Genome-wide CRISPR screens for Shiga toxins and ricin reveal Golgi proteins critical for glycosylation. In PLoS biology, 16, e2006951. doi:10.1371/journal.pbio.2006951. https://pubmed.ncbi.nlm.nih.gov/30481169/