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9.B.312.  The Cytokine Expression and Secretion Mediator and V-type ATPase Regulator, TMEM9 (TMEM9) Family

Human transmembrane protein 9 (TMEM9) is a protein of 183 amino acids with 2 TMSs, one N-terminal, and one about 2/3rds of the way from the N-terminus. The N-terminal region contains several important domains. Homologues are found in animals such as Caenorhabditis elegans and Drosophila melanogaster. In humans, the gene is expressed in many tissues and cells. TMEM9 may play a role in intracellular transportWei et al. 2018 studied the expression of the TMEM9 gene and its effect on cytokine secretion in tumor necrosis factor-alpha (TNF-α)-induced LX-2 cells. They showed that overexpression increased the expression of IL-6 and IL-1β. while knockdown decreased their secretion; this enhanced the expression levels of the canonical Wnt/β-catenin genes, accompanied by increased wnt2b, wnt3a and β-catenin protein levels treated with TNF-α. Thus, TMEM9 plays a role in the modulation  of TNF-α-enhanced cytokine (IL-6 and IL-1β) secretion. The canonical Wnt/β-catenin signaling pathway is involved in the induction of the expression of the relevant gene (Wei et al. 2018).  TMEM9 binds to and facilitates assembly of the vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking (Jung et al. 2018).

TMEM9 is a vesicular acidification regulator, and it is highly upregulated in colorectal cancer. TMEM9 binds to and facilitates assembly of the vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking (Jung et al. 2018). TMEM9-v-ATPase hyperactivates Wnt/beta-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by beta-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer.

References associated with 8.A.123 family:

Jung, Y.S., S. Jun, M.J. Kim, S.H. Lee, H.N. Suh, E.M. Lien, H.Y. Jung, S. Lee, J. Zhang, J.I. Yang, H. Ji, J.Y. Wu, W. Wang, R.K. Miller, J. Chen, P.D. McCrea, S. Kopetz, and J.I. Park. (2018). TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling. Nat. Cell Biol. 20: 1421-1433. 30374053
Wei, W., F. Jiang, X.C. Liu, and Q. Su. (2018). TMEM9 mediates IL-6 and IL-1β secretion and is modulated by the Wnt pathway. Int Immunopharmacol 63: 253-260. 30119033