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8.A.75 The Transmembrane 4 L6 (TM4L6) Family 

The human TransMembrane 4 L6 (TM4L6) protein (8.A.75.1.1)  interacts directly with the thiamin uptake porter, hTHTR-2 (2.A.48.1.4). These two proteins display overlap in intracellular vesicles and at the cell membrane. Co-expression of hTHTR-2 with TM4SF4 led to a significant induction in thiamine uptake, while silencing of TM4SF4 with gene-specific siRNA led to a significant decrease in thiamine uptake.  Thus, TM4SF4 behaves like an activator of hTHTR-2 (Subramanian et al. 2014).The L6 domain tetarspanin TM4SF4 also regluates endocine pancreas differentiation and directed cell migration (Anderson et al. 2011).  It is overexpressed in hepatic cancers and plays a role in promotion of cancer cell proliferation (Li et al. 2012).  This family is the PF05805 family of Pfam with domain L6_membrane.

TM4SF20 (8.A.27.1.4) is a 4 TMS protein that inhibits regulated intramembrane proteolysis of CREB3L1, inhibiting its activation and the induction of collagen synthesis (Chen et al. 2014; Chen et al. 2016). Ceramide alters (inverts) the TM4SF20 membrane topology (Chen et al. 2016) and reverses the direction through which transmembrane helices are translocated into the endoplasmic reticulum membrane during translation of TM4SF20.

References associated with 8.A.75 family:

Anderson, K.R., R.A. Singer, D.A. Balderes, L. Hernandez-Lagunas, C.W. Johnson, K.B. Artinger, and L. Sussel. (2011). The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration. Development 138: 3213-3224. 21750032
Attwood, M.M., A. Krishnan, V. Pivotti, S. Yazdi, M.S. Almén, and H.B. Schiöth. (2016). Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome. BMC Genomics 17: 268. 27030248
Cai, L., Z. Liao, S. Li, R. Wu, J. Li, F. Ren, and H. Zhang. (2022). PLP1 may serve as a potential diagnostic biomarker of uterine fibroids. Front Genet 13: 1045395. 36386836
Chen, Q., B. Denard, C.E. Lee, S. Han, J.S. Ye, and J. Ye. (2016). Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. Mol. Cell 63: 567-578. 27499293
Chen, Q., C.E. Lee, B. Denard, and J. Ye. (2014). Sustained induction of collagen synthesis by TGF-β requires regulated intramembrane proteolysis of CREB3L1. PLoS One 9: e108528. 25310401
Choi, S.I., S.Y. Kim, J. Lee, E.W. Cho, and I.G. Kim. (2014). TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1. Oncotarget 5: 9823-9837. 25344917
Hong, J., B. Wong, C. Huynh, B. Tang, G. Ruffenach, M. Li, S. Umar, X. Yang, and M. Eghbali. (2023). -marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 68: 381-394. 36252184
Jung, J.W., J.E. Kim, E. Kim, and J.W. Lee. (2020). Amino acid transporters as tetraspanin TM4SF5 binding partners. Exp Mol Med 52: 7-14. 31956272
Jung, J.W., J.E. Kim, E. Kim, H. Lee, H. Lee, E.A. Shin, and J.W. Lee. (2022). Liver-originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance. J Extracell Vesicles 11: e12262. 36063136
Jung, J.W., S.J.Y. Macalino, M. Cui, J.E. Kim, H.J. Kim, D.G. Song, S.H. Nam, S. Kim, S. Choi, and J.W. Lee. (2019). Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling. Cell Metab. [Epub: Ahead of Print] 30956113
Kim, J.E., E. Kim, and J.W. Lee. (2022). TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases. Int J Mol Sci 23:. 35955521
Kim, J.E., S.Y. Park, C. Kwak, Y. Lee, D.G. Song, J.W. Jung, H. Lee, E.A. Shin, Y. Pinanga, K.H. Pyo, E.H. Lee, W. Kim, S. Kim, C.D. Jun, J. Yun, S. Choi, H.W. Rhee, K.H. Liu, and J.W. Lee. (2024). Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites. Cancer Commun (Lond) 44: 47-75. 38133457
Lee, H., E. Kim, E.A. Shin, J.C. Shon, H. Sun, J.E. Kim, J.W. Jung, H. Lee, Y. Pinanga, D.G. Song, K.H. Liu, and J.W. Lee. (2022). Crosstalk between TM4SF5 and GLUT8 regulates fructose metabolism in hepatic steatosis. Mol Metab 58: 101451. 35123128
Li, Y., L. Wang, J. Qiu, L. Da, P. Tiollais, Z. Li, and M. Zhao. (2012). Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth. Acta Biochim Biophys Sin (Shanghai) 44: 224-232. 22236579
Park, D., E. Kim, H. Lee, E.A. Shin, H. Lee, and J.W. Lee. (2021). Tetraspanin TM4SF5 in hepatocytes negatively modulates SLC27A transporters during acute fatty acid supply. Arch Biochem Biophys 710: 109004. 34364885
Rossi, G., G. Ordazzo, N.N. Vanni, V. Castoldi, A. Iannielli, D. Di Silvestre, E. Bellini, L. Bernardo, S.G. Giannelli, M. Luoni, S. Muggeo, L. Leocani, P. Mauri, and V. Broccoli. (2023). MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice. Elife 12:. 36645345
Subramanian, V.S., S.M. Nabokina, and H.M. Said. (2014). Association of TM4SF4 with the human thiamine transporter-2 in intestinal epithelial cells. Dig Dis Sci 59: 583-590. 24282057
Wang, J., L.N. Kinch, B. Denard, C.E. Lee, E. Esmaeilzadeh Gharehdaghi, N. Grishin, and J. Ye. (2019). Identification of residues critical for topology inversion of the transmembrane protein TM4SF20 through regulated alternative translocation. J. Biol. Chem. 294: 6054-6061. 30808712
Ye, J. (2020). Transcription factors activated through RIP (Regulated Intramembrane Proteolysis) and RAT (Regulated Alternative Translocation)). J. Biol. Chem. [Epub: Ahead of Print] 32487748
Zhao, J., C. Wang, R. Fan, X. Liu, and W. Zhang. (2022). A prognostic model based on clusters of molecules related to epithelial-mesenchymal transition for idiopathic pulmonary fibrosis. Front Genet 13: 1109903. 36685840
Zheng, Y.W., M. Wang, Z.M. Zhong, G.Q. Wu, T. Zhang, L.L. Chen, and M. Li. (2022). TM4SF1 promotes glioma malignancy through multiple mechanisms. Neoplasma 69: 859-867. 35532297