TMEM127, a transmembrane protein-encoding gene, is a tumor suppressor. It is involved in multiple biological processes. TMEM127 is part of the mTORC1 lysosomal nutrient-sensing complex, regulating mTORC1 signaling in response to amino acids [3]. It also contributes to the ubiquitin system, influencing the cellular positioning, trafficking, and lysosome-mediated degradation of the tyrosine kinase receptor RET [1].

In pheochromocytoma, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with RET-mutated pheochromocytomas [1]. Loss of TMEM127 in human cells and mouse knockout models leads to RET accumulation and increased signaling, promoting cell proliferation and tumor burden [1]. Whole-body Tmem127 knockout mice have decreased adiposity, maintain insulin sensitivity, and show low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion also affects glucose and lipid homeostasis in a tissue-specific manner [2].

In conclusion, TMEM127 functions as a tumor suppressor and is involved in nutrient-sensing related to glucose/lipid homeostasis. Mouse knockout models have revealed its role in pheochromocytoma development and metabolic regulation, providing insights into disease mechanisms and potential therapeutic targets for these conditions.

References:

1. Guo, Qianjin, Cheng, Zi-Ming, Gonzalez-Cantú, Hector, Aguiar, Ricardo C T, Dahia, Patricia L M. 2023. TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation. In Cell reports, 42, 113070. doi:10.1016/j.celrep.2023.113070. https://pubmed.ncbi.nlm.nih.gov/37659079/

2. Srikantan, Subramanya, Deng, Yilun, Cheng, Zi-Ming, Aguiar, Ricardo C T, Dahia, Patricia L M. 2019. The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner. In Nature communications, 10, 4720. doi:10.1038/s41467-019-12661-0. https://pubmed.ncbi.nlm.nih.gov/31624249/

3. Deng, Yilun, Qin, Yuejuan, Srikantan, Subramanya, Wang, Exing, Dahia, Patricia L M. . The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex. In Human molecular genetics, 27, 1794-1808. doi:10.1093/hmg/ddy095. https://pubmed.ncbi.nlm.nih.gov/29547888/