TMEM127 Suppresses Tumor Development by Promoting RET Ubiquitination, Positioning, and Degradation
Overview
Cell Biology
Molecular Biology
Authors
Affiliations
The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.
Liu Y, Li X, Zhang M, Men Y, Wang Y, Zhu X Drug Des Devel Ther. 2025; 19:515-524.
PMID: 39876990 PMC: 11774110. DOI: 10.2147/DDDT.S484310.
Mapping the cancer surface proteome in search of target antigens for immunotherapy.
Di Meo F, Kale B, Koomen J, Perna F Mol Ther. 2024; 32(9):2892-2904.
PMID: 39068512 PMC: 11403220. DOI: 10.1016/j.ymthe.2024.07.019.
Genetic and Molecular Biomarkers in Aggressive Pheochromocytomas and Paragangliomas.
Torresan F, Iacobone C, Giorgino F, Iacobone M Int J Mol Sci. 2024; 25(13).
PMID: 39000254 PMC: 11241596. DOI: 10.3390/ijms25137142.
Walker T, Reyes-Alvarez E, Hyndman B, Sugiyama M, Oliveira L, Rekab A Elife. 2024; 12.
PMID: 38687678 PMC: 11060712. DOI: 10.7554/eLife.89100.
Cali Daylan A, Miao E, Tang K, Chiu G, Cheng H Lung. 2023; 201(6):521-529.
PMID: 37973682 DOI: 10.1007/s00408-023-00661-3.