TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation
Qianjin Guo, Ziming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas‐Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N. Landry, Hector L. Lopez, Cynthia M. Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J. Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M. Mulligan, Ricardo C.T. Aguiar, Patricia L. M. Dahia
Abstract
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.