TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation

Qianjin Guo, Zi Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N. Landry, Hector 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. AguiarPatricia L.M. Dahia

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number113070
JournalCell Reports
Volume42
Issue number9
DOIs
StatePublished - Sep 26 2023

Keywords

  • CP: Cancer
  • NEDD4
  • RET
  • TMEM127
  • degradation
  • oncogene
  • paraganglioma
  • pheochromocytoma
  • positioning
  • single-nucleus sequencing
  • tumor suppressor gene
  • ubiquitin

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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