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

• Published in: Cell reports (Cambridge) Vol. 42; no. 9; p. 113070
• Main Authors: Guo, Qianjin, Cheng, Zi-Ming, Gonzalez-Cantú, Hector, Rotondi, Matthew, Huelgas-Morales, Gabriela, Ethiraj, Purushoth, Qiu, Zhijun, Lefkowitz, Jonathan, Song, Wan, Landry, Bethany N., Lopez, Hector, Estrada-Zuniga, Cynthia M., Goyal, Shivi, Khan, Mohammad Aasif, Walker, Timothy J., Wang, Exing, Li, Faqian, Ding, Yanli, Mulligan, Lois M., Aguiar, Ricardo C.T., Dahia, Patricia L.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2023; Elsevier
• Subjects: Adrenal Gland Neoplasms - genetics; Adrenal Gland Neoplasms - metabolism; Adrenal Gland Neoplasms - pathology; Animals; CP: Cancer; degradation; Germ-Line Mutation; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mutation - genetics; NEDD4; oncogene; paraganglioma; pheochromocytoma; Pheochromocytoma - genetics; Pheochromocytoma - metabolism; Pheochromocytoma - pathology; positioning; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; RET; single-nucleus sequencing; TMEM127; tumor suppressor gene; ubiquitin; Ubiquitination; RET; TMEM127; NEDD4; positioning; CP: Cancer; pheochromocytoma; degradation; single-nucleus sequencing; oncogene; tumor suppressor gene; ubiquitin; paraganglioma
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113070

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. [Display omitted] •TMEM127 loss of function leads to increased RET surface expression and activation•TMEM127 recruits the NEDD4 E3 ligase to RET and promotes its ubiquitination•NEDD4-mediated RET ubiquitination involves the TMEM127 C terminus•Oncogenesis due to TMEM127 deficiency is responsive to RET inhibition Guo et al. report that TMEM127 deficiency leads to pheochromocytoma by reducing NEDD4-mediated RET ubiquitination, positioning, and degradation and that the resulting cell proliferation is responsive to RET selective inhibition.