TY - JOUR
T1 - TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation
AU - Guo, Qianjin
AU - Cheng, Zi Ming
AU - Gonzalez-Cantú, Hector
AU - Rotondi, Matthew
AU - Huelgas-Morales, Gabriela
AU - Ethiraj, Purushoth
AU - Qiu, Zhijun
AU - Lefkowitz, Jonathan
AU - Song, Wan
AU - Landry, Bethany N.
AU - Lopez, Hector
AU - Estrada-Zuniga, Cynthia M.
AU - Goyal, Shivi
AU - Khan, Mohammad Aasif
AU - Walker, Timothy J.
AU - Wang, Exing
AU - Li, Faqian
AU - Ding, Yanli
AU - Mulligan, Lois M.
AU - Aguiar, Ricardo C.T.
AU - Dahia, Patricia L.M.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/9/26
Y1 - 2023/9/26
N2 - 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.
AB - 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.
KW - CP: Cancer
KW - NEDD4
KW - RET
KW - TMEM127
KW - degradation
KW - oncogene
KW - paraganglioma
KW - pheochromocytoma
KW - positioning
KW - single-nucleus sequencing
KW - tumor suppressor gene
KW - ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=85170038735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85170038735&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.113070
DO - 10.1016/j.celrep.2023.113070
M3 - Article
C2 - 37659079
AN - SCOPUS:85170038735
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 9
M1 - 113070
ER -