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

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• The TMEM127 gene encodes a transmembrane protein with an unknown function.
• Mutations in TMEM127 are found in pheochromocytomas, tumors derived from neural crest cells.
• Pheochromocytomas are tumors of the adrenal medulla.

Purpose of the Study:

• To investigate the function of TMEM127 in pheochromocytoma development.
• To elucidate the molecular mechanisms linking TMEM127 mutations to tumor formation.
• To explore therapeutic strategies targeting the RET pathway in TMEM127-mutant pheochromocytomas.

Main Methods:

• Single-nucleus resolution analysis of tumor cells.
• Investigation of TMEM127 and RET protein interactions and signaling.
• Utilizing human cells and mouse knockout models.
• Assessing the efficacy of RET inhibitors in vitro and in vivo.

Main Results:

• TMEM127-mutant tumors share precursor cells with RET-mutant pheochromocytomas.
• Loss of TMEM127 causes accumulation and increased signaling of the RET protein.
• TMEM127 facilitates RET degradation via the ubiquitin-proteasome system.
• Selective RET inhibitors reversed increased cell proliferation and tumor burden in TMEM127-deficient models.

Conclusions:

• TMEM127 is a component of the ubiquitin system regulating RET protein stability.
• Aberrant RET stabilization due to TMEM127 loss-of-function mutations drives pheochromocytoma development.
• Targeting the RET pathway offers a potential therapeutic strategy for TMEM127-mutant pheochromocytomas.