Evaluating the relationship between the RET receptor tyrosine kinase and TMEM127

Abstract

Pheochromocytomas (PCC) are highly heritable neoplasms of the adrenal gland, carrying germline mutations in approximately 40% of cases. PCC susceptibility genes have been subdivided into two clusters: hypoxia-related genes, and kinase-signalling genes, which include the RET receptor tyrosine kinase and Transmembrane protein 127 (TMEM127). RET is an established oncogene that causes aberrant activation of PI3K-AKT and MAPK-ERK signalling in various neuroendocrine cancers. Both wildtype (WT) RET and TMEM127 localize to multiple subcellular compartments including the Golgi apparatus, early endosomes and lysosomes. TMEM127 has been suggested to play a role in endosomal transition, however the function of TMEM127 has yet to be elucidated. In this study we evaluated the relationship between the RET receptor tyrosine kinase and TMEM127. We have identified a potential role of TMEM127 in RET protein maturation and transport to the plasma membrane. We were able to rule out a relationship between RET and TMEM127 at the transcriptional level, and at the level of RET protein folding. We also observed a relationship with TMEM127 mutants and total RET protein expression, which may correlate with TMEM127 mutant diffuse localization. Overall, the findings presented here suggest a novel interplay between RET and TMEM127 that may lead to a more thorough understanding of aberrant protein trafficking in human neoplasms and contribute to our overall understanding of the molecular mechanisms of PCC susceptibility genes.