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Endocrine Abstracts (2023) 94 RET2.1 | DOI: 10.1530/endoabs.94.RET2.1

1Queen’s University, Kingston, Canada. 2Harvard University, Cambridge, USA. 3Toronto Metropolitan University, Toronto, Canada


The RET receptor tyrosine kinase is an established oncogenic driver in multiple cancers. Activating RET point mutations give rise to the cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma and pheochromocytoma. Correlations of specific RET mutations with MEN2 disease phenotypes and severity have been well documented, however the molecular mechanisms that distinguish the functions, locations, and protein interactions of specific MEN2 mutants as compared to wildtype RET receptors remain poorly understood. In cell models for MEN2A and MEN2B RET mutants, our studies suggest differences in MEN2-RET signaling may be determined in part by the localization of RET mutants in distinct cellular compartments and the duration of their stay at the cell membrane or intracellular regions. We have further validated the importance of RET cellular location in cells depleted for the pheochromocytoma susceptibility gene TMEM127 where we showed wildtype RET protein accumulation on the cell surface, altered membrane dynamics and decreased protein internalization and subcellular trafficking. As a result, we demonstrated that increased RET receptor density in cell membrane domains facilitated constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Our data suggest that oncogenicity of MEN2 mutants is determined in part by aberrant subcellular trafficking of these receptors, which alters receptor localisation and signal duration. Further, these effects can be recapitulated by altered location and trafficking of wildtype receptors, as seen in TMEM127 deficient cells. Together, our data suggest novel mechanisms for RET-mediated transformation which may provide alternative therapeutic opportunities that have not been previously explored.

Volume 94

Society for Endocrinology BES 2023

Glasgow, UK
13 Nov 2023 - 15 Nov 2023

Society for Endocrinology 

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