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

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.

doi:10.1016/j.celrep.2023.113070

“…We showed that these pathways can be blocked using selective RET inhibitors, suggesting that targeting RET may be a valuable therapeutic strategy in the subset of PCC tumours where RET mutations have not been recognized but RET expression is detected. In support of this, in recent preliminary studies, we have shown that xenografts of TMEM127 KO SH-SY5Y cells produce larger tumors in nude mice, but that growth is reduced by treatment with the RET inhibitor Selpercatinib (Guo et al, 2023). However, TMEM127 mutations also act as drivers in other cancers, notably renal cell carcinoma, where RET is not highly expressed.…”

Section: Discussionmentioning

confidence: 69%

“…Loss of function mutations of TMEM127 have been identified in both familial and sporadic PCC, leading to loss of TMEM127 protein or mislocalization to the cytosol in tumour cells (Neumann et al, 2019; Qin et al, 2010). Interestingly, our recent data have demonstrated that RET expression is increased in TMEM127 mutant PCC (Guo et al, 2023)…”

Section: Introductionmentioning

confidence: 98%

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics

Walker

¹

,

Reyes-Alvarez

²

,

Hyndman

³

et al. 2023

Preprint

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Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization, including membrane protein diffusability and protein complex assembly, and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

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“…We showed that these pathways can be blocked using selective RET inhibitors, suggesting that targeting RET may be a valuable therapeutic strategy in the subset of PCC tumors where RET mutations have not been recognized but RET expression is detected. In support of this, in recent preliminary studies, we have shown that xenografts of TMEM127 KO SH-SY5Y cells produce larger tumors in nude mice, but that growth is reduced by treatment with the RET inhibitor selpercatinib ( Guo et al, 2023 ). Interestingly, TMEM127 mutations have also been identified as drivers in other cancers, notably renal cell carcinoma, where RET is not highly expressed.…”

Section: Discussionmentioning

confidence: 69%

“…Together, our data suggest that accumulation of RET and other transmembrane proteins at the cell surface in the absence of functional TMEM127 is due to reduced efficiency of clathrin recruitment to CCP, limiting capacity for cargo internalization and reducing CME, and that this correlates with the global disruption of membrane protein composition, protein complex assembly, and organization in other domains, such as membrane rafts. Interestingly, our preliminary studies have suggested that one outcome of this may be impairment of the formation of other membrane-associated complexes and processes, such as recruitment of ubiquitination machinery ( Guo et al, 2023 ), contributing to the TMEM127 phenotype and highlighting the broader implications of altered membrane partitioning.…”

Section: Discussionmentioning

confidence: 99%

“…Loss-of-function mutations of TMEM127 have been identified in both familial and sporadic PCC, leading to loss of TMEM127 protein or mislocalization to the cytosol in tumor cells ( Neumann et al, 2019 ; Qin et al, 2010 ). Interestingly, our recent data have demonstrated that RET expression is increased in TMEM127-mutant PCC ( Guo et al, 2023 ).…”

Section: Introductionmentioning

confidence: 95%

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Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics

Walker,

Reyes-Alvarez,

Hyndman

et al. 2024

eLife

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3

0

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Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization, including membrane protein diffusability and protein complex assembly, and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

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Lung Cancer in Never Smokers: Delving into Epidemiology, Genomic and Immune Landscape, Prognosis, Treatment, and Screening

Daylan,

Miao,

Tang

et al. 2023

Lung

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

Cited by 9 publications

References 80 publications

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics

Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics

Lung Cancer in Never Smokers: Delving into Epidemiology, Genomic and Immune Landscape, Prognosis, Treatment, and Screening

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