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

Core Concepts

Loss of TMEM127 leads to aberrant receptor trafficking, causing cell surface accumulation of RET and promoting constitutive activity, driving oncogenesis in PCC.

Abstract

Abstract: Internalization and endosomal trafficking of RTKs crucial for normal signaling. Loss of TMEM127 causes wildtype RET accumulation on the cell surface. Increased receptor density leads to ligand-independent activity and proliferation. Findings: Loss of TMEM127 disrupts normal cell membrane organization. Alters recruitment and stabilization of membrane protein complexes. Impairs assembly and maturation of clathrin coated pits. Reduces internalization and degradation of cell surface RET. Implications: TMEM127 depletion affects multiple transmembrane proteins on the cell surface. Suggests global defects in surface protein activity due to altered membrane dynamics. Conclusion: TMEM127 crucial for membrane organization, protein diffusability, and complex assembly. Provides a new understanding of oncogenesis in PCC through altered membrane dynamics.

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Key Insights Distilled From

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

by Walker,T. J.... at www.biorxiv.org 06-29-2023

https://www.biorxiv.org/content/10.1101/2023.06.28.546955v3

Deeper Inquiries

How does the disruption of membrane dynamics by TMEM127 loss compare to other mechanisms in cancer progression?

The disruption of membrane dynamics caused by TMEM127 loss represents a unique mechanism in cancer progression. Unlike mutations directly affecting receptor tyrosine kinases (RTKs) or downstream signaling pathways, TMEM127 depletion alters normal cell membrane organization and protein complex assembly. This leads to increased surface accumulation of various transmembrane proteins, including RTKs like RET, promoting constitutive ligand-independent activity and aberrant signaling. In contrast to genetic mutations that drive oncogenesis through specific pathway alterations, TMEM127 loss affects global defects in surface protein activity and function due to disrupted membrane dynamics.

What are potential therapeutic strategies targeting aberrant receptor trafficking in PCC?

Targeting aberrant receptor trafficking in PCC could be approached through several therapeutic strategies. One potential strategy is the development of small molecules or antibodies that specifically inhibit the interaction between mutated RET receptors and their binding partners on the cell surface. By disrupting these interactions, internalization and degradation of activated RTKs can be promoted, reducing downstream signaling cascades driving proliferation. Another approach could involve modulating key components involved in endosomal trafficking processes affected by TMEM127 loss. By restoring proper endocytic machinery function, excessive surface accumulation of growth factor receptors can be mitigated, potentially halting tumor growth.

How can understanding membrane organization lead to insights into other types of cancer development?

Understanding membrane organization not only provides insights into adrenal tumour pheochromocytoma (PCC) driven by TMEM127 loss but also offers valuable implications for other types of cancer development. Disrupted membrane dynamics have been implicated in various cancers where abnormal localization or activation of RTKs contribute to uncontrolled cell growth and survival. Insights gained from studying how altered membrane properties affect receptor trafficking and signaling can be extrapolated to different malignancies with similar dysregulated pathways involving RTKs or other transmembrane proteins. Therefore, unraveling the role of membrane organization may uncover common mechanisms underlying oncogenesis across diverse cancer types.