# Interaction of the TMEM127 tumor suppressor with the mTORC1 lysosomal activating complex

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $297,221

## Abstract

The mTORC1 pathway regulates multiple cellular processes to promote a switch from catabolic to
anabolic metabolism and is thus under tight regulatory control by growth factor signaling and nutrient
sensing pathways. Dysregulation of this complex machinery is implicated in many cancers, so defining
the key mechanisms by which mTORC1 senses changes in cellular homeostasis to activate growth
signals is of great relevance. Spatial regulation of mTORC1 signaling has been recognized as a major
mechanism that influences the cellular response to nutrients and the lysosome is central to this
process. We found that the tumor suppressor TMEM127, a poorly characterized lysosomal protein, is a
component of the lysosome-anchored multiprotein complex involved in the mTORC1 response to
amino acids. In this proposal we seek to define the mechanisms through which the interaction between
TMEM127 and the mTORC1 regulatory machinery is regulated and how this can impact on mTORC1
inhibition.
We previously identified TMEM127 as a tumor suppressor gene mutated in hereditary neuroendocrine
tumors, pheochromocytomas, and in renal cancers, and found that mutant tumors display increased
mTORC1 signaling. Our earlier studies revealed that TMEM127 loss leads to lysosomal expansion with
redistribution of mTOR toward the lysosome. The lysosome functions as a docking platform for
mTORC1 signaling in response to amino acids through the assembly of a multi‐protein complex
involving Rag GTPases, Ragulator (LAMTOR1‐5) and vacuolar ATPase (v‐ATPase). Using multiple in
vivo and in vitro approaches developed in our lab, we found that TMEM127 physically associates with
ragulator, vATPase and Rags, and in its absence the interaction between ragulator and Rags is
enhanced and mTOR recruitment by Rags is increased. Furthermore, our preliminary data support of
an effect of TMEM127 in nutrient sensing. Based on these observations, our general hypothesis is that
TMEM127 disrupts mTOR recruitment to the lysosomal‐centered protein complex through
inhibition of the ragulator-Rag interaction in response to amino acids. To test this hypothesis, we
propose to define the signals that regulate the TMEM127-ragulator-Rag-mTORC1 interaction, including
its response to individual amino acids, to other nutrients (e.g. glucose), to cellular stresses including
starvation, osmolality, oxidative stress, and growth factor signaling. Furthermore, we propose to
systematically define the components of the lysosomal multiprotein assembly that are required for
TMEM127 binding, and conversely, which domains of TMEM127 are necessary for this interaction.
Finally, we will explore the emerging notion that the nutrient sensing and the growth-factor signaling
branches of mTORC1 activation are integrated at the lysosome by defining TMEM127's contribution to
the mTOR inhibitory actions by TSC2 at the lysosomal surface.To carry out these experiments we will
take advantage of tools and models that were developed in our lab, i...

## Key facts

- **NIH application ID:** 9932393
- **Project number:** 5R01GM114102-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** PATRICIA Leal DAHIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $297,221
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932393

## Citation

> US National Institutes of Health, RePORTER application 9932393, Interaction of the TMEM127 tumor suppressor with the mTORC1 lysosomal activating complex (5R01GM114102-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932393. Licensed CC0.

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