The tumorsusceptibilitygene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function

Y. Qin; Y. Deng; C. J. Ricketts; S. Srikantan; E. Wang; E. R. Maher; P. L.M. Dahia

doi:10.1093/hmg/ddt638

The tumorsusceptibilitygene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function

Y. Qin, Y. Deng, C. J. Ricketts, S. Srikantan, E. Wang, E. R. Maher, P. L.M. Dahia^*

^*Corresponding author for this work

Aston Medical School

Research output: Contribution to journal › Article › peer-review

51 Citations (SciVal)

Abstract

TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that somemutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating earlyto- late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminishedmTORcolocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature thatmaycontribute to bothpheochromocytomaandRCCpathogenesis.

Original language	English
Pages (from-to)	2428-2439
Number of pages	12
Journal	Human Molecular Genetics
Volume	23
Issue number	9
Early online date	13 Dec 2013
DOIs	https://doi.org/10.1093/hmg/ddt638
Publication status	Published - May 2014

Funding

This study was supported by grants from the Cancer Prevention and Research Institute of Texas (CPRIT #RP110202), Department of Defense CDMRP (#W81XWH-12-1-0508), Voelcker Fund, Alex’s Lemonade Foundation, Concern Foundation and Greehey Children’s Cancer Research Institute (GCCRI) to P.L.M.D. Images were generated in the Core Optical Imaging Facility which is supported by UTHSCSA, NIH-NCI P30 CA54174 (CTRC at UTHSCSA) and NIH-NIA P01AG19316.

Funders	Funder number
Alex’s Lemonade Foundation
Greehey Children’s Cancer Research Institute
NIH-NCI	P30 CA54174
NIH-NIA	P01AG19316
U.S. Department of Defense	81XWH-12-1-0508
National Cancer Institute	P30CA054174
Concern Foundation
Cancer Prevention and Research Institute of Texas	110202
National Center for Advancing Translational Sciences	KL2TR001118, UL1TR001120
University of Texas Health Science Center at San Antonio

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title = "The tumorsusceptibilitygene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function",

abstract = "TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that somemutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating earlyto- late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminishedmTORcolocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature thatmaycontribute to bothpheochromocytomaandRCCpathogenesis.",

author = "Y. Qin and Y. Deng and Ricketts, {C. J.} and S. Srikantan and E. Wang and Maher, {E. R.} and Dahia, {P. L.M.}",

year = "2014",

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AU - Qin, Y.

AU - Deng, Y.

AU - Ricketts, C. J.

AU - Srikantan, S.

AU - Wang, E.

AU - Maher, E. R.

AU - Dahia, P. L.M.

PY - 2014/5

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N2 - TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that somemutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating earlyto- late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminishedmTORcolocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature thatmaycontribute to bothpheochromocytomaandRCCpathogenesis.

AB - TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that somemutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating earlyto- late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminishedmTORcolocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature thatmaycontribute to bothpheochromocytomaandRCCpathogenesis.

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The tumorsusceptibilitygene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function

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