VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma

Athina Ganner,Christina Gehrke,Fruzsina Kotsis,Ian J Frew,Marinella Klein,Lars Greidl,Lu Wang,Gerd Walz,Tanja Matulenski,Elke Neumann-Haefelin,Lisa Meid,Lena Thegtmeier,Laura Wingendorf,Felicitas Pilz

doi:10.1038/s41598-021-94132-5

Athina Ganner, Christina Gehrke + Show 12 more

Open Access

https://doi.org/10.1038/s41598-021-94132-5

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Journal: Scientific Reports	Publication Date: Jul 21, 2021
Citations: 14	License type: open-access

Affiliation: University of Freiburg

Abstract

Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.

Highlights

Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas
Combining cellular models for clear cell renal cell carcinomas (ccRCC) and the C. elegans system we identify an additional layer of interaction of VHL and the PI3KmTORC1 pathway and directly link VHL to control of regulatory-associated protein of mTOR (RAPTOR), the essential scaffolding protein of mTORC1
VHL interacts with the mTORC1 subunit RAPTOR. mTORC1 is frequently hyperactivated in ccRCC

Summary

Introduction

Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior. Dysregulation of mTORC1 signaling plays a key role in the oncogenesis and progression of ccRCC, and hyperactivation of mTOR correlates with poor outcome in ccRCC patients. The primary role of mTORC1 is to initiate biosynthesis cascades for proteins, lipids and nucleotides to support cell growth, while suppressing catabolic pathways like autophagy[10]

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