TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling

Natsumi Kawasaki,Daizo Koinuma,Carl-Henrik Heldin,Ryoji Yao,Hiroshi Takano,Luna Taguchi,Shingo Dan,Tetsuo Noda,Shogo Ehata,Yasuyuki Morishita,Masato Morikawa,Kazunobu Isogaya,Kohei Miyazono,Takao Yamori

doi:10.1038/s41421-017-0001-2

Abstract

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression.

Highlights

Regulation of intracellular compartment positioning and vesicular trafficking is essential for multiple biological processes
By analyzing data from chromatin immunoprecipitationbased sequencing using antibodies against TTF-1 and SMAD325, we identified tuftelin 1 (TUFT1) as a direct target of transforming growth factor β (TGF-β) which was inhibited by TTF-1 in NCI-H441 lung adenocarcinoma cells
Our results here showed that TUFT1, which likely acts as an adaptor or an effector for RABGAP1, regulated lysosomal positioning and vesicular trafficking

Summary

Introduction

Regulation of intracellular compartment positioning and vesicular trafficking is essential for multiple biological processes. Rab GTPases play critical roles as master regulators in cellular compartment positioning and vesicular trafficking[1, 2]. Over 60 RAB genes are encoded in the human genome. Rab GTPases function as molecular switches through their guanine nucleotide-binding status, like the other Ras superfamily proteins. Many Rab proteins are involved in cancer progression. Increased abundance of Rab5A and expression of RAB7

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Conclusion