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.

Details

Title
TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling
Author
Kawasaki, Natsumi 1 ; Isogaya, Kazunobu 1 ; Shingo Dan 2 ; Yamori, Takao 3 ; Takano, Hiroshi 4 ; Yao, Ryoji 4 ; Morishita, Yasuyuki 1 ; Taguchi, Luna 1 ; Morikawa, Masato 5   VIAFID ORCID Logo  ; Carl-Henrik Heldin 6 ; Noda, Tetsuo 4 ; Ehata, Shogo 1 ; Miyazono, Kohei 5 ; Koinuma, Daizo 1   VIAFID ORCID Logo 

1  Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 
2  Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan 
3  Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Center for Product Evaluation, Pharmaceuticals and Medical Device Agency, Tokyo, Japan 
4  Division of Cell Biology and Director’s Room, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan 
5  Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 
6  Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Uppsala University, Uppsala, Sweden 
First page
1
Publication year
2018
Publication date
Jan 2018
Publisher
Springer Nature B.V.
e-ISSN
20565968
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41421-017-0001-2
ProQuest document ID
1986203023
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.