TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

Hyun-Kyoung Kim, Kashi Raj Bhattarai, Raghu Patil Junjappa, Jin Hee Ahn, Suvarna H. Pagire, Hyun Ju Yoo, Jaeseok Han, Duckgue Lee, Kyung-Woon Kim, Hyung-Ryong Kim () and Han-Jung Chae ()
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Hyun-Kyoung Kim: Jeonbuk National University Medical School
Kashi Raj Bhattarai: Jeonbuk National University Medical School
Raghu Patil Junjappa: Jeonbuk National University Medical School
Jin Hee Ahn: Gwangju Institute of Science and Technology
Suvarna H. Pagire: Gwangju Institute of Science and Technology
Hyun Ju Yoo: University of Ulsan College of Medicine
Jaeseok Han: Sooncynhyang University
Duckgue Lee: Sooncynhyang University
Kyung-Woon Kim: Rural Development Administration (RDA)
Hyung-Ryong Kim: Dankook University
Han-Jung Chae: Jeonbuk National University Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly up-regulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppresses primary tumor growth. Further, mTORC2 activation is up-regulated by TMBIM6 and stimulates glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, is shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identify that the BIA compound, a potentialTMBIM6 antagonist, prevents TMBIM6 binding to mTORC2, decreases mTORC2 activity, and also regulates TMBIM6-leaky Ca2+, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides potential therapeutic targets for various malignancies.

Date: 2020
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DOI: 10.1038/s41467-020-17802-4

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