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,Han-Jung Chae +10 more
TLDR
It is shown that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and an antagonist of TMBIm6 with anti-tumor properties is identified.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. TMBIM6, a member of the transmembrane BI-1 motif-containing family of proteins, is overexpressed in many cancer types. Here, the authors show that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and identify an antagonist of TMBIM6 with anti-tumor properties.read more
Citations
More filters
mTOR Complex 2 Is Required for the Development of Prostate Cancer Induced by Pten Loss in Mice
David A. Guertin,Deanna Stevens,Maki Saitoh,Stephanie Kinkel,Katherine Crosby,Joon-Ho Sheen,David J. Mullholland,Mark A. Magnuson,Hong Wu,David M. Sabatini +9 more
TL;DR: It is shown that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice, and that deleting one copy of Rictor protects Pten heterozygous mice from prostate cancer.
Journal ArticleDOI
T-box transcription factor TBX1, targeted by microRNA-6727-5p, inhibits cell growth and enhances cisplatin chemosensitivity of cervical cancer cells through AKT and MAPK pathways
TL;DR: Wang et al. as mentioned in this paper investigated the functions and underlying mechanisms of TBX1 in CC Online database UALCAN showed that T-box transcription factor 1 (TBX1) was downregulated in CC tissues compared with normal tissues and patients with lower TBX 1 expression level had a poor prognosis.
Journal ArticleDOI
TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.
TL;DR: In this article , the role of transmembrane BAX inhibitor motif containing 6 (TMBIM6) in septic cardiomyopathy (SCM) was evaluated using mice.
Journal ArticleDOI
Helicobacter urease suppresses cytotoxic CD8+ T-cell responses through activating Myh9-dependent induction of PD-L1.
TL;DR: The role and molecular mechanisms of urease B subunit (UreB) involved in immune microenvironment dysregulation still remain largely unknown as mentioned in this paper, however, it has been shown that UreB-induced PD-L1 expression on BMDMs significantly decreased the proliferation and secretion of granzyme B and perforin of splenic CD8+ T cells isolated from inactivated H. pylori-immunized mice.
Journal ArticleDOI
TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.
Kashi Raj Bhattarai,Hyun-Kyoung Kim,Manoj Chaudhary,Mohammad Mamun Ur Rashid,Jisun Kim,Hyung-Ryong Kim,Han-Jung Chae +6 more
TL;DR: In this paper, the authors investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities, and found that the re-expression of TMMI6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence, and increased hepatic lipid accumulation in aging and aging-associated liver diseases.
References
More filters
Journal ArticleDOI
DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival
Timothy R. Peterson,Mathieu Laplante,Carson C. Thoreen,Yasemin Sancak,Seong A. Kang,W. Michael Kuehl,Nathanael S. Gray,David M. Sabatini +7 more
TL;DR: A novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.
Journal ArticleDOI
mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1)
TL;DR: It is demonstrated that SGK1 hydrophobic motif phosphorylation and activity is ablated in knockout fibroblasts possessing mTORC1 activity, but lacking the m TORC2 subunits rictor, Sin1, Sin2, or mLST8 or SEC13 protein 8.
Journal ArticleDOI
Nutrient-sensing mechanisms and pathways
TL;DR: The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life as mentioned in this paper, which is a selective pressure that has shaped the evolution of most cellular processes, such as the mobilization of internal stores through autophagy.
Journal ArticleDOI
Activation of mTORC2 by Association with the Ribosome
TL;DR: Findings with melanoma and colon cancer cells suggest that mTORC2-ribosome association is important in oncogenic PI3K signaling, suggesting that TORC2 is active only in growing cells.
Journal ArticleDOI
Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling
TL;DR: It is shown that the mammalian target of rapamycin complex 2 (mTORC2) has an important function in phosphorylation of both TM and HM in all conventional PKCs, novel PKCε as well as Akt.