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
Reads0
Chats0
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
Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis
Pengda Liu,Wenjian Gan,Hiroyuki Inuzuka,Adam S. Lazorchak,Daming Gao,Omotooke Arojo,Dou Liu,Lixin Wan,Bo Zhai,Yonghao Yu,Yonghao Yu,Min Yuan,Byeong Mo Kim,Shavali Shaik,Suchithra Menon,Steven P. Gygi,Tae Ho Lee,John M. Asara,Brendan D. Manning,John Blenis,Bing Su,Wenyi Wei +21 more
TL;DR: Results reveal a Sin1-phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the m TORC1–S6K–Sin1 signalling axis might cause aberrant hyper-activation of the mtorC2–Akt pathway, which facilitates tumorigenesis.
Journal ArticleDOI
Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot
TL;DR: This work proposes a model in which specific amino acids in assorted compartments activate different mTORC1 complexes, which may have distinct drug sensitivities and functions, and discusses the implications for m TORC1 function in health and disease.
Journal ArticleDOI
Simultaneous evaluation of cell viability by neutral red, MTT and crystal violet staining assays of the same cells.
K Chiba,K Kawakami,K Tohyama +2 more
TL;DR: A convenient assay method, the NMC assay, in which the NR, MTT and CVS assays are performed consecutively on the same cultured HeLa cells, which correlated with the viable cell count, as when the assays were performed individually.
Journal ArticleDOI
Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer
Evan C. Lien,Costas A. Lyssiotis,Ashish Juvekar,Hai Hu,John M. Asara,Lewis C. Cantley,Alex Toker +6 more
TL;DR: In mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes, providing insight into G SH biosynthesis as a metabolic vulnerability associated with PI( 3)K pathway mutant breast cancers.
Journal ArticleDOI
Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex.
Sang Gyun Kim,Gregory R. Hoffman,George Poulogiannis,Gwen R. Buel,Young Jin Jang,Young Jin Jang,Ki Won Lee,Bo Yeon Kim,Raymond L. Erikson,Lewis C. Cantley,Andrew Y. Choo,John Blenis +11 more
TL;DR: The TTT-RUVBL1/2 complex responds to the cell's metabolic state, directly regulating the functional assembly of m TORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.