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

ABSTRACT: Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly upregulated 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 suppressed primary tumor growth. Further, mTORC2 activation was up-regulated by TMBIM6 and stimulated glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, was shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identified that BIA compound, a suggestive TMBIM6 antagonist, prevented TMBIM6 binding to mTORC2, decreased mTORC2 activity, and also regulated 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 effective therapeutic targets for various malignancies. We used microarrays to detail the global of gene expression and identified that most of the differentially expressed genes related to apoptotic process, migration, proliferation, and metabolic pathways were decreased in TMBIM6 KO HT1080 cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE153716 | GEO | 2020/07/15

REPOSITORIES: GEO

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Chaperone dependent coordination of nutrient sensing and energy metabolism by mTORC2

Project description:mTORC2 senses nutrients and coordinates substrate metabolism and macromolecule synthesis program with the availability of external nutrient availability. Knockdown of mTORC2 components and its chaperone partners impairs both nutrient sensing and downstrem metabolism/growth programs.

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

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

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Selectivity in mTORC2-AKT signaling to ATP Citrate Lyase drives brown adipogenesis and de novo lipogenesis

Project description:mTOR complex 2 (mTORC2) phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In adipocytes, mTORC2 regulates glucose and lipid metabolism; however, the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling in brown preadipocytes, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate. mTORC2 appears dispensable for most other AKT actions examined indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments show brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. mTORC2 also acts through ACLY in mature brown adipocytes to increase ChREBP activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.

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Epigenome analysis of control and mTORC2-suppressed glioblastoma cells

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Genome-wide maps of chromatin H3K9ac state in control and mTORC2-suppressed glioblastoma cells

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Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting DNA Damage Response in Glioblastoma Cells

Project description:Glioblastoma (GBM) is a devastating primary brain cancer with a poor prognosis. GBM is associated with an abnormal mechanistic target of rapamycin (mTOR) signaling pathway, consisting of two distinct kinase complexes: mTORC1 and mTORC2. The complexes play critical roles in cell proliferation, survival, migration, metabolism, and DNA damage response. This study investigated the aberrant mTORC2 signaling pathway in GBM cells by performing quantitative phosphoproteomic analysis of U87MG cells under different drug treatment conditions. Interestingly, a functional analysis of phosphoproteome revealed that mTORC2 inhibition might be involved in double-strand break (DSB) repair. We further characterized the relationship between mTORC2 and BRISC and BRCA1-A Complex Member 1 (BABAM1). We demonstrated that pBABAM1 at Ser29 is regulated by mTORC2 to initiate DNA damage response, contributing to DNA repair and cancer cell survival. Accordingly, the inactivation of mTORC2 significantly ablated pBABAM1 (Ser29), reduced DNA repair activities in the nucleus, and promoted apoptosis of the cancer cells. Furthermore, we also recognized that histone H2AX phosphorylation at Ser139 (γH2AX) could be controlled by mTORC2 to repair the DNA. These results provided a better understanding of mTORC2 function in oncogenic DNA damage response and might lead to specific mTORC2 treatments for brain cancer patients in the future.

2022-11-08 | PXD033325 | Pride

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2017-06-28 | PXD006461 | Pride

mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation

Project description:The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development but the underlying molecular mechanisms remain unclear. Here we show that disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the balance of Rho/Rac signaling and reduces cell adhesion. Although these changes have no clear effect on their self-renewal and the expression of pluripotent markers, they significantly impede BMP-induced activation of canonical WNT genes, leading to impaired mesendoderm differentiation. Direct activation of the downstream WNT pathway by inhibiting GSK3 dramatically improves mesendoderm differentiation in mTORC2-deficient hESCs. Our studies uncover a new mechanism by which mTORC2 regulates cell fate determination and link the intercellular contacts with the activation of WNT genes.

2023-11-06 | GSE243723 | GEO

The lipid handling capacity of subcutaneous fat is programmed by mTORC2 during development

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