MTORC1-Driven DDA1 Phosphorylation Promotes DNA Repair and Glioblastoma Progression
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ABSTRACT:
PROVIDER: PRJNA1293952 | ENA |
REPOSITORIES: ENA
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Project description:DDA1 is a protein involved in protein degradation, cell cycle regulation, and DNA damage repair. Interestingly, recent studies have revealed its differential expression across various tumor types. However, how DDA1 functions as a tumorogenic factor remains to be elucidated. Through studies in multiple glioblastoma cell models, we identified a physical association between cytoplasmic DDA1 and Raptor, a key component of lysosome-associated mTORC1. We report that amino acid stimulation triggers phosphorylation of DDA1 at serine 33, promoting its nuclear translocation and involvement in DNA damage repair. Integrated genomic and transcriptomic analyses revealed that the mTORC1-DDA1S33-DNA repair axis regulates the expression of a subset of metabolic genes, including ENO2, a glycolytic enzyme; CA12, which contributes to intracellular and extracellular pH homeostasis; and NMRK1, a key enzyme in nicotinamide riboside metabolism. Notably, DDA1 deficiency markedly impaired glioblastoma growth and triggered a compensatory upregulation of metabolic activity to sustain tumor cell survival. These metabolic genes likely supply essential nutrients required for effective DNA repair. Our findings establish DDA1 as a previously unrecognized phosphorylation target downstream of mTORC1, serving as a critical mediator of mTORC1-driven DNA damage response and a key regulator of glioblastoma progression, thereby expanding our understanding of gliomagenesis.
2025-07-29 | GSE303079 | GEO
Project description:Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.
2023-06-19 | GSE179510 | GEO
Project description:Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation
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Project description:The protein Lgl has key roles in the regulation of cell polarity. We have shown that Lgl is inactivated by hyperphosphorylation in glioblastoma as a consequence of PTEN loss and aberrant activation of the PI 3-kinase pathway; this contributes to glioblastoma pathogenesis both by promoting invasion and repressing glioblastoma cell differentiation. Lgl is phosphorylated by atypical protein kinase C in a complex with Par6 and either activated Cdc42 or activated Rac. Here we have investigated the role of specific Rac guanine nucleotide exchange factors in Lgl hyperphosphorylation in glioblastoma. We used CRISPR/Cas9 to knockout PREX1, a PI 3-kinase pathway-responsive Rac guanine nucleotide exchange factor that is overexpressed in glioblastoma. Knockout of PREX1 in patient-derived glioblastoma cells resulted in a reduction in Lgl phosphorylation and this could be reversed by re-expressing PREX1. PREX1 knockout cells showed reduced motility and altered phenotype suggestive of partial neuronal differentiation; consistent with this, RNA-seq analyses of these cells identified sets of PREX1-regulated genes with roles in promoting cell motility and repressing neuronal differentiation. Knockout of PREX1 in glioblastoma cells derived from a second patient did not affect Lgl phosphorylation. These cells overexpressed a short isoform of the Rac guanine nucleotide exchange factor TIAM1; knockdown of TIAM1 in PREX1-knockout cells from this patient reduced Lgl phosphorylation. These data show that PREX1 links aberrant PI 3-kinase to Lgl phosphorylation in glioblastoma, but that TIAM1 can also promote Lgl phosphorylation in a subset of patients. While this shows redundant mechanisms for Lgl phosphorylation, PREX1 appears to have a non-redundant role in glioblastoma cell motility, as this was impaired in PREX1 knockout cells from both patients.
2021-08-23 | GSE162783 | GEO
Project description:SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells
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Project description:Generate scRNA-Seq profiles for PDGF-driven glioblastoma mouse model.
2018-02-23 | GSE95157 | GEO
Project description:Here we describe a bead-based method capable of profiling tyrosine kinase phosphorylations in a multiplexed, high-throughput and low-cost manner. This approach allows for the discovery of tyrosine kinase-activating events, even when the DNA sequence is wild-type. In an effort to pilot the establishment of a tyrosine kinase activation catalog, we profiled tyrosine phosphorylation levels of 62 tyrosine kinases in 130 human cancer lines, and followed-up on the frequent SRC phosphorylation in glioblastoma. Keywords: quantitative measurements of tyrosine phosphorylation levels on tyrosine kinases Total protein lysates were collected from 130 cancer cell lines. Tyrosine phosphorylation levels on 62 tyrosine kinases were measured with the bead assay.
2010-06-24 | E-GEOD-13808 | biostudies-arrayexpress
Project description:The clinical benefit of current mTOR inhibitors is limited, perhaps reflecting their intrinsic pharmacological profiles. Rapamycin analogs selectively inhibit mTORC1, but fail to suppress phosphorylation of the mTORC1 substrate 4EBP1, a translational repressor that is a key driver of oncogenic mTORC1 signaling. mTOR kinase active-site inhibitors fully suppress mTORC1 and phosphorylation of its substrates, but are active against mTORC2 and additional kinases, potentially contributing to tolerability limitations. The prototype bi-steric inhibitor RapaLink-1 exploits the selective mTORC1 interactions of rapamycin and the broad mTOR kinase inhibitory effects of an active-site inhibitor, through covalent linkage of the two pharmacophores to achieve complete mTORC1/2 inhibition. We demonstrate that the anti-proliferative activity of RapaLink-1 is dependent upon mTORC1 and suppression of 4EBP1 phosphorylation. Using a rational design strategy, we tuned the affinities of the rapamycin core and ATP-mimetic moieties to create novel bi-steric inhibitors with enhanced mTORC1 selectivity and potency against 4EBP1 phosphorylation. mTORC1-selective bi-steric compounds produced durable inhibition of 4EBP1 phosphorylation in vitro and in vivo, and drove tumor regressions at well-tolerated doses in xenograft models of breast cancer.
2021-04-05 | GSE138417 | GEO
Project description:Cohesin phosphorylation accelerates DNA damage repair and reduces translocations
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