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Kathrin Thedieck

Kathrin Thedieck
University of Innsbruck (AT) & European Medical School (EMS), Universities of Groningen (NL) and Oldenburg (D) · Lab for Metabolic Signaling

Prof. Dr.

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68
Publications
8,227
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1,941
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Publications

Publications (68)
Article
Full-text available
Cytotoxic stress activates stress-activated kinases, initiates adaptive mechanisms, including the unfolded protein response (UPR) and autophagy, and induces programmed cell death. Fatty acid unsaturation, controlled by stearoyl-CoA desaturase (SCD)1, prevents cytotoxic stress but the mechanisms are diffuse. Here, we show that 1,2-dioleoyl-sn-glycer...
Article
Background: The insulin/insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardi...
Preprint
With increasing sensitivity and accuracy in mass spectrometry, the tumor phosphoproteome is getting into reach. However, the selection of quantitation techniques best-suited to the biomedical question and diagnostic requirements remains a trial and error decision as no study has directly compared their performance for tumor tissue phosphoproteomics...
Article
Full-text available
The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate...
Article
Full-text available
Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZ...
Article
Full-text available
The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks...
Article
Full-text available
Histone acetylation is an important, reversible post-translational protein modification and a hallmark of epigenetic regulation. However, little is known about the dynamics of this process, due to the lack of analytical methods that can capture site-specific acetylation and deacetylation reactions. We present a new approach that combines metabolic...
Article
Full-text available
Cells have evolved highly intertwined kinase networks to finely tune cellular homeostasis to the environment. The network converging on the mechanistic target of rapamycin (MTOR) kinase constitutes a central hub that integrates metabolic signals and adapts cellular metabolism and functions to nutritional changes and stress. Feedforward and feedback...
Article
Full-text available
Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress act...
Article
Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language proces...
Article
Full-text available
Droplet-based microfluidic systems offer a high potential for miniaturization and automation. Therefore, they are becoming an increasingly important tool in analytical chemistry, biosciences, and medicine. Heterogeneous assays commonly utilize magnetic beads as a solid phase. However, the sensitivity of state of the art microfluidic systems is limi...
Preprint
Full-text available
G3BP1 (Ras GTPase-activating protein-binding protein 1) is widely recognized as a core component of stress granules (SG), non-membranous RNA-protein-assemblies required for cellular survival under stress. We report that in the absence of SG, G3BP1 acts as lysosomal anchor of the Tuberous Sclerosis Complex (TSC) protein complex. By tethering the TSC...
Article
Full-text available
While constant basal levels of macroautophagy/autophagy are a prerequisite to preserve long-lived podocytes at the filtration barrier, MTOR regulates at the same time podocyte size and compensatory hypertrophy. Since MTOR is known to generally suppress autophagy, the apparently independent regulation of these two key pathways of glomerular maintena...
Article
Full-text available
All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as...
Poster
Full-text available
Since 2002 PATH Foundation operates a biobank under uniform SOPs at seven certified breast cancer centers in Germany. High-quality fresh-frozen tissue samples are collected alongside with blood serum and FFPE specimen. Research groups from academia and industry can obtain samples after application and review. PATH Biobank is a not-for-profit organi...
Article
Full-text available
Motivation: Non-homogeneous dynamic Bayesian networks (NH-DBNs) are a popular modelling tool for learning cellular networks from time series data. In systems biology, time series are often measured under different experimental conditions, and not rarely only some network interaction parameters depend on the condition while the other parameters sta...
Article
Full-text available
Dengue is the most common arboviral disease worldwide with 96 million symptomatic cases annually. Despite its major impact on global human health and huge economic burden there is no antiviral drug available to treat the disease. The first tetravalent dengue virus vaccine was licensed in 2015 for individuals aged 9 to 45, however, most cases are re...
Article
Full-text available
Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached t...
Article
Ageing can be defined as the gradual deterioration of physiological functions, increasing the incidence of age-related disorders and the probability of death. Therefore, the term ageing not only reflects the lifespan of an organism but also refers to progressive functional impairment and disease. The nutrient-sensing kinase mTOR (mammalian target o...
Article
Full-text available
Colorectal cancer is driven by cooperating oncogenic mutations. In this study, we use organotypic cultures derived from transgenic mice inducibly expressing oncogenic β-catenin and/or PIK3CA H1047R to follow sequential changes in cancer-related signaling networks, intestinal cell metabolism, and physiology in a three-dimensional environment mimicki...
Article
Full-text available
Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarc...
Data
Supplementary Figures 1-39, Supplementary Tables 1-7, Supplementary References.
Data
List of differentially regulated phosphopeptides. Phosphopeptides showing fold ratio larger than 2 or 1.5 fold changes (FC) and p-values lower than 0.05 between time points 5 minutes, 10 minutes and 15 minutes after amino acid readdition compared to the starting time (0 minutes).
Data
SBML model including only the canonical amino acid input on mTORC1.
Data
SBML model including four amino acids input in the network (simple p70-S6K module).
Data
List of differentially regulated phosphosites. Phosphosites showing fold ratio larger than 2 or 1.5 fold changes (FC) and p-values lower than 0.05 between time points 5 minutes, 10 minutes and 15 minutes after amino acid readdition compared to the starting time (0 minutes).
Data
Text mining input and results for the detection of molecular event partners of AMPK reported in scientific texts (Medline and PubMed Central). Genes and proteins were mapped to their respective UniProt ID to avoid ambiguity. The event partners as well as the textual contexts of the events themselves are listed.
Data
Phosphoproteomic identification data. Contains excerpts from the output files "proteinGroups" including information on protein group identification and quantification, "peptides" including information about peptide identification and quantification and "PhosphoSTY" containing information about phosphopeptide identification and quantification as wel...
Data
SBML model similar to Supplementary Model 2, but including a more complex p70-S6K module.
Article
Full-text available
Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we...
Article
Full-text available
PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in understanding of how to rationally leverage the therapeutic activity. PD-L1 is widely expressed in tumor cells but its contributions to tumor pathogenicity are incompletely understood. In this study, we...
Article
Full-text available
The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this stud...
Article
Full-text available
The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network that encompasses mTOR, but surprisingly few direct mTOR substrates have been established to...
Article
Die Nutrigenomik untersucht an der Grenze zwischen Life Sciences und Medizin den Einfluss von Nahrungskomponenten auf molekulare Prozesse uber alle Skalen hinweg, von der Zelle bis hin zum gesamten Organismus. Eine breite Methodenpalette von Hoch-, Mittel- und Niedrigdurchsatzverfahren sowie bioinformatischen und computergestutzten Modellierungsans...
Article
The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling. They suppress cell growth and proliferation by acting in a heteromeric complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1). In this study, we identify TSC1 as a component of the transforming growth factor β (TGF-β)-Smad2/3 pathway. Here...
Article
Full-text available
Tumors are prime examples of cell growth in unfavorable environments that elicit cellular stress. The high metabolic demand and insufficient vascularization of tumors cause a deficiency of oxygen and nutrients. Oncogenic mutations map to signaling events via mammalian target of rapamycin (mTOR), metabolic pathways, and mitochondrial function. These...
Article
Full-text available
Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF1) have a central role. The TGFβ- and IGF1-pathways cross-talk and share signalling molecules, but in the central nervous system putative points of intersection are unknown. We studied the biolog...
Article
A key feature of the aged human immune system is the accumulation of highly differentiated CD8(+)CD28(-) T cells, a phenomenon that negatively influences immune function in the elderly. However, the mechanisms that regulate survival or death of CD8(+)CD28(-) T cells remain incompletely understood. Macroautophagy has been shown to protect cells from...
Article
Mammalian target of rapamycin complex 1 (mTORC1) controls growth and survival in response to metabolic cues. Oxidative stress affects mTORC1 via inhibitory and stimulatory inputs. Whereas downregulation of TSC1-TSC2 activates mTORC1 upon oxidative stress, the molecular mechanism of mTORC1 inhibition remains unknown. Here, we identify astrin as an e...
Article
We modeled the mammalian or mechanistic target of rapamycin (mTOR) network and proposed a previously unknown mode of activation of the mTOR-containing complex mTORC2 through a phosphoinositide 3-kinase-dependent, and tuberous sclerosis complex-independent mechanism. Manning questions the validity of using the phosphorylation of Ser(2481) of mTOR as...
Article
The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimate...
Article
Mammalian target of rapamycin (mTOR) kinase responds to growth factors, nutrients, and cellular energy status and is a central controller of cellular growth. mTOR exists in two multiprotein complexes that are embedded into a complex signalling network. AMP-dependent kinase (AMPK) is activated by energy deprivation and shuts off ATP-consuming anabol...
Article
Unlabelled: Early detection of malignant biliary tract diseases, especially cholangiocarcinoma (CC) in patients with primary sclerosing cholangitis (PSC), is very difficult and often comes too late to give the patient a therapeutic benefit. We hypothesize that bile proteomic analysis distinguishes CC from nonmalignant lesions. We used capillary el...
Article
This chapter discusses the different levels at which mTORC1 controls translation and how amino acids and energy impinge on this process. Protein synthesis and ribosome biogenesis are major consumers of cellular energy. The addition of each amino acid during translation requires the equivalent of four ATP molecules. Furthermore, half of the amino ac...
Article
Full-text available
Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional rol...
Data
Time course for apoptosis induction. HeLa cells were transfected with PRR5L or control siRNA and incubated for 48 h, followed by apoptosis induction for the indicated time spans by TNFalpha and cycloheximide. Cells were fixed and stained with cleaved PARP antibody, and the percent of apoptotic cells was quantified. (0.64 MB TIF)
Article
Full-text available
TOR (Target of Rapamycin) is a highly conserved protein kinase and a central controller of cell growth. TOR is found in two functionally and structurally distinct multiprotein complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). In the present study, we developed a two-dimensional liquid chromatography tandem mass spectrometry (2D LC-M...
Article
Pathogenic bacteria have to cope with defence mechanisms mediated by adaptive and innate immunity of the host cells. Cationic antimicrobial peptides (CAMPs) represent one of the most effective components of the host innate immune response. Here we establish the function of Lmo1695, a member of the VirR-dependent virulence regulon, recently identifi...

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