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7 Publications visible to you, out of a total of 7
Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy

Abstract (Expand)

Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates …s the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.

Authors: Pauline Pfänder, Lucas Hensen, Patricia Razquin Navas, Marie Solvay, Mirja Tamara Prentzell, Ahmed Sadik, Alexander M. Heberle, Sophie Seifert, Leon Regin, Tobias Bausbacher, Anna-Sophia Egger, Madlen Hotze, Tobias Kipura, Bianca Berdel, Ivana Karabogdan, Luis F. Somarribas Patterson, Michele Reil, Deepak Sayeeram, Vera Peters, Jose Ramos Pittol, Ineke van ’t Land-Kuper, Teresa Börding, Saskia Trump, Alienke van Pijkeren, Yang Zhang, Fabricio Loayza-Puch, Alexander Kowar, Sönke Harder, Lorenz Waltl, André Gollowitzer, Tetsushi Kataura, Viktor I. Korolchuk, Shad A. Mohammed, Phillipp Sievers, Felix Sahm, Hartmut Schlüter, Andreas Koeberle, Carsten Hopf, Marcel Kwiatkowski, Christine Sers, Benoit J. Van den Eynde, Christiane A. Opitz, Kathrin Thedieck

Date Published: 17th Jan 2023

Publication Type: Journal

Cardiac PI3K p110alpha attenuation delays aging and extends lifespan.

Abstract (Expand)

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream … effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.

Authors: M. Abdellatif, T. Eisenberg, A. M. Heberle, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 30th Nov 2022

Publication Type: Journal

Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.

Abstract (Expand)

BACKGROUND: The 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 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. RESULTS: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. CONCLUSIONS: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Authors: M. Abdellatif, V. Trummer-Herbst, A. M. Heberle, A. Humnig, T. Pendl, S. Durand, G. Cerrato, S. J. Hofer, M. Islam, J. Voglhuber, J. M. Ramos Pittol, O. Kepp, G. Hoefler, A. Schmidt, P. P. Rainer, D. Scherr, D. von Lewinski, E. Bisping, J. R. McMullen, A. Diwan, T. Eisenberg, F. Madeo, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 21st Jun 2022

Publication Type: Journal

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Abstract (Expand)

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 …e cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.

Authors: Cecilia Cattelani, Dominik Lesiak, Gudrun Liebscher, Isabel I. Singer, Taras Stasyk, Moritz H. Wallnöfer, Alexander M. Heberle, Corrado Corti, Michael W. Hess, Kristian Pfaller, Marcel Kwiatkowski, Peter P. Pramstaller, Andrew A. Hicks, Kathrin Thedieck, Thomas Müller, Lukas A. Huber, Mariana Eca Guimaraes de Araujo

Date Published: 1st Oct 2021

Publication Type: Journal

Finding new edges: systems approaches to MTOR signaling.

Abstract (Expand)

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 loops, crosstalks and a plethora of modulators finely balance MTOR-driven anabolic and catabolic processes. This complexity renders it difficult - if not impossible - to intuitively decipher signaling dynamics and network topology. Over the last two decades, systems approaches have emerged as powerful tools to simulate signaling network dynamics and responses. In this review, we discuss the contribution of systems studies to the discovery of novel edges and modulators in the MTOR network in healthy cells and in disease.

Authors: A. M. Heberle, U. Rehbein, M. Rodriguez Peiris, K. Thedieck

Date Published: 26th Feb 2021

Publication Type: Journal

Partially non-homogeneous dynamic Bayesian networks based on Bayesian regression models with partitioned design matrices

Abstract (Expand)

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 stay constant across conditions. For this situation, we propose a new partially NH-DBN, based on Bayesian hierarchical regression models with partitioned design matrices. With regard to our main application to semi-quantitative (immunoblot) timecourse data from mammalian target of rapamycin complex 1 (mTORC1) signalling, we also propose a Gaussian process-based method to solve the problem of non-equidistant time series measurements.

Authors: Mahdi Shafiee Kamalabad, Alexander Martin Heberle, Kathrin Thedieck, Marco Grzegorczyk

Date Published: 1st Jun 2019

Publication Type: Journal

The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

Abstract (Expand)

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 translationinhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stressgranule- kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly.When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new prosurvival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.

Authors: Alexander Martin Heberle, Patricia Razquin Navas, Miriam Langelaar-Makkinje, Katharina Kasack, Ahmed Sadik, Erik Faessler, Udo Hahn, Philip Marx-Stoelting, Christiane A Opitz, Christine Sers, Ines Heiland, Sascha Schäuble, Kathrin Thedieck

Date Published: 28th Mar 2019

Publication Type: Not specified

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