Supramolecular assembly of GSK3α as a cellular response to amino acid starvation

Hinze, Laura; Schreek, Sabine; Zeug, André; Ibrahim, Nurul Khalida; Fehlhaber, Beate; Loxha, L; Cinar, B; Ponimaskin, Evgeni; Degar, James; McGuckin, Connor; Chiosis, Gabriela; Eckert, Cornelia; Cario, Gunnar; Bornhäuser, Beat; Bourquin, Jean-Pierre; Stanulla, Martin; Gutiérrez, Alejandro

doi:10.1016/j.molcel.2022.05.025

Cited by 5 publications

(6 citation statements)

References 71 publications

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“…In previous studies, we could demonstrate that resistant leukemia cells, as well as colorectal cancer cells (CRC), rely on GSK3-dependent protein degradation as an alternative source of amino acids to maintain cellular fitness upon amino acid depletion. The inhibition of GSK3-dependent protein degradation leads to the activation of a non-canonical branch of Wnt signaling, termed Wnt-dependent stabilization of proteins (Wnt/STOP) [5], that mediates cell death in the presence of amino acid scarcity [6][7][8]. Importantly, we found that asparaginase sensitization is solely dependent on the alpha isoform of GSK3 [6][7][8].…”

Section: Introductionmentioning

confidence: 80%

“…The inhibition of GSK3-dependent protein degradation leads to the activation of a non-canonical branch of Wnt signaling, termed Wnt-dependent stabilization of proteins (Wnt/STOP) [5], that mediates cell death in the presence of amino acid scarcity [6][7][8]. Importantly, we found that asparaginase sensitization is solely dependent on the alpha isoform of GSK3 [6][7][8]. Due to its role in different cancer entities, GSK3α thus has a pivotal role in regulating the cellular response to amino acid deprivation.…”

Section: Introductionmentioning

confidence: 99%

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GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

Loxha,

Ibrahim,

Stasche

et al. 2023

IJMS

Self Cite

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Amino acid availability is crucial for cancer cells’ survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

Loxha,

Ibrahim,

Stasche

et al. 2023

IJMS

Self Cite

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“…One approach involves a β-catenin-independent branch of the WNT signaling, known as WNT-dependent stabilization of proteins, which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein degradation, a process recycling amino acids for cellular usage [ 56 ]. It has been shown that pharmacological inhibition of GSK3 profoundly sensitizes drug-resistant leukemias to asparaginase [ 57 , 58 ]. Additionally, inhibition of the Bruton’s tyrosine kinase (BTK) signaling pathway interferes with c-MYC-induced proteotoxic stress and thereby suppresses GCN2-dependent AAR pathways [ 59 , 60 ].…”

Section: Asparagine and Its Depletion-based Therapy In All Patientsmentioning

confidence: 99%

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

Chen,

Zhang

2024

Cancers

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Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.

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“…GSK-3α has a glycine-rich Nterminal region which distinguishes its biological function from the GSK-3β isoform [5]. Despite the large functional similarity between the two kinases, global loss of GSK-3α promotes cardiac hypertrophy, dysfunction and mortality post-myocardial infarction (MI), and aging [6][7][8]. Loss-of and gain-of-function in in vivo models have shown that GSK-3α plays a unique role in mitochondrial function and cardiac pathophysiology [9].…”

Section: Introductionmentioning

confidence: 99%

“…Glycogen synthase kinase-3 (GSK-3) has two closely similar isoforms, GSK-3α and GSK-3β, encoded by distinct genes [5]. Even though there is an overall 84% similarity between the two isoforms, they differ only by ∼2% within the catalytic domain [6, 7]. GSK-3α has a glycine-rich N-terminal region which distinguishes its biological function from the GSK-3β isoform [5].…”

Section: Introductionmentioning

confidence: 99%

GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia

Marzook,

Gupta,

Jayakumar

et al. 2024

Preprint

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Dysregulated autophagy/mitophagy is one of the major causes of cardiac injury in ischemic conditions. Glycogen synthase kinase-3alpha (GSK-3alpha) has been shown to play a crucial role in the pathophysiology of cardiac diseases. However, the precise role of GSK-3alpha in cardiac mitophagy remains unknown. Herein, we investigated the role of GSK-3alpha in cardiac mitophagy by employing AC16 human cardiomyocytes under the condition of acute hypoxia. We observed that the gain-of-GSK-3alpha function profoundly induced mitophagy in the AC16 cardiomyocytes post-hypoxia. Moreover, GSK-3alpha overexpression led to increased ROS generation and mitochondrial dysfunction in cardiomyocytes, accompanied by enhanced mitophagy displayed by increased mt-mKeima intensity under hypoxia. Mechanistically, we identified that GSK-3alpha promotes mitophagy through upregulation of BNIP3, caused by GSK-3alpha-mediated increase in expression of HIF-1alpha and FOXO3a in cardiomyocytes post-hypoxia. Moreover, GSK-3alpha displayed a physical interaction with BNIP3 and, inhibited PINK1 and Parkin recruitment to mitochondria was observed specifically under hypoxia. Taken together, we identified a novel mechanism of mitophagy in human cardiomyocytes. GSK-3alpha promotes mitochondrial dysfunction and regulates FOXO3a-mediated BNIP3 overexpression in cardiomyocytes to facilitate mitophagy following hypoxia. An interaction between GSK-3alpha and BNIP3 suggests a role of GSK-3alpha in BNIP3 recruitment to the mitochondrial membrane where it enhances mitophagy in stressed cardiomyocytes independent of the PINK1/Parkin.

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Supramolecular assembly of GSK3α as a cellular response to amino acid starvation

Cited by 5 publications

References 71 publications

GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia

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