Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1

He, Chang; Bian, Yangyang; Xue, Yu; Liu, Zexian; Zhou, Kai; Yao, Cui Fang; Lin, Yan; Zou, Han Fa; Fang, Luo; Qu, Yuan; Zhao, Jian; Ye, Ming Liang; Zhao, Shi Min; Xu, Wei

doi:10.1038/srep21524

Cited by 100 publications

(102 citation statements)

References 64 publications

(79 reference statements)

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“…In T cells, during high glycolytic flux, GAPDH has been shown to induce translation of IFNg and IL-2 while it's interaction with Rheb is inhibited, releasing Rheb to activate mTORC1 40,42 . Similarly, PKM2, one of two transcripts of PKM, can activate mTORC1 by phosphorylating another inhibitor AKT1S1, which could account for increased mTORC1 activation in rapidly cycling cells 43 . GPI, yet another glycolytic enzyme, has been shown to promote growth, increase motility of fibroblasts in a tumor setting, and can be inhibited by the insulin growth factor binding protein 3 (IGFBP3) 40 .…”

Section: Discussionmentioning

confidence: 99%

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

Pfefferle

Jacobs

Ask

et al. 2019

Preprint

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One Sentence Summary: High-resolution flow cytometry combined with single-cell RNA sequencing reveal a role for intra-lineage plasticity and functional reprogramming in maintaining phenotypically and functionally diverse NK cell repertoires during IL-15-driven homeostatic proliferation. 2 Abstract Natural killer (NK) cell repertoires are made up of a vast number of phenotypically distinct subsets with different functional properties. The molecular programs involved in maintaining NK cell repertoire diversity under homeostatic conditions remains elusive. Here we show that subsetspecific NK cell proliferation kinetics correlate with mTOR activation, and that global repertoire diversity is maintained through a high degree of intra-lineage subset plasticity during IL-15-driven homeostatic proliferation in vitro. High-resolution flow cytometry and single cell RNA sequencing revealed that slowly cycling sorted KIR + CD56 dim NK cells with an induced CD57 phenotype display increased functional potential associated with inhibitory MHC interactions and activating DAP12 signaling. In contrast, rapidly cycling cells upregulate NKG2A and display a general loss of functionality associated with a transcriptional increase in RNA-binding metabolic enzymes and cytokine signaling pathways. These results shed new light on the role of intra-lineage plasticity during NK cell homeostasis and suggest that the functional fate of the cell is tightly linked to the acquired phenotype and determined by transcriptional reprogramming.

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Section: Discussionmentioning

confidence: 99%

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

Pfefferle

Jacobs

Ask

et al. 2019

Preprint

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“…The interaction of Hsp90 with PKM2 and Akt has been found in oxidative stress and tumor experiments [30,31]. PKM2 serves as an upstream molecule of Akt to regulate Akt expression and the phosphorylation of Akt-1 substrate 1 [33,45]. Consistently, heat stress stimulated the functional consumption of PKM2 to maintain Akt protein levels and enhance its activation through the sustained interaction of Hsp90 and PKM2.…”

Section: Discussionmentioning

confidence: 86%

Hsp90 Relieves Heat Stress-Induced Damage in Mouse Kidneys: Involvement of Antiapoptotic PKM2-AKT and Autophagic HIF-1α Signaling

Chen

Yang

Zhu

et al. 2020

IJMS

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Heat stress can particularly affect the kidney because of its high rate of adenosine triphosphate consumption. Competition between apoptosis and autophagy-mediated survival always exists in damaged tissue. And Hsp90 can enhance cellular protection to resist heat stress. However, the relationship between Hsp90 and the above competition and its underlying mechanism in the kidney are unclear. The present study found that heat stress induced obvious histopathological and oxidative injury, which was connected with cellular apoptosis and autophagy in the kidney and was associated with the levels of Hsp90 expression or function. The data showed that during heat stress, Hsp90 activated the PKM2-Akt signaling pathway to exert antiapoptotic effects and induce Hsp70 expression regulated by HSF-1, stimulated autophagy-mediated survival through the HIF-1α-BNIP3/BNIP3L pathway, and finally protected the kidney from heat-stress injury. Moreover, the nuclear translocation of PKM2, (p-) Akt, HSF-1, and HIF-1α was enhanced by heat stress, but only intranuclear p-Akt and HSF-1 were specifically influenced by Hsp90, contributing to regulate the cellular ability of resisting heat-stress damage. Our study provided new insights regarding the molecular mechanism of Hsp90 in the kidney in response to heat-stress injury, possibly contributing to finding new targets for the pharmacological regulation of human or animal acute kidney injury from heat stress in future research.Autophagy, a lysosomal degradation pathway, is an essential cellular adaptation mechanism for avoiding oxidative damage. Studies of the role of autophagy in AKI have reported both beneficial and detrimental effects [12][13][14]. Light chain 3 (LC3), is essential for autophagy and serves as a vital component in monitoring autophagy and visualizing autophagosomes in vivo [15]. Pyruvate kinase M2 isoform (PKM2), a rate-limiting terminal glycolytic enzyme, catalyzes the last step of glycolysis, and recent studies have reported that PKM2 is associated with the Akt signal pathway, which regulates cell survival and apoptosis [16,17]. Meanwhile, many cellular signals have been reported to be involved in the regulation of autophagy, including the Akt (protein kinase B)-mTOR (mammalian target of rapamycin) pathway [18,19]. Furthermore, Akt also plays a vital role in resisting heat stress-induced apoptosis [20]. Hypoxia-inducible factor (HIF), especially HIF-1α, is also a major actor in the cell survival autophagy in response to hypoxia stress via BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) and BNIP3L (Bcl-2/adenovirus E1B 19-kDa interacting protein 3 like) [21]. However, understanding the roles and their interplay of autophagy and apoptosis, and identification of the closely related signaling pathways in the kidney, is still very deficient but important for controlling tissue damage during heat stress.At the cellular level, tolerance to heat stress is mainly regulated by heat shock proteins (HSPs), which are also synthesized under various environmental and oxidative...

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“…Further analyses of the downstream molecules revealed upregulated phosphoproteins belonging to the mTOR complex 1/2 (mTORC1/2) pathways, including AKT1S1, RPTOR, RICTOR, and RPS6. It was previously shown that the S202/S203 phosphorylation of AKT1S1 results in the activation of mTORC1 signaling 46 . RPTOR S863 phosphorylation activates and increases the activity of mTORC1 47 .…”

Section: Discussionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells

Chen

Liao

et al. 2020

Exp Mol Med

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Limited therapeutic options are available for advanced-stage hepatocellular carcinoma owing to its poor diagnosis. Drug resistance to sorafenib, the only available targeted agent, is commonly reported. The comprehensive elucidation of the mechanisms underlying sorafenib resistance may thus aid in the development of more efficacious therapeutic agents. To clarify the signaling changes contributing to resistance, we applied quantitative phosphoproteomics to analyze the differential phosphorylation changes between parental and sorafenib-resistant HuH-7 cells. Consequently, an average of~1500 differential phosphoproteins were identified and quantified, among which 533 were significantly upregulated in resistant cells. Further bioinformatic integration via functional categorization annotation, pathway enrichment and interaction linkage analysis led to the discovery of alterations in pathways associated with cell adhesion and motility, cell survival and cell growth and the identification of a novel target, EphA2, in resistant HuH-7 R cells. In vitro functional analysis indicated that the suppression of EphA2 function impairs cell proliferation and motility and, most importantly, overcomes sorafenib resistance. The attenuation of sorafenib resistance may be achieved prior to its development through the modulation of EphA2 and the subsequent inhibition of Akt activity. Binding analyses and in silico modeling revealed a ligand mimic lead compound, prazosin, that could abate the ligand-independent oncogenic activity of EphA2. Finally, data obtained from in vivo animal models verified that the simultaneous inhibition of EphA2 with sorafenib treatment can effectively overcome sorafenib resistance and extend the projected survival of resistant tumor-bearing mice. Thus our findings regarding the targeting of EphA2 may provide an effective approach for overcoming sorafenib resistance and may contribute to the management of advanced hepatocellular carcinoma.

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Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1

Cited by 100 publications

References 64 publications

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

Hsp90 Relieves Heat Stress-Induced Damage in Mouse Kidneys: Involvement of Antiapoptotic PKM2-AKT and Autophagic HIF-1α Signaling

Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells

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