Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells

Cao, Leixi; Wang, Ruijie; Liu, Guang Zhi; Zhang, Yuwei; Thorne, Rick F.; Zhang, Xu Dong; Li, Jin Ming; Xia, Yang; Guo, Lili; Shao, Fengmin; Gu, Hao; Wu, Mian

doi:10.15252/embr.202255683

Cited by 3 publications

(3 citation statements)

References 63 publications

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“…Previous studies have also found that glycolysis can promote endoderm differentiation [57, 58]. One suggested mechanism involves the Lin41 protein kinase as a non-canonical phosphorylation target of glycolytic enzyme Pfkp, resulting in the suppression of Sox2 and leading to increased endodermal differentiation of ESCs [57]. Here, we show that glycolytic activity is needed for the activation of endoderm-promoting Nodal signalling and therefore introduce an additional layer of metabolic control to our understanding of endoderm specification.…”

Section: Discussionsupporting

confidence: 56%

“…While the relationship between glycolysis and mesoderm development has been explored in several studies, little is known about the metabolic control of endoderm specification. Previous studies have also found that glycolysis can promote endoderm differentiation [57, 58]. One suggested mechanism involves the Lin41 protein kinase as a non-canonical phosphorylation target of glycolytic enzyme Pfkp, resulting in the suppression of Sox2 and leading to increased endodermal differentiation of ESCs [57].…”

Section: Discussionmentioning

confidence: 99%

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Metabolic control of germ layer proportions through regulation of Nodal and Wnt signalling

Stapornwongkul,

Hahn,

Palau

et al. 2023

Preprint

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During embryonic development, cells exit pluripotency to give rise to the three germ layers. Metabolic pathways influence cell fate decisions by modulating the epigenetic, transcriptional, and signalling states of cells. However, the interplay between metabolism and the major signalling pathways that drive the emergence of ectoderm, mesoderm, and endoderm remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in activating signalling pathways involved in mesoderm and endoderm induction. Using an in vitro model system for mouse gastrulation, we observed that inhibiting glycolysis prevents the upregulation of primitive streak markers, resulting in a significant increase in ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose-dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. Mechanistically, we found that glycolysis inhibition leads to the downregulation of Wnt, Nodal, and Fgf signalling. Notably, this metabolic phenotype was rescued by Nodal or Wnt signalling agonists in the absence of glycolytic activity, suggesting that glycolytic activity acts upstream of both signalling pathways. Our work underscores the dependence of specific signalling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision making.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Metabolic control of germ layer proportions through regulation of Nodal and Wnt signalling

Stapornwongkul,

Hahn,

Palau

et al. 2023

Preprint

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“…In addition to metabolic reprogramming, PFKP has a close correlation with stemness as well. PFPK served an essential role via LIF-Stat3 signaling to maintain embryonic stem cell (ESC) differentiation ( 72 ). The silencing of PFKP decreased the levels of stemness markers and proliferation capabilities in HCC ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis revealing a novel stemness-metabolism-related gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma

Wang

Wan

2023

Front. Immunol.

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Hepatocellular carcinoma (HCC) is a malignant lethal tumor and both cancer stem cells (CSCs) and metabolism reprogramming have been proven to play indispensable roles in HCC. This study aimed to reveal the connection between metabolism reprogramming and the stemness characteristics of HCC, established a new gene signature related to stemness and metabolism and utilized it to assess HCC prognosis and immunotherapy response. The clinical information and gene expression profiles (GEPs) of 478 HCC patients came from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). The one-class logistic regression (OCLR) algorithm was employed to calculate the messenger ribonucleic acid expression-based stemness index (mRNAsi), a new stemness index quantifying stemness features. Differentially expressed analyses were done between high- and low-mRNAsi groups and 74 differentially expressed metabolism-related genes (DEMRGs) were identified with the help of metabolism-related gene sets from Molecular Signatures Database (MSigDB). After integrated analysis, a risk score model based on the three most efficient prognostic DEMRGs, including Recombinant Phosphofructokinase Platelet (PFKP), phosphodiesterase 2A (PDE2A) and UDP-glucuronosyltransferase 1A5 (UGT1A5) was constructed and HCC patients were divided into high-risk and low-risk groups. Significant differences were found in pathway enrichment, immune cell infiltration patterns, and gene alterations between the two groups. High-risk group patients tended to have worse clinical outcomes and were more likely to respond to immunotherapy. A stemness-metabolism-related model composed of gender, age, the risk score model and tumor-node-metastasis (TNM) staging was generated and showed great discrimination and strong ability in predicting HCC prognosis and immunotherapy response.

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Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells

et al. 2023

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Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.

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Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells

Cited by 3 publications

References 63 publications

Metabolic control of germ layer proportions through regulation of Nodal and Wnt signalling

Metabolic control of germ layer proportions through regulation of Nodal and Wnt signalling

Integrated analysis revealing a novel stemness-metabolism-related gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma

Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells

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