bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2024–07–28
fifteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Characterizing multi-PIK3CA mutations across cancer types: Toward precision oncology.
  2. I told you to stop: obscurin's role in epithelial cell migration.
  3. Click editing enables programmable genome writing using DNA polymerases and HUH endonucleases.
  4. Targeted Mass Spectrometry for Quantification of Receptor Tyrosine Kinase Signaling.
  5. A Rapid One-Pot Workflow for Sensitive Microscale Phosphoproteomics.
  6. Cell-state transitions and density-dependent interactions together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity.
  7. Cloud-based introduction to BASH programming for biologists.
  8. Spinal Dural Arteriovenous Fistulas in a Patient with Cowden Syndrome and a Phosphatase and Tensin Homolog Mutation.
  9. Contextual AI models for single-cell protein biology.
  10. Peptide Nucleic Acid-Mediated Regulation of CRISPR-Cas9 Specificity.
  11. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.
  12. A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo.
  13. FIND-seq: high-throughput nucleic acid cytometry for rare single-cell transcriptomics.
  14. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  15. Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes.
  1. Cancer Med. 2024 Jul;13(14): e70052
    Characterizing multi-PIK3CA mutations across cancer types: Toward precision oncology.
    Keio PleSSision Group
       BACKGROUND: PIK3CA mutations are implicated in various cancers, but the implications of multiple concurrent mutations and their orientations within the gene have not been fully explored.
    METHODS: In this study, we analyzed multi-PIK3CA mutations across a diverse pan-cancer cohort comprising 3564 tumors.
    RESULTS: Multi-PIK3CA mutations were present in 10.3% of all PIK3CA-mutant tumors, predominantly occurring in breast and gynecological cancers. Notably, mutations within the helical domain (E542:E545) exclusively occurred in the trans-orientation, contrasting with mutations in the kinase ABD and C2 domains, which mainly appeared in the cis orientation.
    CONCLUSIONS: The distinct pattern of mutation orientations in PIK3CA suggests variable oncogenic potential, with helical domain mutations in the trans-orientation potentially being less oncogenic. These findings highlight the importance of mutation orientation in the PIK3CA gene as potential biomarkers for targeted therapy. This understanding is crucial for designing clinical trials that leverage PI3K inhibitors, aiming for more effective and precise cancer treatment.
    Keywords:  PI3K inhibitor; cis; multi‐PIK3CA mutations; precision oncology; trans
    DOI:  https://doi.org/10.1002/cam4.70052
  2. Biochem Soc Trans. 2024 Jul 25. pii: BST20240564. [Epub ahead of print]
    I told you to stop: obscurin's role in epithelial cell migration.
    Kamrin D Shultz, Yasmin F Al Anbari, Nathan T Wright.
      The giant cytoskeletal protein obscurin contains multiple cell signaling domains that influence cell migration. Here, we follow each of these pathways, examine how these pathways modulate epithelial cell migration, and discuss the cross-talk between these pathways. Specifically, obscurin uses its PH domain to inhibit phosphoinositide-3-kinase (PI3K)-dependent migration and its RhoGEF domain to activate RhoA and slow cell migration. While obscurin's effect on the PI3K pathway agrees with the literature, obscurin's effect on the RhoA pathway runs counter to most other RhoA effectors, whose activation tends to lead to enhanced motility. Obscurin also phosphorylates cadherins, and this may also influence cell motility. When taken together, obscurin's ability to modulate three independent cell migration pathways is likely why obscurin knockout cells experience enhanced epithelial to mesenchymal transition, and why obscurin is a frequently mutated gene in several types of cancer.
    Keywords:  PI3K; ROCK; RhoA; cadherin; cell motility; obscurin
    DOI:  https://doi.org/10.1042/BST20240564
  3. Nat Biotechnol. 2024 Jul 22.
    Click editing enables programmable genome writing using DNA polymerases and HUH endonucleases.
    Joana Ferreira da Silva, Connor J Tou, Emily M King, Madeline L Eller, David Rufino-Ramos, Linyuan Ma, Christopher R Cromwell, Jasna Metovic, Friederike M C Benning, Luke H Chao, Florian S Eichler, Benjamin P Kleinstiver.
      Genome editing technologies based on DNA-dependent polymerases (DDPs) could offer several benefits compared with other types of editors to install diverse edits. Here, we develop click editing, a genome writing platform that couples the advantageous properties of DDPs with RNA-programmable nickases to permit the installation of a range of edits, including substitutions, insertions and deletions. Click editors (CEs) leverage the 'click'-like bioconjugation ability of HUH endonucleases with single-stranded DNA substrates to covalently tether 'click DNA' (clkDNA) templates encoding user-specifiable edits at targeted genomic loci. Through iterative optimization of the modular components of CEs and their clkDNAs, we demonstrate the ability to install precise genome edits with minimal indels in diverse immortalized human cell types and primary fibroblasts with precise editing efficiencies of up to ~30%. Editing efficiency can be improved by rapidly screening clkDNA oligonucleotides with various modifications, including repair-evading substitutions. Click editing is a precise and versatile genome editing approach for diverse biological applications.
    DOI:  https://doi.org/10.1038/s41587-024-02324-x
  4. Methods Mol Biol. 2024 ;2823 253-267
    Targeted Mass Spectrometry for Quantification of Receptor Tyrosine Kinase Signaling.
    Jeffrey R Whiteaker, Lei Zhao, Jacob J Kennedy, Richard G Ivey, Amanda G Paulovich.
      Targeted proteomics enables sensitive and specific quantification of proteins and post-translational modifications. By coupling peptide immunoaffinity enrichment with targeted mass spectrometry, we have developed the methodology for multiplexed quantification of proteins and phosphosites involved in the RAS/MAPK signaling network. The method uses anti-peptide antibodies to enrich analytes and heavy stable isotope-labeled internal standards, spiked in at known concentrations. The enriched peptides are directly measured by multiple-reaction monitoring (MRM), a well-characterized quantitative mass spectrometry-based method. The analyte (light) peptide response is measured relative to the heavy standard. The method described provides quantitative measurements of phospho-signaling and is generally applicable to other phosphopeptides and sample types.
    Keywords:   LC–MS; Multiplex; Phospho-signaling; Quantitation; RAS/MAPK; Targeted proteomics
    DOI:  https://doi.org/10.1007/978-1-0716-3922-1_16
  5. J Proteome Res. 2024 Jul 22.
    A Rapid One-Pot Workflow for Sensitive Microscale Phosphoproteomics.
    Gul Muneer, Ciao-Syuan Chen, Tzu-Tsung Lee, Bo-Yu Chen, Yu-Ju Chen.
      Compared to advancements in single-cell proteomics, phosphoproteomics sensitivity has lagged behind due to low abundance, complex sample preparation, and substantial sample input requirements. We present a simple and rapid one-pot phosphoproteomics workflow (SOP-Phos) integrated with data-independent acquisition mass spectrometry (DIA-MS) for microscale phosphoproteomic analysis. SOP-Phos adapts sodium deoxycholate based one-step lysis, reduction/alkylation, direct trypsinization, and phosphopeptide enrichment by TiO2 beads in a single-tube format. By reducing surface adsorptive losses via utilizing n-dodecyl β-d-maltoside precoated tubes and shortening the digestion time, SOP-Phos is completed within 3-4 h with a 1.4-fold higher identification coverage. SOP-Phos coupled with DIA demonstrated >90% specificity, enhanced sensitivity, lower missing values (<1%), and improved reproducibility (8%-10% CV). With a sample size-comparable spectral library, SOP-Phos-DIA identified 33,787 ± 670 to 22,070 ± 861 phosphopeptides from 5 to 0.5 μg cell lysate and 30,433 ± 284 to 6,548 ± 21 phosphopeptides from 50,000 to 2,500 cells. Such sensitivity enabled mapping key lung cancer signaling sites, such as EGFR autophosphorylation sites Y1197/Y1172 and drug targets. The feasibility of SOP-Phos-DIA was demonstrated on EGFR-TKI sensitive and resistant cells, revealing the interplay of multipathway Hippo-EGFR-ERBB signaling cascades underlying the mechanistic insight into EGFR-TKI resistance. Overall, SOP-Phos-DIA is an efficient and robust protocol that can be easily adapted in the community for microscale phosphoproteomic analysis.
    Keywords:  Data-Independent Acquisition; EGFR-Tyrosine Kinase Inhibitor (TKI); Lung Cancer; Phosphoproteomics; Sample Preparation
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00862
  6. iScience. 2024 Jul 19. 27(7): 110310
    Cell-state transitions and density-dependent interactions together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity.
    Paras Jain, Ramanarayanan Kizhuttil, Madhav B Nair, Sugandha Bhatia, Erik W Thompson, Jason T George, Mohit Kumar Jolly.
      Cancer cell populations comprise phenotypes distributed among the epithelial-mesenchymal (E-M) spectrum. However, it remains unclear which population-level processes give rise to the observed experimental distribution and dynamical changes in E-M heterogeneity, including (1) differential growth, (2) cell-state switching, and (3) population density-dependent growth or state-transition rates. Here, we analyze the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that, while cell-state transition is necessary to reproduce experimental observations of dynamical changes in E-M fractions, including density-dependent growth interactions (cooperation or suppression) better explains the data. Further, our models predict that treatment of HCC38 cells with transforming growth factor β (TGF-β) signaling and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/3) inhibitors enhances the rate of mesenchymal-epithelial transition (MET) instead of lowering that of E-M transition (EMT). Overall, our study identifies the population-level processes shaping the dynamics of spontaneous E-M heterogeneity in breast cancer cells.
    Keywords:  Cancer; Cell biology; Mathematical biosciences
    DOI:  https://doi.org/10.1016/j.isci.2024.110310
  7. Brief Bioinform. 2024 Jul 23. pii: bbae244. [Epub ahead of print]25(Supplement_1):
    Cloud-based introduction to BASH programming for biologists.
    Owen M Wilkins, Ross Campbell, Zelaikha Yosufzai, Valena Doe, Shannon M Soucy.
      This manuscript describes the development of a resource module that is part of a learning platform named 'NIGMS Sandbox for Cloud-based Learning', https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial authored by National Institute of General Medical Sciences: NIGMS Sandbox: A Learning Platform toward Democratizing Cloud Computing for Biomedical Research at the beginning of this supplement. This module delivers learning materials introducing the utility of the BASH (Bourne Again Shell) programming language for genomic data analysis in an interactive format that uses appropriate cloud resources for data access and analyses. The next-generation sequencing revolution has generated massive amounts of novel biological data from a multitude of platforms that survey an ever-growing list of genomic modalities. These data require significant downstream computational and statistical analyses to glean meaningful biological insights. However, the skill sets required to generate these data are vastly different from the skills required to analyze these data. Bench scientists that generate next-generation data often lack the training required to perform analysis of these datasets and require support from bioinformatics specialists. Dedicated computational training is required to empower biologists in the area of genomic data analysis, however, learning to efficiently leverage a command line interface is a significant barrier in learning how to leverage common analytical tools. Cloud platforms have the potential to democratize access to the technical tools and computational resources necessary to work with modern sequencing data, providing an effective framework for bioinformatics education. This module aims to provide an interactive platform that slowly builds technical skills and knowledge needed to interact with genomics data on the command line in the Cloud. The sandbox format of this module enables users to move through the material at their own pace and test their grasp of the material with knowledge self-checks before building on that material in the next sub-module. This manuscript describes the development of a resource module that is part of a learning platform named ``NIGMS Sandbox for Cloud-based Learning'' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [1] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses.
    Keywords:  bioinformatics; cloud computing; data Science; education; training
    DOI:  https://doi.org/10.1093/bib/bbae244
  8. Intern Med. 2024 Jul 25.
    Spinal Dural Arteriovenous Fistulas in a Patient with Cowden Syndrome and a Phosphatase and Tensin Homolog Mutation.
    Atsuhito Fuse, Jiro Fukae, Asuka Nakjima, Takashi Mitsuhashi, Ami Kurita, Kohsuke Teranishi, Masami Arai, Yasushi Shimo, Nobutaka Hattori.
      Cowden syndrome (CS) is an autosomal dominant syndrome characterized by the development of hamartomas and an increased cancer risk. Most CS patients harbor mutations in the phosphatase and tensin homolog (PTEN) gene. We herein report a 70-year-old patient with CS who presented with lower extremity weakness caused by multiple thoracic dural arteriovenous fistulas. Genetic testing revealed a truncated PTEN mutation (c.485_487delACAinsCC and p.D162Afs*5). Vascular malformations are common in CS, particularly in the extremities. However, spinal dural arteriovenous fistulas (AVFs) are extremely rare. Furthermore, in our case, the number of AVFs increased, and both lower limbs became flaccid four months after embolization. Therefore, we suggest that physicians carefully observe the changes in symptoms for prolonged periods after embolization.
    Keywords:  Cowden syndrome; dural arteriovenous fistulas; phosphatase and tensin homolog; spinal cord
    DOI:  https://doi.org/10.2169/internalmedicine.3809-24
  9. Nat Methods. 2024 Jul 22.
    Contextual AI models for single-cell protein biology.
    Michelle M Li, Yepeng Huang, Marissa Sumathipala, Man Qing Liang, Alberto Valdeolivas, Ashwin N Ananthakrishnan, Katherine Liao, Daniel Marbach, Marinka Zitnik.
      Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here we introduce PINNACLE, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multiorgan single-cell atlas, PINNACLE learns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. PINNACLE's embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs' effects across cell types. PINNACLE outperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases and pinpoints cell type contexts with higher predictive capability than context-free models. PINNACLE's ability to adjust its outputs on the basis of the context in which it operates paves the way for large-scale context-specific predictions in biology.
    DOI:  https://doi.org/10.1038/s41592-024-02341-3
  10. Nucleic Acid Ther. 2024 Jul 22.
    Peptide Nucleic Acid-Mediated Regulation of CRISPR-Cas9 Specificity.
    Kelly E W Carufe, Nicholas G Economos, Peter M Glazer.
      Although CRISPR-Cas9 gene therapies have proven to be a powerful tool across many applications, improvements are necessary to increase the specificity of this technology. Cas9 cutting in off-target sites remains an issue that limits CRISPR's application in human-based therapies. Treatment of autosomal dominant diseases also remains a challenge when mutant alleles differ from the wild-type sequence by only one base pair. Here, we utilize synthetic peptide nucleic acids (PNAs) that bind selected spacer sequences in the guide RNA (gRNA) to increase Cas9 specificity up to 10-fold. We interrogate variations in PNA length, binding position, and degree of homology with the gRNA. Our findings reveal that PNAs bound in the region distal to the protospacer adjacent motif (PAM) site effectively enhance specificity in both on-target/off-target and allele-specific scenarios. In addition, we demonstrate that introducing deliberate mismatches between PNAs bound in the PAM-proximal region of the gRNA can modulate Cas9 activity in an allele-specific manner. These advancements hold promise for addressing current limitations and expanding the therapeutic potential of CRISPR technology.
    Keywords:  CRISPR-Cas9; allele specificity; off-target; peptide nucleic acids; regulation; specificity
    DOI:  https://doi.org/10.1089/nat.2024.0007
  11. Nat Chem Biol. 2024 Jul 22.
    Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.
    Zhiqiang Peng, Wei Fang, Bo Wu, Ming He, Shaohua Li, Jun Wei, Yang Hao, Lujia Jin, Mingqiu Liu, Xin Zhang, Yange Wei, Yingwei Ge, Yinghua Wei, Haili Qian, Yangjun Zhang, Junyi Jiang, Zhijie Chang, Yu Rao, Xueli Zhang, Chun-Ping Cui, Lingqiang Zhang.
      The phosphoinositide 3-kinase (PI3K)-Akt axis is one of the most frequently activated pathways and is demonstrated as a therapeutic target in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated colorectal cancer (CRC). Targeting the PI3K-Akt pathway has been a challenging undertaking through the decades. Here we unveiled an essential role of E3 ligase SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated phosphoinositide-dependent protein kinase 1 (PDK1) neddylation in PI3K-Akt signaling and tumorigenesis. Upon growth factor stimulation, Smurf1 immediately triggers PDK1 neddylation and the poly-neural precursor cell expressed developmentally downregulated protein 8 (poly-Nedd8) chains recruit methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1). The cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) consisting of PDK1, Smurf1 and SETDB1 directs Akt membrane attachment and T308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1-Akt blockade and potent tumor suppression alone or combined with PDK1 inhibitor in KRAS-mutated CRC. The findings presented here unveil previously unrecognized roles of PDK1 neddylation and offer a potential strategy for targeting the PI3K-Akt pathway and KRAS mutant cancer therapy.
    DOI:  https://doi.org/10.1038/s41589-024-01683-5
  12. Elife. 2024 Jul 25. pii: RP93077. [Epub ahead of print]13
    A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo.
    Alex Weiss, Cassandra D'Amata, Bret J Pearson, Madeline N Hayes.
      High-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevant in vivo model of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIII and PI3KCAH1047R under the control of the radial glial-specific promoter her4.1 in syngeneic tp53 loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in an in vivo and endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells by mpeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factors irf7 or irf8 led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor-suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.
    Keywords:  cancer biology; cancer variant modeling; cell biology; glioblastoma; inflammation; tumor microenvironment; zebrafish
    DOI:  https://doi.org/10.7554/eLife.93077
  13. Nat Protoc. 2024 Jul 22.
    FIND-seq: high-throughput nucleic acid cytometry for rare single-cell transcriptomics.
    Seung Won Shin, Prakriti Mudvari, Shravan Thaploo, Michael A Wheeler, Daniel C Douek, Francisco J Quintana, Eli A Boritz, Adam R Abate, Iain C Clark.
      Rare cells have an important role in development and disease, and methods for isolating and studying cell subsets are therefore an essential part of biology research. Such methods traditionally rely on labeled antibodies targeted to cell surface proteins, but large public databases and sophisticated computational approaches increasingly define cell subsets on the basis of genomic, epigenomic and transcriptomic sequencing data. Methods for isolating cells on the basis of nucleic acid sequences powerfully complement these approaches by providing experimental access to cell subsets discovered in cell atlases, as well as those that cannot be otherwise isolated, including cells infected with pathogens, with specific DNA mutations or with unique transcriptional or splicing signatures. We recently developed a nucleic acid cytometry platform called 'focused interrogation of cells by nucleic acid detection and sequencing' (FIND-seq), capable of isolating rare cells on the basis of RNA or DNA markers, followed by bulk or single-cell transcriptomic analysis. This platform has previously been used to characterize the splicing-dependent activation of the transcription factor XBP1 in astrocytes and HIV persistence in memory CD4 T cells from people on long-term antiretroviral therapy. Here, we outline the molecular and microfluidic steps involved in performing FIND-seq, including protocol updates that allow detection and whole transcriptome sequencing of rare HIV-infected cells that harbor genetically intact virus genomes. FIND-seq requires knowledge of microfluidics, optics and molecular biology. We expect that FIND-seq, and this comprehensive protocol, will enable mechanistic studies of rare HIV+ cells, as well as other cell subsets that were previously difficult to recover and sequence.
    DOI:  https://doi.org/10.1038/s41596-024-01021-y
  14. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  15. Nat Commun. 2024 Jul 25. 15(1): 6279
    Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes.
    Yasuhiro Maejima, Jihoon Nah, Zahra Aryan, Peiyong Zhai, Eun-Ah Sung, Tong Liu, Koichiro Takayama, Siavash Moghadami, Tetsuo Sasano, Hong Li, Junichi Sadoshima.
      The molecular mechanisms by which FoxO transcription factors mediate diametrically opposite cellular responses, namely death and survival, remain unknown. Here we show that Mst1 phosphorylates FoxO1 Ser209/Ser215/Ser218/Thr228/Ser232/Ser243, thereby inhibiting FoxO1-mediated transcription of proapoptotic genes. On the other hand, Mst1 increases FoxO1-C/EBP-β interaction and activates C/EBP-β by phosphorylating it at Thr299, thereby promoting transcription of prosurvival genes. Myocardial ischemia/reperfusion injury is larger in cardiac-specific FoxO1 knockout mice than in control mice. However, the concurrent presence of a C/EBP-β T299E phospho-mimetic mutation reduces infarct size in cardiac-specific FoxO1 knockout mice. The C/EBP-β phospho-mimetic mutant exhibits greater binding to the promoter of prosurvival genes than wild type C/EBP-β. In conclusion, phosphorylation of FoxO1 by Mst1 inhibits binding of FoxO1 to pro-apoptotic gene promoters but enhances its binding to C/EBP-β, phosphorylation of C/EBP-β, and transcription of prosurvival genes, which stimulate protective mechanisms in the heart.
    DOI:  https://doi.org/10.1038/s41467-024-50393-y
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