Oncogenic PIK3CA corrupts growth factor signaling specificity
Abstract Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise ca...
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-12-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/s44320-024-00078-x |
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| author | Ralitsa R Madsen Alix Le Marois Oliwia N Mruk Margaritis Voliotis Shaozhen Yin Jahangir Sufi Xiao Qin Salome J Zhao Julia Gorczynska Daniele Morelli Lindsay Davidson Erik Sahai Viktor I Korolchuk Christopher J Tape Bart Vanhaesebroeck |
| author_facet | Ralitsa R Madsen Alix Le Marois Oliwia N Mruk Margaritis Voliotis Shaozhen Yin Jahangir Sufi Xiao Qin Salome J Zhao Julia Gorczynska Daniele Morelli Lindsay Davidson Erik Sahai Viktor I Korolchuk Christopher J Tape Bart Vanhaesebroeck |
| author_sort | Ralitsa R Madsen |
| collection | DOAJ |
| description | Abstract Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time. Using this framework, we found that the PIK3CA H1047R oncogene was not a simple, constitutive activator of the pathway as often presented. Dose-dependent expression of PIK3CA H1047R in human cervical cancer and induced pluripotent stem cells corrupted the fidelity of growth factor-induced information transfer, with preferential amplification of epidermal growth factor receptor (EGFR) signaling responses compared to insulin-like growth factor 1 (IGF1) and insulin receptor signaling. PIK3CA H1047R did not only shift these responses to a higher mean but also enhanced signaling heterogeneity. We conclude that oncogenic PIK3CA H1047R corrupts information transfer in a growth factor-dependent manner and suggest new opportunities for tuning of receptor-specific PI3K pathway outputs for therapeutic benefit. |
| format | Article |
| id | doaj-art-2b6eabd5c14c47ab9fef73205a36ff8e |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-2b6eabd5c14c47ab9fef73205a36ff8e2025-02-09T13:00:47ZengSpringer NatureMolecular Systems Biology1744-42922024-12-0121212615710.1038/s44320-024-00078-xOncogenic PIK3CA corrupts growth factor signaling specificityRalitsa R Madsen0Alix Le Marois1Oliwia N Mruk2Margaritis Voliotis3Shaozhen Yin4Jahangir Sufi5Xiao Qin6Salome J Zhao7Julia Gorczynska8Daniele Morelli9Lindsay Davidson10Erik Sahai11Viktor I Korolchuk12Christopher J Tape13Bart Vanhaesebroeck14Cell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O’Gorman Building, University College LondonTumour Cell Biology Laboratory, The Francis Crick InstituteMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of DundeeDepartment of Mathematics and Statistics and Living Systems Institute; University of ExeterCell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O’Gorman Building, University College LondonCell Communication Lab, Department of Oncology, University College London Cancer InstituteCell Communication Lab, Department of Oncology, University College London Cancer InstituteCell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O’Gorman Building, University College LondonCell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O’Gorman Building, University College LondonCell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O’Gorman Building, University College LondonHuman Pluripotent Stem Cell Facility, School of Life Sciences, University of DundeeTumour Cell Biology Laboratory, The Francis Crick InstituteBiosciences Institute, Faculty of Medical Sciences, Newcastle UniversityCell Communication Lab, Department of Oncology, University College London Cancer InstituteCell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O’Gorman Building, University College LondonAbstract Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time. Using this framework, we found that the PIK3CA H1047R oncogene was not a simple, constitutive activator of the pathway as often presented. Dose-dependent expression of PIK3CA H1047R in human cervical cancer and induced pluripotent stem cells corrupted the fidelity of growth factor-induced information transfer, with preferential amplification of epidermal growth factor receptor (EGFR) signaling responses compared to insulin-like growth factor 1 (IGF1) and insulin receptor signaling. PIK3CA H1047R did not only shift these responses to a higher mean but also enhanced signaling heterogeneity. We conclude that oncogenic PIK3CA H1047R corrupts information transfer in a growth factor-dependent manner and suggest new opportunities for tuning of receptor-specific PI3K pathway outputs for therapeutic benefit.https://doi.org/10.1038/s44320-024-00078-xPI3K Signaling DynamicsInformation TransferGrowth Factor SpecificitySingle-cell Biology |
| spellingShingle | Ralitsa R Madsen Alix Le Marois Oliwia N Mruk Margaritis Voliotis Shaozhen Yin Jahangir Sufi Xiao Qin Salome J Zhao Julia Gorczynska Daniele Morelli Lindsay Davidson Erik Sahai Viktor I Korolchuk Christopher J Tape Bart Vanhaesebroeck Oncogenic PIK3CA corrupts growth factor signaling specificity Molecular Systems Biology PI3K Signaling Dynamics Information Transfer Growth Factor Specificity Single-cell Biology |
| title | Oncogenic PIK3CA corrupts growth factor signaling specificity |
| title_full | Oncogenic PIK3CA corrupts growth factor signaling specificity |
| title_fullStr | Oncogenic PIK3CA corrupts growth factor signaling specificity |
| title_full_unstemmed | Oncogenic PIK3CA corrupts growth factor signaling specificity |
| title_short | Oncogenic PIK3CA corrupts growth factor signaling specificity |
| title_sort | oncogenic pik3ca corrupts growth factor signaling specificity |
| topic | PI3K Signaling Dynamics Information Transfer Growth Factor Specificity Single-cell Biology |
| url | https://doi.org/10.1038/s44320-024-00078-x |
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