Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation
Abstract Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, alt...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55766-x |
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| author | Daniel Czyzyk Wupeng Yan Simon Messing William Gillette Takashi Tsuji Mitsuhiro Yamaguchi Shinji Furuzono David M. Turner Dominic Esposito Dwight V. Nissley Frank McCormick Dhirendra K. Simanshu |
| author_facet | Daniel Czyzyk Wupeng Yan Simon Messing William Gillette Takashi Tsuji Mitsuhiro Yamaguchi Shinji Furuzono David M. Turner Dominic Esposito Dwight V. Nissley Frank McCormick Dhirendra K. Simanshu |
| author_sort | Daniel Czyzyk |
| collection | DOAJ |
| description | Abstract Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction. |
| format | Article |
| id | doaj-art-e9a35321e79e40d2b76192a197224adb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e9a35321e79e40d2b76192a197224adb2025-01-12T12:31:38ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55766-xStructural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activationDaniel Czyzyk0Wupeng Yan1Simon Messing2William Gillette3Takashi Tsuji4Mitsuhiro Yamaguchi5Shinji Furuzono6David M. Turner7Dominic Esposito8Dwight V. Nissley9Frank McCormick10Dhirendra K. Simanshu11NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchMedicinal Chemistry Research Laboratories, Daiichi Sankyo Co, LtdMedicinal Chemistry Research Laboratories, Daiichi Sankyo Co, LtdCardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co., Ltd.NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer ResearchAbstract Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.https://doi.org/10.1038/s41467-024-55766-x |
| spellingShingle | Daniel Czyzyk Wupeng Yan Simon Messing William Gillette Takashi Tsuji Mitsuhiro Yamaguchi Shinji Furuzono David M. Turner Dominic Esposito Dwight V. Nissley Frank McCormick Dhirendra K. Simanshu Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation Nature Communications |
| title | Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation |
| title_full | Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation |
| title_fullStr | Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation |
| title_full_unstemmed | Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation |
| title_short | Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation |
| title_sort | structural insights into isoform specific ras pi3kα interactions and the role of ras in pi3kα activation |
| url | https://doi.org/10.1038/s41467-024-55766-x |
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