Molecular basis of VEGFR1 autoinhibition at the plasma membrane
Abstract Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45499-2 |
| _version_ | 1797274139327725568 |
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| author | Manas Pratim Chakraborty Diptatanu Das Purav Mondal Pragya Kaul Soumi Bhattacharyya Prosad Kumar Das Rahul Das |
| author_facet | Manas Pratim Chakraborty Diptatanu Das Purav Mondal Pragya Kaul Soumi Bhattacharyya Prosad Kumar Das Rahul Das |
| author_sort | Manas Pratim Chakraborty |
| collection | DOAJ |
| description | Abstract Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation. |
| first_indexed | 2024-03-07T14:54:05Z |
| format | Article |
| id | doaj.art-ffcc5d949ba44e549777336d0d41935d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:54:05Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ffcc5d949ba44e549777336d0d41935d2024-03-05T19:33:07ZengNature PortfolioNature Communications2041-17232024-02-0115111610.1038/s41467-024-45499-2Molecular basis of VEGFR1 autoinhibition at the plasma membraneManas Pratim Chakraborty0Diptatanu Das1Purav Mondal2Pragya Kaul3Soumi Bhattacharyya4Prosad Kumar Das5Rahul Das6Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusDepartment of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusDepartment of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusDepartment of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusDepartment of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusDepartment of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusDepartment of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campusAbstract Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation.https://doi.org/10.1038/s41467-024-45499-2 |
| spellingShingle | Manas Pratim Chakraborty Diptatanu Das Purav Mondal Pragya Kaul Soumi Bhattacharyya Prosad Kumar Das Rahul Das Molecular basis of VEGFR1 autoinhibition at the plasma membrane Nature Communications |
| title | Molecular basis of VEGFR1 autoinhibition at the plasma membrane |
| title_full | Molecular basis of VEGFR1 autoinhibition at the plasma membrane |
| title_fullStr | Molecular basis of VEGFR1 autoinhibition at the plasma membrane |
| title_full_unstemmed | Molecular basis of VEGFR1 autoinhibition at the plasma membrane |
| title_short | Molecular basis of VEGFR1 autoinhibition at the plasma membrane |
| title_sort | molecular basis of vegfr1 autoinhibition at the plasma membrane |
| url | https://doi.org/10.1038/s41467-024-45499-2 |
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