Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling
Abstract The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains,...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38390-z |
| _version_ | 1797827457068302336 |
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| author | Michael G. Sugiyama Aidan I. Brown Jesus Vega-Lugo Jazlyn P. Borges Andrew M. Scott Khuloud Jaqaman Gregory D. Fairn Costin N. Antonescu |
| author_facet | Michael G. Sugiyama Aidan I. Brown Jesus Vega-Lugo Jazlyn P. Borges Andrew M. Scott Khuloud Jaqaman Gregory D. Fairn Costin N. Antonescu |
| author_sort | Michael G. Sugiyama |
| collection | DOAJ |
| description | Abstract The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand binding is poorly understood. To resolve how EGFR nanoscale compartmentalization gates ligand binding, we developed single-particle tracking methods to track the mobility of ligand-bound and total EGFR, in combination with modeling of EGFR ligand binding. In comparison to unliganded EGFR, ligand-bound EGFR is more confined and distinctly regulated by clathrin and tetraspanin nanodomains. Ligand binding to unliganded EGFR occurs preferentially in tetraspanin nanodomains, and disruption of tetraspanin nanodomains impairs EGFR ligand binding and alters the conformation of the receptor’s ectodomain. We thus reveal a mechanism by which EGFR confinement within tetraspanin nanodomains regulates receptor signaling at the level of ligand binding. |
| first_indexed | 2024-04-09T12:48:37Z |
| format | Article |
| id | doaj.art-a76bca4ec1bb40f1bbe42379e8c8888d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T12:48:37Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a76bca4ec1bb40f1bbe42379e8c8888d2023-05-14T11:22:12ZengNature PortfolioNature Communications2041-17232023-05-0114111710.1038/s41467-023-38390-zConfinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signalingMichael G. Sugiyama0Aidan I. Brown1Jesus Vega-Lugo2Jazlyn P. Borges3Andrew M. Scott4Khuloud Jaqaman5Gregory D. Fairn6Costin N. Antonescu7Department of Chemistry and Biology, Toronto Metropolitan UniversityDepartment of Physics, Toronto Metropolitan UniversityDepartment of Biophysics, UT Southwestern Medical CenterProgram in Neuroscience and Mental Health, Hospital for Sick ChildrenOlivia Newton-John Cancer Research Institute, La Trobe UniversityDepartment of Biophysics, UT Southwestern Medical CenterDepartment of Pathology, Dalhousie UniversityDepartment of Chemistry and Biology, Toronto Metropolitan UniversityAbstract The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand binding is poorly understood. To resolve how EGFR nanoscale compartmentalization gates ligand binding, we developed single-particle tracking methods to track the mobility of ligand-bound and total EGFR, in combination with modeling of EGFR ligand binding. In comparison to unliganded EGFR, ligand-bound EGFR is more confined and distinctly regulated by clathrin and tetraspanin nanodomains. Ligand binding to unliganded EGFR occurs preferentially in tetraspanin nanodomains, and disruption of tetraspanin nanodomains impairs EGFR ligand binding and alters the conformation of the receptor’s ectodomain. We thus reveal a mechanism by which EGFR confinement within tetraspanin nanodomains regulates receptor signaling at the level of ligand binding.https://doi.org/10.1038/s41467-023-38390-z |
| spellingShingle | Michael G. Sugiyama Aidan I. Brown Jesus Vega-Lugo Jazlyn P. Borges Andrew M. Scott Khuloud Jaqaman Gregory D. Fairn Costin N. Antonescu Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling Nature Communications |
| title | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
| title_full | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
| title_fullStr | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
| title_full_unstemmed | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
| title_short | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
| title_sort | confinement of unliganded egfr by tetraspanin nanodomains gates egfr ligand binding and signaling |
| url | https://doi.org/10.1038/s41467-023-38390-z |
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