Ligand- and integrin-independent mechano-sensitive EGFR activation in lung cancer cells.
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| Názov: | Ligand- and integrin-independent mechano-sensitive EGFR activation in lung cancer cells. |
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| Autori: | Shaikh A; Randall Centre for Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK., Mohan A; Randall Centre for Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK., Collins M; Randall Centre for Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK., Santis G; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King's College London, London SE1 1UL, UK., Parsons M; Randall Centre for Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK. |
| Zdroj: | Journal of cell science [J Cell Sci] 2025 Nov 15; Vol. 138 (22). Date of Electronic Publication: 2025 Nov 24. |
| Spôsob vydávania: | Journal Article |
| Jazyk: | English |
| Informácie o časopise: | Publisher: Company of Biologists Country of Publication: England NLM ID: 0052457 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9137 (Electronic) Linking ISSN: 00219533 NLM ISO Abbreviation: J Cell Sci Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge : Company of Biologists Original Publication: London. |
| Výrazy zo slovníka MeSH: | ErbB Receptors*/chemistry , ErbB Receptors*/metabolism , Lung Neoplasms*/metabolism , Lung Neoplasms*/pathology, Humans ; Mutation ; Ligands ; Extracellular Matrix/metabolism ; Mechanotransduction, Cellular ; A549 Cells ; Integrins/metabolism ; Enzyme Activation ; src-Family Kinases/metabolism ; Cell Adhesion ; Cell Movement |
| Abstrakt: | Competing Interests: Competing interests The authors declare no competing or financial interests. Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that plays important roles in cell proliferation, differentiation and migration. EGFR overexpression or mutation is a hallmark of some cancers, leading to hyperactivation of downstream signalling. Co-regulation between EGF-dependent EGFR signalling and extracellular matrix (ECM) adhesion occurs in both healthy and malignant cells. Increasing ECM stiffness can contribute to lung cancer progression and is sensed by integrins to promote proliferation and invasion. Emerging evidence suggests non-canonical roles for EGFR in mechano-sensing, but the molecular mechanisms and functional consequences remain unclear. Here, we demonstrate that EGFR is activated in human lung cancer cells upon early adhesion to ECM substrates with physiologically relevant stiffness (28 kPa versus 1.5 kPa), independently of canonical ligands and integrins. Mechano-induced EGFR activation correlates with and requires active Src and F-actin, and it is coupled to stiffness-dependent plasma membrane retention of EGFR within disordered lipid microdomains. Early stiffness-dependent EGFR activation is required for enhanced migration. These findings uncover a non-canonical role for EGFR in early adhesion related mechano-sensing with potential implications for treatment of lung cancer. (© 2025. Published by The Company of Biologists.) |
| Grant Information: | MR/N013700/1 United Kingdom MRC_ Medical Research Council; MR/W024985/1 United Kingdom MRC_ Medical Research Council |
| Contributed Indexing: | Keywords: Cytoskeleton; EGFR; Lung cancer; Membrane domains; Migration; Src; Substrate stiffness |
| Substance Nomenclature: | EC 2.7.10.1 (EGFR protein, human) EC 2.7.10.1 (ErbB Receptors) 0 (Ligands) 0 (Integrins) EC 2.7.10.2 (src-Family Kinases) |
| Entry Date(s): | Date Created: 20251023 Date Completed: 20251201 Latest Revision: 20251201 |
| Update Code: | 20251201 |
| DOI: | 10.1242/jcs.264107 |
| PMID: | 41128101 |
| Databáza: | MEDLINE |
Nájsť tento článok vo Web of Science | Abstrakt: | Competing Interests: Competing interests The authors declare no competing or financial interests.<br />Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that plays important roles in cell proliferation, differentiation and migration. EGFR overexpression or mutation is a hallmark of some cancers, leading to hyperactivation of downstream signalling. Co-regulation between EGF-dependent EGFR signalling and extracellular matrix (ECM) adhesion occurs in both healthy and malignant cells. Increasing ECM stiffness can contribute to lung cancer progression and is sensed by integrins to promote proliferation and invasion. Emerging evidence suggests non-canonical roles for EGFR in mechano-sensing, but the molecular mechanisms and functional consequences remain unclear. Here, we demonstrate that EGFR is activated in human lung cancer cells upon early adhesion to ECM substrates with physiologically relevant stiffness (28 kPa versus 1.5 kPa), independently of canonical ligands and integrins. Mechano-induced EGFR activation correlates with and requires active Src and F-actin, and it is coupled to stiffness-dependent plasma membrane retention of EGFR within disordered lipid microdomains. Early stiffness-dependent EGFR activation is required for enhanced migration. These findings uncover a non-canonical role for EGFR in early adhesion related mechano-sensing with potential implications for treatment of lung cancer.<br /> (© 2025. Published by The Company of Biologists.) |
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| ISSN: | 1477-9137 |
| DOI: | 10.1242/jcs.264107 |