E‐cadherin‐mediated adhesion inhibits ligand‐dependent activation of diverse receptor tyrosine kinases
Open accessAbstract
E-cadherin is an essential adhesion protein as well as a tumor suppressor that is silenced in many cancers. Its adhesion-dependent regulation of signaling has not been elucidated. We report that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases (RTKs), by inhibiting their ligand-dependent activation in association with decreases in receptor mobility and in ligand-binding affinity. E-cadherin did not regulate a constitutively active mutant RTK (Neu*) or the ligand-dependent activation of LPA receptors or muscarinic receptors, which are two classes of G protein-coupled receptors. EGFR regulation by E-cadherin was associated with complex formation between EGFR and E-cadherin that depended on the extracellular domain of E-cadherin but was independent of beta-catenin binding or p120-catenin binding. Transfection of E-cadherin conferred negative RTK regulation to human melanoma and breast cancer lines with downregulated endogenous E-cadherin. Abrogation of E-cadherin regulation may contribute to the frequent ligand-dependent activation of RTK in tumors.
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Both c-Met and EGFR are known to form complexes with E-cadherin in cancer cells, and formation of such complexes is usually associated with inhibition of c-Met or EGFR phosphorylation.
“While both c-Met and EGFR are known to form complexes with E-cadherin in cancer cells, the formation of such complexes is usually associated with inhibition of c-Met or EGFR phosphorylation [36–38].”
From Candida albicans stimulates formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection (2023) · cites this paper as [37]
The Introduction reports that both c-Met and EGFR form complexes containing E-cadherin, and the EGFR/Neu results show reduced EGFR tyrosine phosphorylation under E-cadherin-mediated adhesion. However, the reported complexes and receptor-phosphorylation measurements are not in cancer cells. The tumor-cell results show attenuated EGF and HGF responses, not that c-Met/E-cadherin complex formation is associated with reduced c-Met phosphorylation; the Discussion describes the role of complex formation in regulation as a suggestion. (LLM, conf=0.86)
Experimental — accuracy not yet measuredE-cadherin itself was shown to interact with and regulate EGFR in vitro.
“Along the same lines, E-cadherin itself was shown to interact with and regulate EGFR in vitro46–49.”
From E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning (2017) · cites this paper as [48]
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Blume-Jensen, P., & Hunter, T. (2001) · Nature · doi:10.1038/35077225 · Cited by 3,738 · see citing works
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- Yamazaki T, Zaal K, Hailey D, Presley J, Lippincott-Schwartz J, Samelson LE (2002) Role of Grb2 in EGF-stimulated EGFR inter- nalization. J Cell Sci 115: 1791-1802
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Yauch, R. L., Januario, T., Eberhard, D. A., Cavet, G., Zhu, W., Fu, L., Pham, T. Q., Soriano, R., Stinson, J., Seshagiri, S., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1492 · Cited by 495 · see citing works
Rübsam, M., Mertz, A. F., Kubo, A., Marg, S., Jüngst, C., Goranci-Buzhala, G., Schauss, A. C., Horsley, V., Dufresne, E. R., Moser, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01170-7 · Cited by 210 · see citing works
Li, P., Silvis, M. R., Honaker, Y., Lien, W.-H., Arron, S. T., & Vasioukhin, V. (2016) · Genes & Development · doi:10.1101/gad.274951.115 · Cited by 180 · see citing works
Nuclear signaling from cadherin adhesion complexes
McCrea, P. D., Maher, M. T., & Gottardi, C. J. (2015) · Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2014.11.018 · Cited by 85 · see citing works
Simpkins, F., Jang, K., Yoon, H., Hew, K. E., Kim, M., Azzam, D. J., Sun, J., Zhao, D., Ince, T. A., Liu, W., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3697 · Cited by 67 · see citing works
Heyen, L., Müller, U., Siegemund, S., Schulze, B., Protschka, M., Alber, G., & Piehler, D. (2016) · Pathogens and Disease · doi:10.1093/femspd/ftw086 · Cited by 45 · see citing works
Phan, Q. T., Solis, N. V., Cravener, M. V., Swidergall, M., Lin, J., Huang, M. Y., Liu, H., Singh, S., Ibrahim, A. S., Mazzone, M., et al. (2023) · PLOS Pathogens · doi:10.1371/journal.ppat.1011579 · Cited by 29 · see citing works
- Authors
- Qian, X., Karpova, T., Sheppard, A. M., McNally, J., & Lowy, D. R.
- Affiliations
- National Cancer Institute (US)
- Corresponding author
- Lowy, Douglas R
- Venue
- The EMBO Journal
- Published
- 2004-04-01
- Volume
- 23
- Issue
- 8
- Pages
- 1739-1748
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC394229
- OpenAlex
- W2037977870
- Cited by
- 396
- References
- 1
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 6 · 2023: 20 · 2022: 13 · 2021: 15 · 2020: 8 · 2019: 16 · 2018: 19 · 2017: 15 · 2016: 22 · 2015: 14 · 2014: 16 · 2013: 20 · 2012: 30
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- E-cadherin, receptor tyrosine kinase, ligand-dependent receptor activation, cell adhesion, EGFR, receptor mobility, ligand binding affinity, tumor suppressor, melanoma, breast cancer, receptor signaling regulation
- MeSH terms
- Delta Catenin, Animals, Cell Adhesion, Cell Line, Cell Membrane, Cytoskeletal Proteins, DNA, Dogs, Enzyme Activation, Epidermal Growth Factor, Epithelial Cells, Humans, Ligands, Mutation, Phosphoproteins, Transformation, Genetic, Trans-Activators, Cell Adhesion Molecules, Cadherins, Receptor, IGF Type 1, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Protein Transport, Receptors, G-Protein-Coupled, beta Catenin, Catenins, ErbB Receptors
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