Ramirez Moreno, M. orcid.org/0000-0003-1559-8976, Quinton, A., Jacobsen, E. orcid.org/0009-0008-7963-5557 et al. (3 more authors) (2025) E-cadherin endocytosis promotes non-canonical EGFR:STAT signalling to induce cell death and inhibit heterochromatinisation. PLoS Genetics, 21 (7). e1011781. ISSN: 1553-7390
Abstract
Signalling molecules often contribute to several downstream pathways that produce distinct transcriptional outputs and cellular phenotypes. One of the major unanswered questions in cell biology is how multiple activities of signalling molecules are coordinated in space and time in vivo. Here, we focus on the Signal Transducer and Activator of Transcription (STAT) protein as a paradigm of signalling molecules involved in several independent signalling pathways. Using Drosophila wing discs as an in vivo model, we demonstrate an interplay of at least three STAT activities in this tissue. In addition to the ‘canonical’ pathways, in which STAT is phosphorylated and activated by Janus Kinases, STAT is involved in two ‘non-canonical’ pathways. In one pathway, STAT is activated by the Epidermal Growth Factor Receptor (EGFR), promoting apoptosis. In the other, it binds the Heterochromatin Protein 1 (HP1) to enhance heterochromatin formation. We provide evidence that while the ‘canonical’ STAT signalling is dominant over ‘non-canonical’ pathways, EGFR:STAT and HP1:STAT pathways compete for the availability of unphosphorylated STAT. We also describe a central role for the cell-cell adhesion protein E-cadherin, with both EGFR and STAT colocalising with E-cadherin at cell-cell junctions and on intracellular vesicles. We show that elevated intracellular E-cadherin promotes EGFR:STAT pathway leading to apoptosis, which is prevented by inhibiting E-cad endocytosis. Taken together, we conclude that E-cadherin controls the balance between two non-canonical STAT activities. We hypothesise that this balance represents a tumour-suppressive mechanism, in which junctional disassembly in dysregulated epithelial-to-mesenchymal transitions would shift this balance towards the EGFR:STAT signalling to promote apoptosis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 Ramirez Moreno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Keywords: | Biochemistry and Cell Biology; Biological Sciences; Normal biological development and functioning; Biological and endogenous factors; Cancer; Generic health relevance |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Aug 2025 11:28 |
Last Modified: | 06 Aug 2025 11:28 |
Status: | Published |
Publisher: | Public Library of Science (PLoS) |
Refereed: | Yes |
Identification Number: | 10.1371/journal.pgen.1011781 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:229989 |