Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia
Open accessAbstract
Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.
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Disrupting Ecad-mediated adhesion is an important feature of the scribble mutant cell extrusion process.
“Although it is not known how the Slit-Robo2-Ena pathway is mechanically coupled to cell extrusion, disrupting Ecad-mediated adhesion is an important feature of the process (Vaughen and Igaki, 2016).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Vaughen and Igaki, 2016
JNK signaling amplified Slit-Robo2-Ena signaling in scribble mutant cells but not in surrounding wild-type cells.
“JNK signaling amplified Slit-Robo2-Ena signaling in scribble mutant cells but not in surrounding wild-type cells (Vaughen and Igaki, 2016).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Vaughen and Igaki, 2016
The actin regulator Enabled/VASP (Ena) is essential for scribble mutant cell extrusion, acting downstream of Slit-Robo2 signaling.
“This revealed the actin regulator Enabled/VASP (Ena) as essential for scribble mutant cell extrusion, acting downstream of Slit-Robo2 signaling.”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Vaughen and Igaki, 2016
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Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation
Bonello, T. T., & Peifer, M. (2019) · Journal of Cell Biology · doi:10.1083/jcb.201810103 · Cited by 127 · see citing works
“Although it is not known how the Slit-Robo2-Ena pathway is mechanically coupled to cell extrusion, disrupting Ecad-mediated adhesion is an important feature of the process (Vaughen and Igaki, 2016).”
BackgroundTwo-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model
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- Authors
- Vaughen, J., & Igaki, T.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Igaki, Tatsushi
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 39
- Issue
- 6
- Pages
- 683-695
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC6207184
- OpenAlex
- W2564039928
- Cited by
- 79
- References
- 69
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 16 · 2017: 7 · 2016: 1
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Grant-in-Aid for Scientific Research (16H02505, 26114002)
- Naito Foundation
- Takeda Science Foundation
- Japan Science and Technology Agency
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- Slit-Robo signaling, JNK signaling, Scribble, cell extrusion, cell elimination, E-cadherin, epithelial homeostasis, Drosophila, tumor formation, positive feedback loop
- MeSH terms
- Roundabout Proteins, Animals, Clone Cells, Drosophila melanogaster, Epithelium, Models, Biological, Neoplasms, Nerve Tissue Proteins, Receptors, Immunologic, Signal Transduction, Cadherins, Up-Regulation, Feedback, Physiological, Drosophila Proteins, JNK Mitogen-Activated Protein Kinases, Carcinogenesis
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