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Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways

Oncogene volume 29, pages 4033–4045 (2010)Cite this article

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Abstract

The Abelson (Abl) family of non-receptor tyrosine kinases has an important role in cell morphogenesis, motility, and proliferation. Although the function of Abl has been extensively studied in leukemia, its role in epithelial cell invasion remains obscure. Using the Drosophila wing epithelium as an in vivo model system, we show that overexpression (activation) of Drosophila Abl (dAbl) causes loss of epithelial apical/basal cell polarity and secretion of matrix metalloproteinases, resulting in a cellular invasion and apoptosis. Our in vivo data indicate that dAbl acts downstream of the Src kinases, which are known regulators of cell adhesion and invasion. Downstream of dAbl, Rac GTPases activate two distinct MAPK pathways: c-Jun N-terminal kinase signaling (required for cell invasion and apoptosis) and ERK signaling (inducing cell proliferation). Activated Abl also increases the activity of Src members through a positive feedback loop leading to signal amplification. Thus, targeting Src-Abl, using available dual inhibitors, could be of therapeutic importance in tumor cell metastasis.

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Acknowledgements

We thank the Bloomington Stock Center, DSHB, Ed Giniger, and Ross Cagan for fly stocks and antibodies. We are grateful to members of the Mlodzik lab for helpful suggestions, discussions, and criticism, Ross Cagan and members of the Cagan lab for discussion and reagents, in particular Tirtha Das. We also thank William Gault for critical reading of the manuscript, Nadinath Nillegoda, and Maneesha Chhikara for helpful comments and suggestions, and Joyce Lau, Sophy Okello, and Andrea Blitzer for technical help. Confocal laser microscopy was performed at the MSSM Microscopy SRF, supported by an NIH/NCI shared instrumentation grant. This research was supported by NIH/National Eye Institute Grant R01 EY14597 to MM.

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  1. Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA

    J Singh & M Mlodzik

  2. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA

    S A Aaronson

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Correspondence to M Mlodzik.

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Singh, J., Aaronson, S. & Mlodzik, M. Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways. Oncogene 29, 4033–4045 (2010). https://doi.org/10.1038/onc.2010.155

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