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Drosophila Src-family kinases function with Csk to regulate cell proliferation and apoptosis

Oncogene volume 23, pages 4754–4762 (2004)Cite this article

Abstract

Elevated Src protein levels and activity are associated with the development and progression of a variety of cancers. The consequences of deregulated Src activity have been studied extensively in cell culture; however, the effects of this deregulation in vivo, as well as the mechanisms of Src-induced tumorigenesis, remain poorly understood. In this study, the effect of expressing wild-type and constitutively active Drosophila Src-family kinases (SFKs) in the developing eye was examined. Overexpression of either wild-type Drosophila SFK (Src64 and Src42) is sufficient to induce ectopic proliferation in G1/G0-arrested, uncommitted cells in eye imaginal discs. In addition, both kinases trigger apoptosis in vivo, in a dosage-dependent manner. Constitutively active mutants are hypermorphic as they trigger proliferation and death more potently than their wild-type counterparts. Moreover, SFK-induced proliferation and apoptosis are largely independent events, as blocking ectopic proliferation does not block cell death. Further, DCsk (the Drosophila homolog of the C-terminal Src kinase) phosphorylates and interacts genetically with the wild-type SFKs, but not with the constitutively active mutants in which a conserved C-terminal tyrosine was mutated to phenylalanine, providing the first in vivo evidence that Csk regulates SFKs during development through phosphorylation of their C-terminal tyrosine.

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Acknowledgements

We thank L Cooley, G Daftary, K Mishra, R Pagliarini and L Xue for critical reading of the manuscript, Y Hao and K Sepanek for assistance, M Simon for the Src64 cDNA, B Casey and H Huang for helpful discussion, and the Developmental Studies Hybridoma Bank for strains and reagents. This work was supported by a grant from the NIH (CA69408) to TX, who is an HHMI Investigator.

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  1. Rodney A Stewart

    Present address: Department of Pediatric Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Mayer Building 625, 44 Binney St, Boston, MA, 02115, USA

Authors and Affiliations

  1. Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, PO Box 9812, 295 Congress Avenue, New Haven, 06536-0812, CT, USA

    Laura G Pedraza, Rodney A Stewart, Da-Ming Li & Tian Xu

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  1. Laura G Pedraza
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Correspondence to Tian Xu.

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Pedraza, L., Stewart, R., Li, DM. et al. Drosophila Src-family kinases function with Csk to regulate cell proliferation and apoptosis. Oncogene 23, 4754–4762 (2004). https://doi.org/10.1038/sj.onc.1207635

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