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A Jnk–Rho–Actin remodeling positive feedback network directs Src-driven invasion

Oncogene volume 33, pages 2801–2806 (2014)Cite this article

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Abstract

Current models of tumor cell invasion propose that oncogenic signaling converges upon key orchestrators of cytoskeletal dynamics, including c-Jun N-terminal kinase (Jnk) and RhoGTPase family members; these signals dynamically direct Actin remodeling proteins (ARPs) to catalyze the cytoskeletal changes required for migration. Src is a key driver of tumor aggression, metastasis and patient mortality. To clarify how Src regulates Actin dynamics to promote invasive migration, we performed a genetic modifier screen in a Drosophila model of invasion. Nine genes linked to Actin dynamics were identified that mediate invasion in situ. We found that ARPs were required for many oncogenic effects of Src including Mmp1 expression and initiation of apoptosis. Surprisingly, they were also regulators of Jnk pathway activity: both Src and the small GTPase Rho1 activated Jnk in a manner dependent on ARPs during invasion. Our results suggest that ARPs are not simply downstream executors of signal transduction pathways. Rather, they participate in a positive feedback network involving canonical oncogenic signaling pathways that promote tumor invasion.

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Acknowledgements

We thank members of the Cagan laboratory for important discussions and especially Jay Pendse for statistical assistance and Ruth Johnson for discussions and support regarding actin remodeling. Stocks were obtained from the Bloomington Drosophila Stock Center, Vienna Drosophila RNAi Center and the National Institute of Genetics Fly Stock Center. VAR was supported by 5T32CA078207 and 5T32GM007280. This work was also supported by the National Institutes of Health grants NCI R01 CA109730 and 5R01EY011495.

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  1. V A Rudrapatna and E Bangi: These authors contributed equally to this work.

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

    V A Rudrapatna, E Bangi & R L Cagan

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  1. V A Rudrapatna
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  2. E Bangi
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  3. R L Cagan
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Correspondence to R L Cagan.

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Rudrapatna, V., Bangi, E. & Cagan, R. A Jnk–Rho–Actin remodeling positive feedback network directs Src-driven invasion. Oncogene 33, 2801–2806 (2014). https://doi.org/10.1038/onc.2013.232

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