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Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

Abstract

The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Csk-dependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.

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Acknowledgements

We thank M Okada, S Parsons, P Mangeat and N Morin for various reagents; C Naudin, G Collin and C Leroy for technical assistance; Sylvain De Rossi and Virginie Georget (Montpellier RIO Imaging platform) for confocal microscopy analysis; and J Hickmann for helpful discussion. This work was supported by Servier Laboratories, la Ligue Nationale Contre le Cancer, the CNRS, the University of Montpellier 1 and 2 and l’Association pour la Recherche contre le Cancer (ARC, n° 4025). AS was supported by Servier Laboratories and by the INCa. SR and CB are INSERM investigators.

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Correspondence to S Roche.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Sirvent, A., Bénistant, C., Pannequin, J. et al. Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization. Oncogene 29, 1303–1315 (2010). https://doi.org/10.1038/onc.2009.450

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