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An invasion-related complex of cortactin, paxillin and PKCμ associates with invadopodia at sites of extracellular matrix degradation

Abstract

Invasive breast cancer cells have the ability to extend membrane protrusions, invadopodia, into the extracellular matrix (ECM). These structures are associated with sites of active matrix degradation. The amount of matrix degradation associated with the activity of these membrane protrusions has been shown to directly correlate with invasive potential. We demonstrate here that microinjection of polyclonal anti-cortactin antibodies blocks matrix degradation at invadopodia supporting the hypothesis that cortactin has a direct role in invasive behavior. MDA-MB-231, invasive breast cancer cells were sheared from the surface of a gelatin matrix to isolate invadopodia. Cortactin, paxillin and protein kinase C (PKC) μ, a serine kinase, were co-immunoprecipitated as a complex from invadopodia-enriched membranes. We confirmed the subcellular distribution of these proteins by immunolocalization and Western blotting. We also determined that, in contrast to its presence in invasive cells, this complex of proteins was not detected in lysates from non-invasive cells that do not form invadopodia. Taken together, these data suggest that the formation of this cortactin-containing complex correlates with cellular invasiveness. We hypothesize that this complex of molecules has a role in the formation and function of invadopodia during cellular invasion.

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Acknowledgements

We gratefully acknowledge Tom Parsons for mouse mAb anti-cortactin clone 4F11 and the GST-cortactin constructs used to generate fusion protein for pAb production. We would like to thank Carolyn L Smith and the Light Imaging Facility (National Institute for Neurological Disorders and Stroke) for assistance with confocal microscopy. We also thank Sandra McLeskey and Steven Byers for critical reading of the manuscript and Donna Almario and Maozheng Dai for technical assistance. This work was supported in part by the National Institutes of Health grants R01DK48910, R21CA62232 and R01CA61273 to SCM, R01CA57244 and R01NS34431 to RIG and by the Lombardi Cancer Center Microscopy/Imaging and Tissue Culture shared resources supported by US Public Health Service Grant 1P30CA51008.

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Bowden, E., Barth, M., Thomas, D. et al. An invasion-related complex of cortactin, paxillin and PKCμ associates with invadopodia at sites of extracellular matrix degradation. Oncogene 18, 4440–4449 (1999). https://doi.org/10.1038/sj.onc.1202827

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