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CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

Oncogene volume 26, pages 5939–5949 (2007)Cite this article

Abstract

Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor β (TGFβ). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Src-regulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating C-terminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.

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Acknowledgements

This work was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG) to PM. We thank Susanne Braun for expert technical assistance.

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Author notes

  1. T Aleksic, M Bechtel, T M Gress and P Michl: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine I, University of Ulm, Ulm, Germany

    T Aleksic, D Krndija, G von Wichert & B Knobel

  2. Division of Gastroenterology and Endocrinology, Department of Internal Medicine, Philipps-University, Marburg, Hessen, Germany

    M Bechtel, T M Gress & P Michl

  3. Department of Pharmacology and Toxicology, University of Ulm, Ulm, Germany

    K Giehl

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  1. T Aleksic
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  2. M Bechtel
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Correspondence to P Michl.

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Aleksic, T., Bechtel, M., Krndija, D. et al. CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation. Oncogene 26, 5939–5949 (2007). https://doi.org/10.1038/sj.onc.1210398

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  • DOI: https://doi.org/10.1038/sj.onc.1210398

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