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Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC

Oncogene volume 29, pages 2441–2448 (2010)Cite this article

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Abstract

Invasive cell migration is a key step for cancer metastasis and involves Rho GTPase-controlled reorganization of the actin cytoskeleton. Altered Rho GTPase expression is found in various malignancies. Particularly, the closely related GTPases RhoA and RhoC are upregulated in many aggressive tumours, but specific effectors that distinguish between these two GTPases to explain mechanistic differences have not been identified. The formins are by far the largest family of Rho GTPase effectors and are characterized by the actin-nucleating formin homology 2 domain. Using siRNA-based screening against all 15 human formins, we systematically analysed their functions in 3D cell motility using three different cancer cell lines. These results reveal distinct requirements for specific formins in amoeboid versus mesenchymal invasive cell migration. Importantly, by knocking down all Rho proteins, we identified formin-like 2 (FMNL2) as a specific RhoC effector, showing selective interaction of FMNL2 with active RhoC, but not RhoA or RhoB. Functional analysis shows that RhoC regulates autoinhibition of FMNL2, whereas suppression of FMNL2 inhibits RhoC-, but not RhoA-dependent, rounded invasive cell migration. Thus, our data uncover a novel regulatory and functional interaction between RhoC and FMNL2 for modulating cell shape and invasiveness and provide mechanistic insight into RhoC-specific signalling events.

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Acknowledgements

We thank Erik Sahai for supplying siRNAs against human Rho proteins. We thank Barbara Di Ventura for comments on the paper, Philippe Chavrier for discussions and Anke Niemann for excellent technical assistance. This work was funded by the Deutsche Krebshilfe e.V. (108293) and a group leader fellowship from the C.H.S.-Foundation to RG. JWC is supported by the Heart and Stroke Foundation of Ontario (T6317) and OP by grants from the Krebsliga beider Basel.

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  1. T M Kitzing

    Present address: 6Current address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,

Authors and Affiliations

  1. Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany

    T M Kitzing & Y Wang

  2. HBIGS, University of Heidelberg, Heidelberg, Germany

    Y Wang

  3. Center of Biomedicine, University of Basel, Basel, Switzerland

    O Pertz

  4. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    J W Copeland

  5. Institute of Pharmacology, University of Marburg, Marburg, Germany

    R Grosse

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  1. T M Kitzing
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Correspondence to R Grosse.

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Kitzing, T., Wang, Y., Pertz, O. et al. Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC. Oncogene 29, 2441–2448 (2010). https://doi.org/10.1038/onc.2009.515

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