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Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways

Oncogene volume 29, pages 93–104 (2010)Cite this article

Abstract

Wnt-signal transduction is critical for development and tissue homeostasis in a wide range of animal species and is frequently deregulated in human cancers. Members of the Frat/GBP family of glycogen synthase kinase 3β (Gsk3b)-binding oncoproteins are recognized as potent activators of the Wnt/β-catenin pathway in vertebrates. Here, we reveal a novel, Gsk3b-independent function of Frat converging on the activation of JNK and AP-1. Both these have been used as readouts for the noncanonical Frizzled/PCP pathway, which controls polarized cell movements and the establishment of tissue polarity. We find that Frat synergizes with Diversin, the mammalian homolog of the Drosophila PCP protein diego, in the activation of JNK/AP-1 signaling. Importantly, Frat mutants deficient for binding to Gsk3b retain oncogenic activity in vivo, suggesting that Wnt/β-catenin-independent events contribute to Frat-induced malignant transformation. The observed activities of Frat are reminiscent of the dual function of Dishevelled in the Wnt/β-catenin and Frizzled/PCP pathways and suggest that Frat may also function to bridge canonical and noncanonical Wnt pathways.

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Acknowledgements

We thank Dr Walter Birchmeier, Dr Hans Clevers, Dr Gerald Crabtree, Dr Trevor Dale, Dr Jolita Hendriksen, Dr Rob Michalides, and Dr Rob Wolthuis for providing constructs and reagents and Dr Ping Chen for advice on cochlear dissections. We thank Fina van de Ahé, Sjaak Greven, Loes Rijswijk, and Maaike Voetel for tail vein injections, Hanneke van de Gulden for generating the Frat1IAQA mutant, and Dr Joaquim Calbo-Angrill for reading of an early version of the manuscript. This work received financial support from the Centre of Biomedical Genetics (CBG).

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Author notes

  1. R van Amerongen

    Present address: 5Current address: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.,

  2. M C Nawijn

    Present address: 6Current address: Laboratory Allergology and Pulmonary Diseases, Section Pathology and Medical Biology, Groningen University Medical Centre, 9713 GZ, Groningen, The Netherlands.,

Authors and Affiliations

  1. Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands

    R van Amerongen, M C Nawijn, J -P Lambooij, N Proost & A Berns

  2. Centre of Biomedical Genetics, Amsterdam, The Netherlands

    R van Amerongen, M C Nawijn, J -P Lambooij, N Proost & A Berns

  3. Division of Molecular Biology, Amsterdam, The Netherlands

    J Jonkers

  4. Academic Medical Center, Amsterdam, The Netherlands

    A Berns

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  1. R van Amerongen
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Correspondence to A Berns.

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

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van Amerongen, R., Nawijn, M., Lambooij, JP. et al. Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways. Oncogene 29, 93–104 (2010). https://doi.org/10.1038/onc.2009.310

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