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Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP

Oncogene volume 31, pages 128–134 (2012)Cite this article

Abstract

YAP (Yes-associated protein) oncogene has been found to form a stable complex with members of the Angiomotin (Amot) family of proteins, which bind WW domains of YAP and sequester the protein in the cytoplasm and junctional complexes. The Amot-mediated retention of YAP in the cytoplasm results in the inhibition of its proliferative function. Using apoptotic ‘read-out’ of YAP in HEK293 cells, we confirmed the molecular mode by which Amot regulates YAP. We showed that a representative member of the Amot family, AmotL1 (Angiomotin-like-1), uses its PPxY motifs to bind WW domains of YAP and inhibit YAP's nuclear translocation and pro-apoptotic function. Recently we also showed that YAP uses its PDZ-binding motif to interact with zona occludens-2 (ZO-2) protein, which promotes YAP's translocation to the nucleus. We also asked if AmotL1, YAP and ZO-2 signal together. We report here that AmotL1 and ZO-2 form a tripartite complex with YAP and regulate its function in HEK293 cells in opposite directions. AmotL1 inhibits pro-apoptotic function of YAP, whereas ZO-2 enhances it. As YAP is a potent oncogene, the identification and characterization of its regulators is important. AmotL1 and ZO-2 are two candidates that could be harnessed to control the oncogenic function of YAP.

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Acknowledgements

We thank Dr Makoto Adachi from Kyoto University in Japan for a kind gift of HA-tagged mouse Amot family plasmids and Priya Raghavan for experiments, which confirmed our initial observations. We also acknowledge members of the Sudol laboratory for helpful comments on the manuscript.

This research was supported by PA Breast Cancer Coalition grants (#60707 and #9200903) and by Geisinger Clinic.

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  1. T Oka

    Present address: 4Current address: Tokyo Medical and Dental University, Medical Research Institute, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.,

Authors and Affiliations

  1. Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, Danville, PA, USA

    T Oka & M Sudol

  2. Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA

    A P Schmitt

  3. Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA

    M Sudol

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  1. T Oka
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Correspondence to M Sudol.

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Oka, T., Schmitt, A. & Sudol, M. Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP. Oncogene 31, 128–134 (2012). https://doi.org/10.1038/onc.2011.216

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