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The Hippo Signaling Pathway and Cancer pp 53–70Cite as

YAP1 Uses Its Modular Protein Domains and Conserved Sequence Motifs to Orchestrate Diverse Repertoires of Signaling

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Abstract

Yes-associated protein 1 (YAP1) is a potent oncogenic protein and is one of the two main effectors of the Hippo tumor suppressor pathway. Originally, YAP1 cDNA was isolated by screening expression libraries for proteins that associate with SH3 domains of Yes and Src protein-tyrosine kinases. Subsequently, YAP1 was shown by homology searches or functional assays to encode multiple protein–protein binding modules including a WW domain, a PDZ domain-binding motif, and TEAD-interaction domain (TID) as well as a transcriptional activation domain (TAD). The TID region encodes a major regulatory phosphorylation site, Serine 127, which plays a critical role in regulating the subcellular localization of YAP1. The TAD region contains a putative coiled-coil region, whose function is unknown, and a tyrosine phosphorylation site that is the subject of intense study. Through reductionistic approaches of molecular and cellular biology, we have gained insight into the detailed function of most of the individual domains, motifs, and selected phosphorylation sites of YAP1. Here, we review how these YAP1 domains act in concert to regulate cell contact inhibition as well as a balance between cell proliferation and apoptosis. Given the mounting evidence that many parameters of malignant cancer progression are driven by Hippo-regulated pathways, understanding the details of how YAP1 regulates signaling is of paramount importance in designing effective strategies to control the oncogenic function of YAP1.

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Acknowledgments

We thank our colleagues Virginia Mazack and Wannian Yang for valuable comments on the first version of the manuscript and Gregory Yochum for valuable discussions, comments, and for sharing his unpublished data. This work was supported by PA Breast Cancer Coalition Grants (#60707 an #920093) plus the Geisinger Clinic (to MS), by funds from the National Institutes of Health (Grants# R01-CA94108 and P30-CA016056) and the Department of Defense (PC074228, PC101210) (to IHG), and by Roswell Park Cancer Institute and NCI grant #P30 CA016056 (to JZ).

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  1. Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, 100 North Academy Avenue, Danville, PA, 17821-2608, USA

    Marius Sudol Ph.D.

  2. Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY, 10029-6574, USA

    Marius Sudol Ph.D.

  3. Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Irwin H. Gelman Ph.D. & Jianmin Zhang Ph.D.

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  1. Marius Sudol Ph.D.
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Correspondence to Marius Sudol Ph.D. .

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  1. , Department of Molecular Cell Biology, Weizmann Institute of Science, Herzl St. 234, Rehovot, 76100, Israel

    Moshe Oren

  2. , Department of Molecular Cell Biology, Weizmann Institute of Science, Herzl St. 234, Rehovot, 76100, Israel

    Yael Aylon

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Sudol, M., Gelman, I.H., Zhang, J. (2013). YAP1 Uses Its Modular Protein Domains and Conserved Sequence Motifs to Orchestrate Diverse Repertoires of Signaling. In: Oren, M., Aylon, Y. (eds) The Hippo Signaling Pathway and Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6220-0_4

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