Abstract
Coordination between cell proliferation and cell death is essential to maintain homeostasis in multicellular organisms. In Drosophila, these two processes are regulated by a pathway involving the Ste20-like kinase Hippo (Hpo) and the NDR family kinase Warts (Wts; also called Lats). Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1. Here we identify Yorkie (Yki), the Drosophila ortholog of the mammalian transcriptional coactivator yes-associated protein (YAP), as a missing link between Wts and transcriptional regulation. Yki is required for normal tissue growth and diap1 transcription and is phosphorylated and inactivated by Wts. Overexpression of yki phenocopies loss-of-function mutations of hpo or wts, including elevated transcription of cycE and diap1, increased proliferation, defective apoptosis, and tissue overgrowth. Thus, Yki is a critical target of the Wts/Lats protein kinase and a potential oncogene.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / physiology*
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Cell Cycle Proteins
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Cell Proliferation*
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Drosophila
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Drosophila Proteins / antagonists & inhibitors
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Kinase Kinases
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phenotype
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Photoreceptor Cells, Invertebrate / abnormalities
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Photoreceptor Cells, Invertebrate / growth & development
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Saccharomyces cerevisiae Proteins / metabolism*
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Signal Transduction / physiology*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
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YAP-Signaling Proteins
Substances
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Cell Cycle Proteins
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Drosophila Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Phosphoproteins
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Saccharomyces cerevisiae Proteins
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Trans-Activators
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Transcription Factors
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YAP-Signaling Proteins
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YY1AP1 protein, human
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Yki protein, Drosophila
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Protein Kinases
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wts protein, Drosophila
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Protein Serine-Threonine Kinases
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hpo protein, Drosophila
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MAP Kinase Kinase Kinases
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STE20 protein, S cerevisiae