Abstract
Coordination of cell proliferation and cell death is essential to attain proper organ size during development and for maintaining tissue homeostasis throughout postnatal life. In Drosophila, these two processes are orchestrated by the Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yorkie (Yki). Here we demonstrate that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway. Hippo-mediated phosphorylation inactivates Yki by excluding it from the nucleus, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. We further delineate a mammalian Hippo signaling pathway that culminates in the phosphorylation of YAP, the mammalian homolog of Yki. Using a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent regulator of organ size, and that its dysregulation leads to tumorigenesis. These results uncover a universal size-control mechanism in metazoan.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis*
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Cell Cycle Proteins / metabolism
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Cell Line
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Cell Nucleus / metabolism
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Cell Proliferation*
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Cytoplasm / metabolism
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Doxorubicin
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Drosophila / cytology
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Drosophila / enzymology
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Drosophila / genetics
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Drosophila / growth & development*
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Drosophila / metabolism
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Homeostasis
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Humans
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Intracellular Signaling Peptides and Proteins
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Large Neutral Amino Acid-Transporter 1 / metabolism
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Liver Neoplasms, Experimental / chemically induced
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Liver Neoplasms, Experimental / enzymology
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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Mammals / growth & development*
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Mammals / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Organ Size
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Phosphorylation
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Serine / metabolism
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Serine-Threonine Kinase 3
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Signal Transduction*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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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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LAT2 protein, human
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Large Neutral Amino Acid-Transporter 1
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Nuclear Proteins
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SAV1 protein, human
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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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Serine
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Doxorubicin
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Protein Kinases
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wts protein, Drosophila
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STK4 protein, human
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Protein Serine-Threonine Kinases
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STK3 protein, human
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Serine-Threonine Kinase 3
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hpo protein, Drosophila