Abstract
LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Motifs / genetics
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Animals
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Cell Cycle Proteins
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Drosophila
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / genetics
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / genetics
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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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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HEMGN protein, human
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Oncogene Proteins
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Phosphoproteins
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Transcription Factors
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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YY1AP1 protein, human
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Yap1 protein, mouse
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LATS1 protein, human
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Lats1 protein, mouse
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Protein Serine-Threonine Kinases
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hpo protein, Drosophila