Abstract
The polyomavirus middle T antigen (PyMT) oncogene activates the cellular nonreceptor tyrosine kinase c-Src and recruits the Hippo pathway effectors, Yap (yes-associated protein) and Taz (transcriptional coactivator with PDZ-binding motif), as key steps in oncogenesis. Yap and Taz are transcription coactivators shuttling from the cytoplasm to the nucleus. The Hippo pathway kinase Lats1/2 (large tumor suppressor homolog) reduces Yap/Taz nuclear localization and minimizes their cytoplasmic levels by facilitating their ubiquitination by the E3 ligase SCF(β-TrCP). In contrast, PyMT increases the cytoplasmic Taz level. Here we show that this unique PyMT behavior is mediated by Src. We demonstrate that PyMT-induced Src activation inhibits degradation of both wild-type and tyrosine-less Taz, ruling out Taz modification as a mechanism of escaping degradation. Instead, we found that Src attenuates the SCF(β-TrCP) E3-ligase activity in blunting Taz proteasomal degradation. The role of Src in rescuing Taz from TrCP-mediated degradation gives rise to higher cell proliferation under dense cell culture. Finally, IkB (NF-kappa-B inhibitor), a known substrate of β-TrCP, was rescued by Src, suggesting a wider effect of Src on β-TrCP substrates. These findings introduce the Src tyrosine kinase as a regulator of SCF(β-TrCP).
Keywords:
Hippo pathway; SCF(β-TrCP); middle T antigen; viral oncogene; virus host interaction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism
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CSK Tyrosine-Protein Kinase
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Cell Line
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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HCT116 Cells
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HEK293 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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NIH 3T3 Cells
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Proteasome Endopeptidase Complex / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proteolysis
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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YAP-Signaling Proteins
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beta-Transducin Repeat-Containing Proteins / genetics
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beta-Transducin Repeat-Containing Proteins / metabolism*
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Polyomavirus Transforming
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Tumor Suppressor Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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beta-Transducin Repeat-Containing Proteins
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Ubiquitin-Protein Ligases
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LATS1 protein, human
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LATS2 protein, human
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Protein Serine-Threonine Kinases
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Proteasome Endopeptidase Complex