Abstract
RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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DNA-Binding Proteins / metabolism*
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Humans
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Models, Biological
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Nuclear Proteins / metabolism*
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-raf / metabolism
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Serine-Threonine Kinase 3
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Signal Transduction
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Transcription Factors
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Transcription, Genetic*
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Tumor Protein p73
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Tumor Suppressor Protein p53 / metabolism
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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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Apoptosis Regulatory Proteins
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BBC3 protein, human
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DNA-Binding Proteins
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MAS1 protein, human
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Nuclear Proteins
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Phosphoproteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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RASSF1 protein, human
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TP73 protein, human
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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YAP1 protein, human
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LATS1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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STK3 protein, human
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Serine-Threonine Kinase 3