Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene

Epithelial-to-mesenchymal transition (EMT) and its reversal (MET) are crucial cell plasticity programs that act during development and tumor metastasis. We have previously shown that the splicing factor and proto-oncogene SF2/ASF impacts EMT/MET through production of a constitutively active splice v...

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Bibliographic Details
Published in:The Journal of cell biology 2010-10, Vol.191 (1), p.87-99
Main Authors: Valacca, Cristina, Bonomi, Serena, Buratti, Emanuele, Pedrotti, Simona, Baralle, Francisco Ernesto, Sette, Claudio, Ghigna, Claudia, Biamonti, Giuseppe
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - physiology
Alternative Splicing
Base Sequence
Cell Differentiation
Cells
Codon, Nonsense - physiology
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - physiology
Epithelial Cells - cytology
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
Mesoderm - cytology
Metastasis
Mitochondria
Molecular Sequence Data
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
Ribonucleic acid
RNA
RNA Stability
RNA, Messenger - chemistry
RNA, Messenger - metabolism
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
RNA-Binding Proteins - physiology
Serine-Arginine Splicing Factors
Tumors
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Summary:Epithelial-to-mesenchymal transition (EMT) and its reversal (MET) are crucial cell plasticity programs that act during development and tumor metastasis. We have previously shown that the splicing factor and proto-oncogene SF2/ASF impacts EMT/MET through production of a constitutively active splice variant of the Ron proto-oncogene. Using an in vitro model, we now show that SF2/ASF is also regulated during EMT/MET by alternative splicing associated with the nonsense-mediated mRNA decay pathway (AS-NMD). Overexpression and small interfering RNA experiments implicate the splicing regulator Sam68 in AS-NMD of SF2/ASF transcripts and in the choice between EMT/MET programs. Moreover, Sam68 modulation of SF2/ASF splicing appears to be controlled by epithelial cell-derived soluble factors that act through the ERK1/2 signaling pathway to regulate Sam68 phosphorylation. Collectively, our results reveal a hierarchy of splicing factors that integrate splicing decisions into EMT/MET programs in response to extracellular stimuli.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201001073