Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / physiology*
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Alternative Splicing*
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Base Sequence
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Cell Differentiation
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Codon, Nonsense / physiology*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / physiology*
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Epithelial Cells / cytology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Mesoderm / cytology
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Molecular Sequence Data
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Proto-Oncogene Mas
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RNA Stability*
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RNA, Messenger / chemistry
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RNA, Messenger / metabolism*
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RNA-Binding Proteins / chemistry
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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RNA-Binding Proteins / physiology*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Serine-Arginine Splicing Factors
Substances
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3' Untranslated Regions
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Adaptor Proteins, Signal Transducing
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Codon, Nonsense
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DNA-Binding Proteins
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KHDRBS1 protein, human
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MAS1 protein, human
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Nuclear Proteins
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Proto-Oncogene Mas
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RNA, Messenger
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RNA-Binding Proteins
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Serine-Arginine Splicing Factors
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RON protein
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Receptor Protein-Tyrosine Kinases
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Extracellular Signal-Regulated MAP Kinases