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 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.
Valacca
Cristina
C
Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy.
Bonomi
Serena
S
Buratti
Emanuele
E
Pedrotti
Simona
S
Baralle
Francisco Ernesto
FE
Sette
Claudio
C
Ghigna
Claudia
C
Biamonti
Giuseppe
G
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000502:physiology*; D017398:Alternative Splicing; D001483:Base Sequence; D002454:Cell Differentiation; D018389:Codon, Nonsense / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases