Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene.
Ron, the tyrosine kinase receptor for the Macrophage-stimulating protein, is involved in cell dissociation, motility, and matrix invasion. DeltaRon, a constitutively active isoform that confers increased motility to expressing cells, is generated through the skipping of exon 11. We show that abnormal accumulation of DeltaRon mRNA occurs in breast and colon tumors. Skipping of exon 11 is controlled by a silencer and an enhancer of splicing located in the constitutive exon 12. The strength of the enhancer parallels the relative abundance of DeltaRon mRNA and depends on a sequence directly bound by splicing factor SF2/ASF. Overexpression and RNAi experiments demonstrate that SF2/ASF, by controlling the production of DeltaRon, activates epithelial to mesenchymal transition leading to cell locomotion. The effect of SF2/ASF overexpression is reverted by specific knockdown of DeltaRon mRNA. This demonstrates a direct link between SF2/ASF-regulated splicing and cell motility, an activity important for embryogenesis, tissue formation, and tumor metastasis.
Ghigna
Claudia
C
Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy.
Giordano
Silvia
S
Shen
Haihong
H
Benvenuto
Federica
F
Castiglioni
Fabio
F
Comoglio
Paolo Maria
PM
Green
Michael R
MR
Riva
Silvano
S
Biamonti
Giuseppe
G
D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D014018:Tissue Distribution
D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases