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. ΔRon, a constitutively active isoform that confers increased motility to expressing cells, is generated through the skipping of exon 11. We show that abnormal ac...

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Bibliographic Details
Published in:Molecular cell 2005-12, Vol.20 (6), p.881-890
Main Authors: Ghigna, Claudia, Giordano, Silvia, Shen, Haihong, Benvenuto, Federica, Castiglioni, Fabio, Comoglio, Paolo Maria, Green, Michael R., Riva, Silvano, Biamonti, Giuseppe
Format: Article
Language:English
Subjects:
Alternative Splicing
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cell Line, Tumor
Cell Movement - physiology
CELLBIO
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
DEVBIO
Enhancer Elements, Genetic
Exons
Female
Gene Expression Regulation
Humans
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Protein Isoforms - genetics
Protein Isoforms - metabolism
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
RNA
RNA Interference
RNA, Messenger - metabolism
RNA-Binding Proteins
Serine-Arginine Splicing Factors
Tissue Distribution
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Summary:Ron, the tyrosine kinase receptor for the Macrophage-stimulating protein, is involved in cell dissociation, motility, and matrix invasion. ΔRon, 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 ΔRon 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 ΔRon 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 ΔRon, activates epithelial to mesenchymal transition leading to cell locomotion. The effect of SF2/ASF overexpression is reverted by specific knockdown of ΔRon mRNA. This demonstrates a direct link between SF2/ASF-regulated splicing and cell motility, an activity important for embryogenesis, tissue formation, and tumor metastasis.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2005.10.026