TY - JOUR
T1 - Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene
AU - Ghigna, Claudia
AU - Giordano, Silvia
AU - Shen, Haihong
AU - Benvenuto, Federica
AU - Castiglioni, Fabio
AU - Comoglio, Paolo Maria
AU - Green, Michael R.
AU - Riva, Silvano
AU - Biamonti, Giuseppe
PY - 2005/12/22
Y1 - 2005/12/22
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2005.10.026
DO - 10.1016/j.molcel.2005.10.026
M3 - Article
C2 - 16364913
AN - SCOPUS:29144447982
VL - 20
SP - 881
EP - 890
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -