Molecular Cell
Volume 43, Issue 6, 16 September 2011, Pages 927-939
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Article
Induction of Antagonistic Soluble Decoy Receptor Tyrosine Kinases by Intronic PolyA Activation

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Summary

Alternative intronic polyadenylation (IPA) can generate truncated protein isoforms with significantly altered functions. Here, we describe 31 dominant-negative, secreted variant isoforms of receptor tyrosine kinases (RTKs) that are produced by activation of intronic poly(A) sites. We show that blocking U1-snRNP can activate IPA, indicating a larger role for U1-snRNP in RNA surveillance. Moreover, we report the development of an antisense-based method to effectively and specifically activate expression of individual soluble decoy RTKs (sdRTKs) to alter signaling, with potential therapeutic implications. In particular, a quantitative switch from signal transducing full-length vascular endothelial growth factor receptor-2 (VEGFR2/KDR) to a dominant-negative sKDR results in a strong antiangiogenic effect both on directly targeted cells and on naive cells exposed to conditioned media, suggesting a role for this approach in interfering with angiogenic paracrine and autocrine loops.

Highlights

▸ Soluble decoy RTK (sdRTKs) are commonly generated by intronic polyadenylation (IPA) ▸ IPA is suppressed by a U1snRNP-dependent RNA surveillance mechanism ▸ Antisense block of U1 binding to the 5′ ss specifically activates individual sdRTKs ▸ IPA-driven sdRTKs inhibit RTK signaling by three separate but simultaneous mechanisms

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