Induction of Antagonistic Soluble Decoy Receptor Tyrosine Kinases by Intronic PolyA Activation

Sandra Vorlová, Gina Rocco, Clare V. LeFave, Francine M. Jodelka, Ken Hess, Michelle L. Hastings, Erik Henke, Luca Cartegni

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)927-939
Number of pages13
JournalMolecular Cell
Volume43
Issue number6
DOIs
StatePublished - Sep 16 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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