Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation

Mol Cell. 2011 Sep 16;43(6):927-39. doi: 10.1016/j.molcel.2011.08.009.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Introns*
  • Neovascularization, Physiologic / physiology
  • Poly A / chemistry
  • Poly A / genetics
  • Polyadenylation*
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / chemistry
  • Protein Isoforms / physiology
  • RNA Splicing
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / physiology
  • Ribonucleoprotein, U1 Small Nuclear / physiology
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / physiology


  • Protein Isoforms
  • Ribonucleoprotein, U1 Small Nuclear
  • Poly A
  • Receptor Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2