title: Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation.
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.
authors.affiliation: Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Vorlová
authors.forename: Gina
authors.initials: G
authors.lastname: Rocco
authors.forename: Clare V
authors.initials: CV
authors.lastname: Lefave
authors.forename: Francine M
authors.initials: FM
authors.lastname: Jodelka
authors.forename: Ken
authors.initials: K
authors.lastname: Hess
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hastings
authors.forename: Erik
authors.initials: E
authors.lastname: Henke
authors.forename: Luca
authors.initials: L
authors.lastname: Cartegni
mesh_terms: D006801:Humans; D007438:Introns; D018919:Neovascularization, Physiologic / Q000502:physiology; D011061:Poly A / Q000737:chemistry / Q000235:genetics; D026723:Polyadenylation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D012326:RNA Splicing; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000737:chemistry / Q000502:physiology; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000502:physiology; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology
chemical_list: D020033:Protein Isoforms; D017412:Ribonucleoprotein, U1 Small Nuclear; D011061:Poly A; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2