title: Decorin differentially modulates the activity of insulin receptor isoform A ligands.
abstract: The proteoglycan decorin, a key component of the tumor stroma, regulates the action of several tyrosine-kinase receptors, including the EGFR, Met and the IGF-IR. Notably, the action of decorin in regulating the IGF-I system differs between normal and transformed cells. In normal cells, decorin binds with high affinity to both the natural ligand IGF-I and the IGF-I receptor (IGF-IR) and positively regulates IGF-IR activation and downstream signaling. In contrast, in transformed cells, decorin negatively regulates ligand-induced IGF-IR activation, downstream signaling and IGF-IR-dependent biological responses. Whether decorin may bind another member of the IGF-I system, the insulin receptor A isoform (IR-A) and its cognate ligands, insulin, IGF-II and proinsulin, have not been established. Here we show that decorin bound with high affinity insulin and IGF-II and, to a lesser extent, proinsulin and IR-A. We utilized as a cell model system mouse embryonic fibroblasts homozygous for a targeted disruption of the Igf1r gene (designated R(-) cells) which were stably transfected with a human construct harboring the IR-A isoform of the receptor. Using these R(-)/IR-A cells, we demonstrate that decorin did not affect ligand-induced phosphorylation of the IR-A but enhanced IR-A downregulation after prolonged IGF-II stimulation without affecting insulin and proinsulin-dependent effects on IR-A stability. In addition, decorin significantly inhibited IGF-II-mediated activation of the Akt pathways, without affecting insulin and proinsulin-dependent signaling. Notably, decorin significantly inhibited IGF-II-mediated cell proliferation of R(-)/IR-A cells but affected neither insulin- nor proinsulin-dependent mitogenesis. Collectively, these results suggest that decorin differentially regulates the action of IR-A ligands. Decorin preferentially inhibits IGF-II-mediated biological responses but does not affect insulin- or proinsulin-dependent signaling. Thus, decorin loss may contribute to tumor initiation and progression in malignant neoplasms which depend on an IGF-II/IR-A autocrine loop.
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Health, Endocrinology, University of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Alaide
authors.initials: A
authors.lastname: Morcavallo
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.affiliation: Department of Health, Endocrinology, University of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Pharmazentrum Frankfurt, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: renato.iozzo@jefferson.edu.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: Andrea.Morrione@jefferson.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D000818:Animals; D015153:Blotting, Western; D058575:Decorin / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D011384:Proinsulin / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C546878:DCN protein, human; D058575:Decorin; D007328:Insulin; D020033:Protein Isoforms; D007335:Insulin-Like Growth Factor II; D011384:Proinsulin; D011972:Receptor, Insulin
keywords: Decorin; IR-A; Proliferation; Signaling