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: Alaide Morcavallo, Simone Buraschi, Shi-Qiong Xu, Antonino Belfiore, Liliana Schaefer, Renato V Iozzo, Andrea Morrione
• Journal: Matrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 35 Pg. 82-90 (Apr 2014) ISSN: 1569-1802 [Electronic] Netherlands
• PMID: 24389353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Chemical References

• DCN protein, human
• Decorin
• Insulin
• Protein Isoforms
• Insulin-Like Growth Factor II
• Proinsulin
• Receptor, Insulin

Topics

• Animals
• Blotting, Western
• Decorin (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Insulin (metabolism)
• Insulin-Like Growth Factor II (metabolism)
• Mice
• Proinsulin (metabolism)
• Protein Isoforms (metabolism)
• Receptor, Insulin (metabolism)
• Signal Transduction (physiology)