Decorin Is a Biological Ligand for the Epidermal Growth Factor Receptor

Abstract

Ectopic expression of decorin induces profound cytostatic effects in transformed cells with diverse histogenetic backgrounds. The mechanism of action has only recently begun to be elucidated. Exogenous decorin activates the epidermal growth factor (EGF) receptor, thereby triggering a signaling cascade that leads to phosphorylation of mitogen-activated protein (MAP) kinase, induction of p21, and growth suppression. In this study we demonstrate a direct interaction of decorin with the EGF receptor. Binding of decorin induces dimerization of the EGF receptor and rapid and sustained phosphorylation of MAP kinase in squamous carcinoma cells. In a cell-free system, decorin induces autophosphorylation of purified EGF receptor by activating the receptor tyrosine kinase and can also act as a substrate for the EGF receptor kinase itself. Using radioligand binding assays we show that both immobilized and soluble decorin bind to the EGF receptor ectodomain or to purified EGF receptor. The binding is mediated by the protein core and has relatively low affinity (K d ϳ87 nM). Thus, decorin should be considered as a novel biological ligand for the EGF receptor, an interaction that could regulate cell growth during remodeling and cancer growth.

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

“…In addition, the cyclically strained collagen gels seeded with Dcn −/− cells contained the greatest final density of cells, as shown in our previous study [16]. It has been widely recognized that decorin can inhibit cell proliferation, both by sequestering TGF-β and by blocking the epidermal growth factor receptor [26][27][28][29][30].…”

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

“…5 Decorin has been shown to arrest cells in the G1 phase of the cell cycle, and growth suppression could be restored by treatment with decorin antisense nucleotides. [6][7][8] The mechanism of action of decorin-induced growth suppression appears to be mediated by interaction with the epidermal growth factor receptor (EGFR), [8][9][10] which leads to an upregulation of p21, a potent inhibitor of cyclin-dependent kinases. 6,7 In agreement with this, it has been shown that adenovirusmediated gene transfer of decorin attenuates EGFR activity and suppresses in vivo tumorigenesis.…”

Gros1, a potential growth suppressor on chromosome 1: its identity to basement membrane-associated proteoglycan, leprecan

“…It was mediated by reversal of TGF-beta-induced immunosuppression and activation of the epidermal growth factor (EGF) receptor that triggered a signaling cascade leading to phosphorylation of mitogen-activated protein (MAP) kinase and induction of p21 WAF1 . By virtue of its growth regulatory and immuno-modulatory properties decorin has been proposed as a novel target for the experimental therapy of human cancers (Iozzo et al, 1999;Stander et al, 1998Stander et al, , 1999. In addition to their role in histoarchitecture, sequestration of growth factors, cell ± cell and cell ± matrix interactions that recruit them for cancer therapy, proteoglycans have also been implicated to have role in developing mammalian brain (Oohira et al, 2000), altered elasticity, strength and other physical properties of aging skin (Carrino et al, 2000) and Alzheimer's diseased brain (Verbeek et al, 1999).…”