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Decorin is a biological ligand for the epidermal growth factor receptor
R V Iozzo1, D K Moscatello, D J McQuillan
1Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. iozzo@lac.jci.tju.edu
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 (Kd approximately 87 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.
Insights
Decorin, a protein, directly binds to the epidermal growth factor (EGF) receptor, inhibiting cancer cell growth. This interaction activates signaling pathways, leading to cell cycle arrest and reduced tumor progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Ectopic decorin expression causes cytostatic effects in various cancer cells.
- The precise mechanism involves activation of the epidermal growth factor (EGF) receptor signaling pathway.
- This pathway leads to mitogen-activated protein (MAP) kinase phosphorylation and p21 induction, ultimately suppressing growth.
Purpose of the Study:
- To elucidate the direct interaction between decorin and the EGF receptor.
- To investigate how decorin binding affects EGF receptor activity and downstream signaling.
- To characterize the binding kinetics and mediating elements of the decorin-EGF receptor interaction.
Main Methods:
- Demonstration of direct decorin-EGF receptor interaction in squamous carcinoma cells.
- Assessment of EGF receptor dimerization and MAP kinase phosphorylation.
- Cell-free assays to evaluate decorin's effect on purified EGF receptor tyrosine kinase activity.
- Radioligand binding assays to quantify decorin binding affinity and specificity.
Main Results:
- Decorin directly binds to the EGF receptor, inducing its dimerization and sustained MAP kinase phosphorylation.
- In cell-free systems, decorin activates purified EGF receptor tyrosine kinase and acts as a substrate.
- Both soluble and immobilized decorin bind to the EGF receptor ectodomain with low affinity (Kd ≈ 87 nM).
- The protein core of decorin mediates this binding.
Conclusions:
- Decorin acts as a novel biological ligand for the EGF receptor.
- This interaction provides a new mechanism for regulating cell growth, relevant to tissue remodeling and cancer.
- Targeting the decorin-EGF receptor axis may offer therapeutic strategies for cancer treatment.