Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis.
Decorin inhibits the epidermal growth factor receptor (EGFR) by down-regulating its tyrosine kinase activity, thereby blocking the growth of a variety of transformed cells and tumor xenografts. In this study we provide evidence that decorin directly binds to the EGFR causing its dimerization, internalization, and ultimately its degradation. Using various pharmacological agents to disrupt clathrin-dependent and -independent endocytosis, we demonstrate that decorin evokes a protracted internalization of the EGFR primarily via caveolar-mediated endocytosis. In contrast to EGF, decorin targets the EGFR to caveolae, but not to early or recycling endosomes. Ultimately, however, both EGF- and decorin-induced pathways converge into late endosomes/lysosomes for final degradation. Thus, we have discovered a novel biological mechanism for decorin that could explain its anti-proliferative and anti-oncogenic mode of action.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Jing-Xu
JX
Zhu
Silvia
S
Goldoni
Gregory
G
Bix
Rick T
RT
Owens
David J
DJ
McQuillan
Charles C
CC
Reed
Renato V
RV
Iozzo
D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D002966:Clathrin / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D058575:Decorin; D019281:Dimerization; D015536:Down-Regulation; D004705:Endocytosis; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors
D000970:Antineoplastic Agents; D002966:Clathrin; D003432:Cross-Linking Reagents; C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D008024:Ligands; D011509:Proteoglycans; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D066246:ErbB Receptors