Overexpression of the C-terminal PG-M/versican domain impairs growth of tumor cells by intervening in the interaction between epidermal growth factor receptor and beta1-integrin.
Versican is highly expressed in many types of tumors. In a previous study, we found that a G3 mutant [G3DeltaEGF; a versican G3 domain lacking two epidermal growth factor (EGF)-like motifs] exerted a dominant-negative effect on versican secretion and binding. Here, we report that astrocytoma U87 cells expressing the versican G3 mutant lost the hallmark of cell transformation and tumorigenesis in vitro and in vivo. U87 cells expressing G3DeltaEGF had enhanced cell adhesion and spreading, but lost the tumor characteristic of anchorage-independent growth. When U87 cells were deprived of serum, FAK was quickly dephosphorylated, integrin/EGF-receptor (EGFR) complexes dissociated and the cells retained an appropriate level of EGFR phosphorylation. These cells quickly detached, migrated, rounded, reorganized and survived. However, after serum withdrawal from G3DeltaEGF-transfected U87 cells, sustained FAK phosphorylation and integrin-EGFR association were observed, but a greatly reduced EGFR phosphorylation. These cells remained spread and continued to grow before undergoing massive apoptosis. The addition of EGF promoted U87 cell rounding but had little effect on G3DeltaEGF-transfected cells owing to reduced EGFR phosphorylation. Our study sheds light on the question of how the matrix molecule versican modulates tumorigenesis by affecting integrin and EGFR signals.
Wu
Yaojiong
Y
Sunnybrook & Women's College Health Sciences Centre and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada.
Chen
Liwen
L
Cao
Liu
L
Sheng
Wang
W
Yang
Burton B
BB
D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D037181:Lectins, C-Type; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D014162:Transfection; D014410:Tumor Stem Cell Assay; D053675:Versicans
D011508:Chondroitin Sulfate Proteoglycans; D016895:Culture Media, Serum-Free; D019012:Integrin beta1; D037181:Lectins, C-Type; C508322:VCAN protein, human; D053675:Versicans; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human