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First published online May 4, 2004
doi: 10.1242/10.1242/jcs.01057

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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 ß₁-integrin

Sunnybrook & Women's College Health Sciences Centre and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada

^* Author for correspondence (e-mail: burton.yang{at}sw.ca)

Accepted 11 December 2003

Versican is highly expressed in many types of tumors. In a previous study, we found that a G3 mutant [G3EGF; 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 G3EGF 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 G3EGF-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 G3EGF-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.

Key words: EGFR, G3 domain, Phosphorylation, Interaction, Cell cycle, Immunoprecipitation

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