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Vol. 273, Issue 3, 1662-1669, January 16, 1998

Disruption of Fibronectin Binding to the ₅₁ Integrin Stimulates the Expression of Cyclin-dependent Kinases and DNA Synthesis through Activation of Extracellular Signal-regulated Kinase

JianGen Gong, Tien C. Ko^¶, and Michael G. Brattain

From the  Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699-0008 and the ^¶ Departments of Surgery and Human Biological Chemistry & Genetics, The University of Texas Medical Branch, Galveston, Texas 77555-0542

The ₅₁ integrin, a fibronectin receptor, has been implicated in the control of cell growth and the regulation of gene expression. We report that disruption of ligation between ₅₁ and fibronectin by integrin ₅ subunit or fibronectin monoclonal antibodies stimulated DNA synthesis in growth-arrested FET human colon carcinoma cells. This stimulation only occurred when monoclonal antibody was added in the early G₁ phase of the cell cycle after release from quiescence by fresh medium. Stimulation of DNA synthesis by ₅ or fibronectin antibody was concentration- and time-dependent. FET cells expressed ₄₁ integrin (another fibronectin receptor); however, addition of anti-human integrin ₄ monoclonal antibody had no effect on DNA synthesis. Treatment with ₅ monoclonal antibody led to a marked increase in the expression of CDK4 in G₁ phase of the cell cycle and consequently increased the phosphorylation of retinoblastoma protein. ₅ monoclonal antibody treatment increased both cyclin A- and cyclin E-associated kinase activity which was accompanied by increased protein levels of CDK2 and cyclin A. Western blotting of immunoprecipitates demonstrated increased CDK2-cyclin E and CDK2-cyclin A complexes in cells treated with ₅ monoclonal antibody. Furthermore, disruption of ₅₁/fibronectin ligation activated mitogen-activated protein kinase p44 and p42 (extracellular signal-regulated kinase 1 and 2). Pretreatment of the cells with a specific inhibitor of MEK-1, PD98059, blocked the ₅ monoclonal antibody-induced mitogen-activated protein kinase activity. In addition PD98059 prevented ₅ monoclonal antibody-induced DNA synthesis. Since ₅₁ ligation to fibronectin is associated with decreased growth parameters, our results indicate that ligation of ₅₁ integrin to fibronectin results in suppressed mitogen-activated protein kinase activity which in turn inhibits cyclin-dependent kinase activity in growth-arrested cells.

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