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Volume 272, Number 30, Issue of July 25, 1997 pp. 18656-18665
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor

(Received for publication, January 8, 1997, and in revised form, April 29, 1997)

From the Department of Tumor Biology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The function of epidermal growth factor receptor (EGFR) was found to be negatively regulated in M phase in which it showed less phosphotyrosine content and reduced intrinsic kinase activity accompanied by retarded electrophoretic mobility owing to total hyperphosphorylation. Ligand-induced autophosphorylation and downstream signaling of EGFR were tightly suppressed in M phase due to a decrease in ligand binding affinity and the inability of epidermal growth factor (EGF) to induce receptor dimerization. There was no change in the number of surface-exposed EGF receptors between G₀/G₁ and M phases of the cell cycle. Hyperphosphorylation (due to serine and/or threonine phosphorylation) correlates with the unresponsiveness of cells to EGF-mediated stimulation of tyrosine phosphorylation in cells that express the normal or basal level of EGFR. This M phase-specific negative regulation was overcome by overexpression of EGFR, which was responsive to ligand throughout the cell cycle and revealed ligand-induced signaling in the M phase. These findings indicate that EGFR does not respond to ligand stimulation in M phase and suggest that a negative regulation of ligand-receptor interactions in M phase may control the normal function of receptor tyrosine kinase and that receptor overexpression will disrupt this cell cycle-dependent regulation of receptor tyrosine kinases.

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