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.
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.
Kiyokawa
N
N
Department of Tumor Biology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lee
E K
EK
Karunagaran
D
D
Lin
S Y
SY
Hung
M C
MC
D016475:3T3 Cells; D000818:Animals; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D051379:Mice; D008938:Mitosis; D010766:Phosphorylation; D051381:Rats; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism
D008024:Ligands; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors