Identification of epidermal growth factor receptor as a target of Cdc25A protein phosphatase.
Cdc25A, a dual-specificity protein phosphatase, plays a critical role in cell cycle progression. Although cyclin-dependent kinases are established substrates, Cdc25A may also affect other proteins. We have shown here that Cdc25A interacts with epidermal growth factor receptor (EGFR) both physically and functionally in Hep3B human hepatoma cells. Cdc25A inhibitor Cpd 5, a vitamin K analog, inhibited Cdc25A activity in the Cdc25A-EGFR immunocomplex and consequently caused prolonged EGFR tyrosine phosphorylation. Both purified GST-Cdc25A protein and endogenous Hep3B cellular Cdc25A dephosphorylated tyrosine-phosphorylated EGFR, and Cpd 5 antagonized the phosphatase activity of Cdc25A. A functional Cdc25A-EGFR interaction was seen in NR-6 fibroblasts expressing ectopic EGFR but not with a receptor lacking the C terminus or a mutated kinase domain. These data link the cell cycle control Cdc25A phosphatase to an EGFR-linked mitogenic signaling pathway specifically involving EGFR dephosphorylation.
Wang
Ziqiu
Z
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Wang
Meifang
M
Lazo
John S
JS
Carr
Brian I
BI
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014812:Vitamin K / Q000031:analogs & derivatives / Q000494:pharmacology; D020687:cdc25 Phosphatases / Q000378:metabolism*
C446520:2-(2-hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone; D006131:Growth Inhibitors; D014812:Vitamin K; D014443:Tyrosine; D005982:Glutathione Transferase; D066246:ErbB Receptors; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases