Crosstalk between epidermal growth factor receptor and P-glycoprotein in actinomycin D-resistant Chinese hamster lung cells.
Multidrug-resistant cells can manifest an increase in epidermal growth factor (EGF) receptor number along with increased P-glycoprotein (Pgp) synthesis. An interrelationship of the two membrane proteins in actinomycin D-resistant Chinese hamster lung cells (DC-3F/AD X) in terms of the effect of EGF on Pgp phosphorylation was investigated. EGF was not a mitogen for the resistant cells, nor was it mitogenic for DC-3F, the parental drug-sensitive line. Brief treatment of DC-3F/AD X cells with EGF resulted in a 30-50% decrease in the level of Pgp phosphorylation, and treatment of the cells with okadaic acid, a specific inhibitor of protein phosphatases-1 and -2A (PP1 and 2A), increased Pgp phosphorylation. Okadaic acid also increased phosphorylation of Pgp in plasma membranes isolated from DC-3F/AD X cells by 30-40%. Protein phosphatase activity in extracts of cells grown in EGF-containing medium was greater by 30% than that of cells grown in standard medium, and okadaic acid inhibited the increases. The results suggested that EGF activated PP1 and PP2A in DC-3F/AD X cells and that Pgp was a substrate for the phosphatases. The properties of Pgp may be modulated by the signalling system transduced by ligand-activated EGF receptor.
Meyers
M B
MB
Laboratory of Cellular and Biochemical Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Yu
P
P
Mendelsohn
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003609:Dactinomycin / Q000494:pharmacology*; D004351:Drug Resistance; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D004988:Ethers, Cyclic; D008562:Membrane Glycoproteins; D003609:Dactinomycin; D019319:Okadaic Acid; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010749:Phosphoprotein Phosphatases