EFFECTS OF PHOSPHORYLATION OF P-GLYCOPROTEIN ON MULTIDRUG-RESISTANCE

Cells expressing elevated levels of the membrane phosphoprotein P-glyc oprotein exhibit a multidrug resistance phenotype. Studies involving p rotein kinase activators and inhibitors have implied that covalent mod ification of P-glycoprotein by phosphorylation may modulate its biolog ical activity as a multidrug transporter. Most of these reagents, howe ver, have additional mechanisms of action and may alter drug accumulat ion within multidrug resistant cells independent of, or in addition to , their effects on the state of phosphorylation of P-glycoprotein. The protein kinase(s) responsible for P-glycoprotein phosphorylation has( ve) not been unambiguously identified, although several possible candi dates have been suggested. Recent biochemical analyses demonstrate tha t the major sites of phosphorylation are clustered within the linker r egion that connects the two homologous halves of P-glycoprotein. Mutat ional analyses have been initiated to confirm this finding. Preliminar y data obtained from phosphorylation- and dephosphorylation-defective mutants suggest that phosphorylation of P-glycoprotein is not essentia l to confer multidrug resistance.