CELL CYCLE-DEPENDENT REGULATION OF P185(NEU) - A RELATIONSHIP BETWEEN DISRUPTION OF THIS REGULATION AND TRANSFORMATION

Structure and function of p185(neu) receptor tyrosine kinase were found to be regulated in a cell cycle-dependent manner. In M phase, p185(neu) is hyperphosphorylated at serine and/or threonine residues. The phosphotyrosine [Tyr(P)] content of p185(neu) is at its highest level in G(0)/G(1) phase, decreases through S and G(2) phases, and reaches its lowest level in M phase. Phospholipase C-gamma (PLC-gamma) and GTPase-activating protein (GAP), substrates of p185(neu), also have a similar profile of Tyr(P) content during the cell cycle. These results, along with in vitro immune complex kinase assays, suggest that the tyrosine kinase activity of p185(neu) is least active in M phase. Interestingly, the mutation-activated neu oncogene (neu*)-encoded protein product, p185(neu)*, escaped from cell cycle regulation. Taken together, we demonstrate in this report that the structure and function of p185(neu) are regulated in a cell cycle-dependent manner, yet p185(neu)* escapes from this regulation and remains active through the cell cycle. Disruption of this cell cycle regulation may define a mechanism for p185(neu)*-mediated cellular transformation.