The Role of EGF Receptor Negative Regulatory Components in Breast Cell Growth

An amplified epidermal growth factor (EGF) receptor (EGF-R) cell line was compared with a non-amplified EGF-R variant of that cell line. An EGF treatment time-course showed that the amplified cell line was unable to reduce its number of activated EGF-R's as efficiently as the non-amplified cell line. This lack of negative regulation does not depend on covalent modification of the receptor by protein kinase C. However, the non-amplified variant line is negatively regulated by tyrosine phosphatases although the amplified cell line is not. Another difference between activated receptor negative regulation in these cell lines is that the variants can rapidly down-regulate activated receptors whereas the parental cell line cannot. Both differences may be due to limitations in the negative regulatory apparatus due to EGF-R amplification. In addition, another cell line that is not transformed but expresses an EGF-R compliment intermediate to the variant and the parental cell lines rapidly attenuates activated receptors with a rate similar to the non-amplified variants. The data supports the hypothesis that, amplification of the receptor in the absence of concomitant amplification of its negative regulatory components leads to dysregulated kinase activity and uncontrolled receptor signaling.