Modulation of the epidermal growth factor receptor by brain‐derived growth factor in Swiss mouse 3T3 cells

Incubation of Swiss mouse 3T3 cells at 37°C with bovine brain‐derived growth factor (BDGF) decreased the cell surface ¹²⁵I‐EGF binding activity of these cells by 70–80%. This down‐modulation of the EOF receptor by BDGF was time, temperature, and dose dependent Scatchard plot analysis indicated that BDGF binding led to a selective decrease in the number of high‐affinity EGF receptors. The BDGF‐induced down‐modulation of the EGF receptor was completely blocked by protamine, a potent inhibitor of receptor binding and mitogenic activities of BDGF. BDGF down‐modulated the EGF receptor in phorbol myristic acetate (PMA)‐pretreated cells, as well as in control cells. Furthermore, PMA‐pretreated cells responded mitogenically to BDGF, whereas PMA itself failed to stimulate the mitogenic response of PMA‐pretreated cells. This BDGF‐induced down‐modulation of the EGF receptor in PMA‐desensitized cells suggests that BDGF down‐regulates the EGF receptor by a mechanism distinct from that of PMA. Incubation of cells with compounds which are known to inhibit pinocytosis blocked the down‐modulation induced either by BDGF or by platelet‐derived growth factor (PDGF) but had no effect on the PMA‐induced down‐modulation. Incubation of cells with inhibitors of receptor recycling enhanced the BDGF‐induced down‐modulation of the EGF receptor. These results suggest that BDGF and PDGF induce down‐modulation of the EGF receptor by increasing the internalization of cell surface high‐affinity receptors and that the internalization process may not be required for down‐modulation induced by PMA.