The relative role of ErbB1-4 receptor tyrosine kinases in radiation signaltransduction responses of human carcinoma cells

Activation of the epidermal growth receptor (ErbB1) occurs within minutes o f a radiation exposure. Immediate downstream consequences of this activatio n are currently indistinguishable from those obtained with growth factors ( GF), e.g. stimulation of the pro-proliferative mitogen-activated protein ki nase (MAPK). To identify potential differences, the effects of GFs and radi ation on other members of the ErbB family have been compared in mammary car cinoma cell lines differing in their ErbB expression profiles. Treatment of cells with EGF (ErbB1-specific) or heregulin (ErbB4-specific) resulted in a hierarchic transactivations of ErbB2 and ErbB3 dependent on GF binding sp ecificity. In contrast, radiation indiscriminately activated all ErbB speci es with the activation profile reflecting that cell's ErbB expression profi le. Downstream consequences of these ErbB interactions were examined with M APK after specifically inhibiting ErbB1 (or 4) with tyrphostin AG1478 or Er bB2 with tyrphostin AG825. MAPK activation by GFs or radiation was complete ly inhibited by AG1478 indicating total dependance on ErbB1 (or 4) dependin g on which ErbB is expressed. Inhibiting ErbB2 caused an enhanced MAPK resp onse simulating an amplified ErbB1 (or 4) response. Thus ErbB2 is a modulat or of ErbB1 (or 4) function leading to different MAPK response profiles to GF or radiation exposure.