Control of epidermal growth factor receptor endocytosis by receptor dimerization, rather than receptor kinase activation.
Given that ligand binding is essential for the rapid internalization of epidermal growth factor receptor (EGFR), the events induced by ligand binding probably contribute to the regulation of EGFR internalization. These events include receptor dimerization, activation of intrinsic tyrosine kinase activity and autophosphorylation. Whereas the initial results are controversial regarding the role of EGFR kinase activity in EGFR internalization, more recent data suggest that EGFR kinase activation is essential for EGFR internalization. However, we have shown here that inhibition of EGFR kinase activation by mutation or by chemical inhibitors did not block EGF-induced EGFR internalization. Instead, proper EGFR dimerization is necessary and sufficient to stimulate EGFR internalization. We conclude that EGFR internalization is controlled by EGFR dimerization, rather than EGFR kinase activation. Our results also define a new role for EGFR dimerization: by itself it can drive EGFR internalization, independent of its role in the activation of EGFR kinase.
Wang
Qian
Q
Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Villeneuve
Greg
G
Wang
Zhixiang
Z
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003432:Cross-Linking Reagents; D019281:Dimerization; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000235:genetics; D014162:Transfection
D003432:Cross-Linking Reagents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors