Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor.
The monoclonal antibody C225 interacts with the ectodomain of the epidermal growth factor (EGF) receptor (EGFR) to block ligand binding and initiates receptor endocytosis and intracellular trafficking. The data herein show that C225-dependent EGFR trafficking relocalizes the receptor to the endoplasmic reticulum (ER) and nucleus. This mechanism, which also involves interaction of the C225-internalized receptor with the Sec61 translocon within the ER, is, in most respects, analogous to the pathway previously described for EGF-induced trafficking to the ER and nucleus. However, although inhibition of receptor tyrosine kinase activity blocks EGF-induced nuclear localization of the receptor, the same kinase inhibitors stimulate C225-dependent nuclear localization of EGFR in the nucleus. In contrast, the kinase inhibitor Lapatinib fails to stimulate nuclear accumulation of the receptor in C225-treated cells and does not provoke receptor dimerization as do inhibitors that recognize the open conformation of the receptor kinase. This suggests that inhibitor-dependent receptor dimerization may facilitate C225-induced receptor trafficking.
Liao
Hong-Jun
HJ
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenessee 37232-0146, USA.
Carpenter
Graham
G
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000068818:Cetuximab; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D000077341:Lapatinib; D008565:Membrane Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics; D000069816:SEC Translocation Channels; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D037282:Calreticulin; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; D000069816:SEC Translocation Channels; C499388:SEC61B protein, human; D000077341:Lapatinib; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors; D000068818:Cetuximab