earticle

영어

ErbB signaling is implicated in the pathology of various types of carcinoma. Ligand binding to the extracellular domain of ErbB induces conformational changes that lead to homo- or heterodimerization of the receptors and subsequent signaling. It has been reported that N-glycans of the ErbB family regulate its function. We previously reported that N-glycans of EGFR are involved in receptor dimerization and endocytosis. N-glycans of ErbB3 are also involved in receptor dimerization and activation status; deletion of the N-glycan on Asn418 of ErbB3 leads to both spontaneous homodimerization of ErbB3 and heterodimerization of ErbB2-ErbB3. The promoted heterodimerization with ErbB2 leads to upregulation of receptor tyrosine phosphorylation, downstream signalings, and transforming activity. We recently found that N-glycans of ErbB4 also regulate ligand-induced signaling. Thus, N-glycans of the ErbB family seem to play an important role in receptor activation, especially in receptor dimerization. To examine the role of N-glycans of the ErbB in detail, we prepared a wild type and an N-glycan deleted mutant of sErbB3 (domains I, II, III and IV) and compared their properties. When added to culture cells expressing ErbB2 and ErbB3, the sErbB3 N418Q mutant downregulated the heregulin b signaling more effectively than the wild type sErbB3. Through mass spectrometry analysis, we were able to determine the structure of the N-glycan on Asn418 of sErbB3. This suggests that the specific N-glycan of sErbB3 regulates the binding status of sErbB3 to ligands or receptors. We consider that the sErbB3 N418Q mutant is a potent inhibitor of transforming activity of ErbB, and may have therapeutic applications in cancer.