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Inhibition of heregulin signaling by N-glycan deleted soluble ErbB3
Motoko Takahashi,Yoshinao Wada,Michiko Tajiri,Motoko Araki,Yoshiki Yamaguchi,Naoyuki Taniguchi,YoshioKuroki 한국당과학회 2011 한국당과학회 학술대회 Vol.2011 No.1
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.
Mechanism for the Differentiation of EoL-1 Cells into Eosinophils by Histone Deacetylase Inhibitors
Kaneko, Motoko,Ishihara, Kenji,Takahashi, Aki,Hong, JangJa,Hirasawa, Noriyasu,Zee, OkPyo,Ohuchi, Kazuo S.Karger 2007 International archives of allergy and immunology Vol.143//SUP1 No.-
<P><I>Background:</I> EoL-1 cells have a <I>FIP1L1-PDGFRA</I> fusion gene which causes the transformation of eosinophilic precursor cells into leukemia cells. Recently, we suggested that the induction of differentiation of EoL-1 cells into eosinophils by the HDAC inhibitors apicidin and n-butyrate is due to the continuous inhibition of HDACs. However, neither apicidin nor n-butyrate inhibited the expression of FIP1L1-PDGFRA mRNA, although both these inhibitors suppressed cell proliferation. Therefore, in this study, we analyzed whether the levels of FIP1L1-PDGFRα protein and phosphorylated-Stat5 involved in the signaling for the proliferation of EoL-1 cells are attenuated by HDAC inhibitors. <I>Methods:</I> EoL-1 cells were incubated in the presence of apicidin, TSA or n-butyrate. FIP1L1-PDGFRα and phosphorylated-Stat5 were detected by Western blotting. <I>Results:</I> Treatment of EoL-1 cells with apicidin at 100 n<I>M</I> or n-butyrate at 500 μ<I>M</I> decreased the levels of FIP1L1-PDGFRα protein and phosphorylated-Stat5, while that with trichostatin A at 30 n<I>M</I> did not. <I>Conclusions:</I> The decrease in the level of FIP1L1-PDGFRα protein caused by apicidin and n-butyrate might be one of the mechanisms by which EoL-1 cells are induced to differentiate into eosinophils by these HDAC inhibitors.</P><P>Copyright © 2007 S. Karger AG, Basel</P>