Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand

Arun Vaidyanath, Toshihiro Hashizume, Tadahiro Nagaoka, Nao Takeyasu, Hitomi Satoh, Ling Chen, Jiyou Wang, Tomonari Kasai, Takayuki Kudoh, Ayano Satoh, Li Fu, Masaharu Seno

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Abstract

Targeting and down-regulation of ErbB2, a member of EGF receptor family, is regarded as one of the key aspect for cancer treatment because it is often overexpressed in breast and ovarian cancer cells. Although natural ligands for ErbB2 have not been found, unlike other ErbB receptors, EC-1, a 20-amino acid circular peptide, has been shown to bind to ErbB2 as an artificial ligand. Previously we showed EC-1 peptide did not induce the internalization of ErbB2 in SK-BR-3 cells. In this report, we designed divalent and multivalent forms of EC-1 peptide with the Fc portion of the human IgG and bionanocapsule modified with ZZ-tag on its surface to improve the interaction with ErbB2. These forms showed higher affinity to ErbB2 than that of EC-1 monomer. Furthermore, prominent endosomal accumulation of ErbB2 occurred in SK-BR-3 cells when stimulated with EC-Fc ligand multivalently displayed on the surface of the bionanocapsule, whereas SK-BR-3 cells as themselves displayed stringent mechanism against ErbB2 internalization without stimulation. The multivalent form of EC-1 peptide appeared to internalize ErbB2 more efficiently than divalent form did. This internalization was unaffected by the inhibition of clathrin association, but inhibited when the cholesterol was depleted which explained either caveolar or GPI-AP-early endocytic compartment (GEEC) pathway. Because of the lack of caveolin-1 expression, caveolar machinery may be lost in SK-BR-3 cell line. Therefore, it is suggested that the multivalent form of EC-1 induces the internalization of ErbB2 through the GEEC pathway.

Original languageEnglish
Pages (from-to)2525-2538
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume15
Issue number11
DOIs
Publication statusPublished - 01-11-2011

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Cell Biology

Cite this

Vaidyanath, A., Hashizume, T., Nagaoka, T., Takeyasu, N., Satoh, H., Chen, L., Wang, J., Kasai, T., Kudoh, T., Satoh, A., Fu, L., & Seno, M. (2011). Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand. Journal of Cellular and Molecular Medicine, 15(11), 2525-2538. https://doi.org/10.1111/j.1582-4934.2011.01277.x