EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44

Zsuzsanna Pályi-Krekk, Márk Barok, Tamás Kovács, Hideyuki Saya, Osamu Nagano, János Szöllosi, Peter Nagy

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Activation of the ErbB family of receptor tyrosine kinases is involved in a range of human cancers. Transmembrane signaling mediated by ErbB proteins is stimulated by peptide growth factors and is blocked by monoclonal antibodies such as trastuzumab and pertuzumab. ErbB receptors exert their function in conjunction with non-ErbB proteins, e.g. CD44. Here we show that epidermal growth factor (EGF) and heregulin induce CD44 shedding in JIMT-1, an ErbB2-overexpressing cell line resistant to trastuzumab, accompanied by internalization and intramembrane proteolysis of CD44 and enhanced cellular motility. These effects of EGF and heregulin are blocked by pertuzumab. Trastuzumab inhibits the heregulin- and hyaluronan oligosaccharide-induced shedding and internalization of CD44 and their motogenic effect. Trastuzumab also blocks CD44 shedding from JIMT-1 xenograft tumors in vivo. At the same time the internalization rate of trastuzumab is increased by hyaluronan oligosaccharide treatment in vitro. Our experiments point to an unexpected, but potentially important mechanism of action of ErbB receptor-targeted monoclonal antibodies used in the treatment of cancer.

Original languageEnglish
Pages (from-to)231-242
Number of pages12
JournalCancer Letters
Volume263
Issue number2
DOIs
Publication statusPublished - 2008 May 18

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Neuregulin-1
Hyaluronic Acid
Oligosaccharides
Epidermal Growth Factor
Monoclonal Antibodies
Neoplasms
Heterografts
Protein-Tyrosine Kinases
Proteolysis
Intercellular Signaling Peptides and Proteins
Proteins
Trastuzumab
Cell Line
Peptides
ErbB Receptors
pertuzumab

Keywords

  • CD44 shedding
  • EGFR
  • ErbB2
  • Pertuzumab
  • Trastuzumab

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

Cite this

EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44. / Pályi-Krekk, Zsuzsanna; Barok, Márk; Kovács, Tamás; Saya, Hideyuki; Nagano, Osamu; Szöllosi, János; Nagy, Peter.

In: Cancer Letters, Vol. 263, No. 2, 18.05.2008, p. 231-242.

Research output: Contribution to journalArticle

Pályi-Krekk, Zsuzsanna ; Barok, Márk ; Kovács, Tamás ; Saya, Hideyuki ; Nagano, Osamu ; Szöllosi, János ; Nagy, Peter. / EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44. In: Cancer Letters. 2008 ; Vol. 263, No. 2. pp. 231-242.
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