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

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 thei...

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Bibliographic Details
Published in:Cancer letters 2008-05, Vol.263 (2), p.231-242
Main Authors: Pályi-Krekk, Zsuzsanna, Barok, Márk, Kovács, Tamás, Saya, Hideyuki, Nagano, Osamu, Szöllősi, János, Nagy, Peter
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Antibodies, Monoclonal - metabolism
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Humanized
Breast cancer
Cancer therapies
CD44 shedding
Cell Line, Tumor
Cell Movement - drug effects
Clinical medicine
Colleges & universities
EGFR
Epidermal growth factor
ErbB Receptors
ErbB2
Hematology, Oncology and Palliative Medicine
Humans
Hyaluronan Receptors - metabolism
Hyaluronic Acid - pharmacology
Kinases
Medical prognosis
Mice
Mice, SCID
Molecular weight
Motility
Neoplasm Transplantation
Neuregulin-1 - pharmacology
Pertuzumab
Proteins
Receptor, ErbB-2
Trastuzumab
Tumors
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Summary: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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2008.01.014