EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44.
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.
Pályi-Krekk
Zsuzsanna
Z
Department of Biophysics and Cell Biology, Medical and Health Science Center, University of Debrecen, 1 Egyetem Square, H-4010 Debrecen, Hungary. krekkzs@dote.hu
Barok
Márk
M
Kovács
Tamás
T
Saya
Hideyuki
H
Nagano
Osamu
O
Szöllosi
János
J
Nagy
Peter
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D066246:ErbB Receptors; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D020890:Neuregulin-1 / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C413364:ERBIN protein, human; C485206:pertuzumab