Members of the CD44 family of transmembrane glycoproteins control cell signaling pathways from numerous cell surface receptors, including receptor tyrosine kinases (RTKs). The decisive factor (ligand, RTKs or both) that controls the recruitment of specific CD44 isoforms is still unknown. We investigated this question by using the EGFR signaling pathway, in which one receptor can be activated by a broad range of ligands. By means of siRNA-mediated downregulation of CD44 expression and blocking experiments, we identified CD44v6 as a co-receptor for EGF- and ER-induced ErbB1 activation and for NRG1-induced ErbB3 and ErbB4 activation. In contrast, TGFα is independent of all CD44 isoforms, even though it addresses the same receptor pairs as EGF. Moreover, the heparin-sulfated CD44v3 isoform is required for HB-EGF-induced EGFR signaling. These data suggest that specific CD44 isoforms are recruited in a ligand-dependent manner as co-receptors in the EGFR signaling pathways and that the specificity is determined by the ligand and not by the receptors themselves. The in vivo relevance of this interplay between CD44 isoforms and EGFR ligands is underlined by the decreased metastatic spreading of mammary carcinomas in mice treated with a CD44v6-specific peptide. Most importantly, we found a clear correlation between the presence of CD44v6/ErbB1 complexes in breast cancer patients and lymph node metastases.
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The authors are very thankful to Selma Huber and the animal facility of the Institute of Toxicology and Genetics for their excellent work and help with the animal experiments. This work was supported by a grant from Mildred Scheel Foundation.
Conflict of interest
These authors disclose the following: V.O.-R. is a co-founder and shareholder of amcure GmbH, which developed a CD44v6 targeting peptide for clinical study. The remaining authors declare that they have no competing interests.
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Morath, I., Jung, C., Lévêque, R. et al. Differential recruitment of CD44 isoforms by ErbB ligands reveals an involvement of CD44 in breast cancer. Oncogene 37, 1472–1484 (2018) doi:10.1038/s41388-017-0030-1
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