Molecular mechanisms of action of CD44 in Wnt signaling

• Applicant: Professorin Dr. Véronique Orian-Rousseau
• Subject Area: Cell Biology ; Developmental Biology
• Term: from 2012 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233546300

Wnt signaling is essential for embryonic development and tissue homeostasis in the adult organism and deregulation of Wnt signaling is involved in several human diseases including cancer. While a considerable amount of data has been generated on the regulation of the Wnt pathway, the control of receptor activation processes at the membrane of receiving cells is still not fully understood. The CD44 transmembrane glycoproteins mediate a variety of (patho)physiological functions not only by binding to their specific ligand but also via interaction with other signaling molecules. We have recently identified a novel pathway where CD44 regulates Wnt/b-catenin signaling through association with LRP6. To exert its function CD44 requires a cytoplasmic partner of the ERM (Ezrin-Radixin-Moesin) family of proteins that links CD44 to the cytoskeleton. CD44 controls both the targeting of LRP6 to the membrane and the Wnt-dependent phosphorylation of LRP6 at the membrane. Clustering of Wnt-Fz-LRP6 complexes at the membrane into so-called LRP6 signalosomes is essential for activation of the Wnt pathway and b-catenin stabilization. In the present application, we will study the recruitment of CD44 to the LRP6 signalosome complex and its impact on LRP6 activation. The project will also concentrate on the role of CD44 in targeting LRP6 to the membrane. The CD44/LRP6 interactions will be characterized by means of advanced imaging techniques such as fluorescence correlation spectroscopy. Moreover, preliminary data indicate a possible involvement of CD44 in Ror2 activation. Therefore, another part of the project will focus on the CD44-Ror2 interplay in b-catenin independent Wnt signaling. The relevance of our findings will be tested in several model organisms including Xenopus, zebrafish and mouse. In mice we will use Cd44 floxed strains that allow the conditional inactivation of CD44 in target tissues at will. In addition, the contribution of CD44v6 to the Wnt-driven colorectal cancer will be examined in several derivative lines of the ApcMin/+ mice using an inhibitory CD44v6 peptide. The overarching aim is to understand the molecular functions of CD44 in Wnt signaling in order to manipulate the CD44-Wnt interactions thereby controlling Wnt-dependent cellular functions.

• DFG Programme: Research Grants