Group Leader: Véronique Orian-Rousseau
tel.: +49 721 608 26523
Cell Adhesion Molecules (CAMs) located at the cell surface, mediate cell-cell and cell-to-extracellular matrix contacts. Since they are connected to the major signaling pathways they can induce signaling in response to the microenvironment. Such a CAM is CD44, a family of transmembrane glycoproteins that mediates proliferation, differentiation, migration and survival. The members of the CD44 family differ in the extracellular domain where ten variant exons are subjected to alternative splicing.
We have discovered that CD44v6 acts as a co-receptor for various receptor tyrosine kinases (RTKs) amongst which VEGFR2 and Met, two major RTKs that are instrumental for angiogenesis and metastasis.
The role of CD44v6 for these RTKs is two-fold: The ectodomain of CD44v6 is involved in RTK activation and the cytoplasmic domain promotes signaling upon binding to the cytoskeleton through ERM (Ezrin-Radixin-Moesin) proteins. CD44v6 colocalizes with Met in internal compartments upon induction with HGF. These data suggest that collaboration between CD44v6 and Met is also required for Met signaling from endosomal compartments. CD44v6 takes part in tumor progression and metastasis through its interaction with RTKs. During development collaboration between CD44v6 and Met was shown upon crossing of Cd44 germline knock out mice with Met+/- mice. Cd44-/-;Met+/- mice die after birth from impaired synaptic transmission in the respiratory rhythm generating system and from alterations in the phrenic nerve. These data indicate that met is haploinsufficient in a cd44 null context and that CD44 and Met collaborate in vivo.
CD44 isoforms also collaborate with other cell surface receptors. Indeed, hyaluronan (HA), the main ligand for CD44 augments CXCL12-induced CXCR4 signaling, a step that is required during angiogenesis. In contrast small HA fragments (sHA) exert the opposite effect.
The functions of CD44 and other CAMs such as ICAM-1 are studied in development and tumor progression.
The themes developed in the group are:
- Mutational analysis of the Cd44 exon v6 identified 3 amino acids that are essential for Met and VEGFR2 activation. A peptide covering these three amino acids (v6 pep) blocks the activation of these RTKs. We currently develop the CD44v6 peptide and modified peptides as a drug against pancreatic cancer and several other types of cancers.
- The co-receptor function of CD44v6 for Met and VEGFR2 is further analyzed in angiogenesis, metastasis and the in establishment of a favorable metastatic niche. The molecular mechanism of action of CD44v6 in the activation and signaling of RTKS is dissected.
- We discovered a ligand specific recruitment of CD44 isoforms for members of the EGFR family of RTKs, an aspect that we study in mammary gland development and breast cancer.
- The role of CD44 and HA in chemokine signaling is studied in angiogenesis and in homing of hematopoietic stem cells. Analysis of the bone marrow niche will be performed using artificial niches in an interdisciplinary approach and taking advantage of the Cd44 floxed mice.
- We have established a Cd44 floxed and a Cd44v6 floxed mouse and study the role of CD44 in development upon conditional activation of Cd44 in liver, intestine, breast and skin.
- The mechanism of action of CD44 in Wnt signaling is under scrutiny as well as the role of CD44 in the development of the intestine and colorectal cancer.
Updated: February 18, 2014