Cooperativity between Cell Adhesion Molecules and Receptor Tyrosine Kinases in tumor progression and in development

Research Topics

Collaboration between RTKs and CAMs in tumor progression

Cell surface receptors such as Receptor Tyrosine Kinases (RTKs), the main recipients of extracellular signals, regulate cell fate by transducing signals to the nucleus. A question that remains unsolved is what decides for the specificity of signaling in time and in space. The idea that the receptor-ligand complex is the decisive unit turned out to be too simplistic. We have shown that in the case of the c-Met RTK, not only is HGF (Hepatocyte Growth Factor), the authentic c-Met ligand, required for its activation and subsequent signaling but also another cell surface molecule, a cell adhesion molecule (CAMs), CD44v6. More and more evidences show that also other RTKs recruit CAMs in order to fulfill their function.

CD44 is a family of transmembrane glycoproteins in which the members differ in the extracellular domain. In this domain, insertion of various combinations of 10 variant exons by alternative splicing can occur. CD44v6 is one member of this huge family of proteins. Our interest in CD44 originates from the observation that CD44v6 containing isoforms are involved in the metastatic process. We suspect that the role of CD44v6 in tumorigenesis is due to its collaboration with the c-Met RTK. The function of CD44v6 for c-Met is two-fold. The extracellular domain of CD44 promotes the RTK activation by establishing a ternary complex containing the ligand, the RTK and the CAM (see Figure 1). The CD44 cytoplasmic tail is then required for the signal transfer from the activated receptor that finally results in changes in the genetic program triggering proliferation, migration or apoptosis dependent on the cellular constituents. For the signal transfer the cytoplasmic tail of CD44 associates with proteins that mediate binding of the cytoskeleton to the membrane to recruit a signalosome complex (see Figure 1). One such protein is ezrin, a member of the ERM family of proteins. These experiments unravel a decisive role of the cytoskeleton in signal transduction that had been postulated by many laboratories before.

We have produced CD44v6 peptides that block c-Met activation in vitro and in vivo and study the effects of these peptides in several xenograft and orthotopic models. CD44v6 also acts as a co-receptor for other RTKs than c-Met. Particularly interesting is the collaboration of CD44v6 with VEGFR-2, the main RTK triggering new blood vessel formation, indicating a role of CD44v6 in angiogenesis. Therefore, the effect of the CD44v6 peptides is currently being tested on several angiogenic systems.

Internalization of the c-Met RTK and its co-receptor CD44v6

Activation of RTKs has to be tightly regulated. Once they get activated, the receptors are very quickly internalized in the cells where they traffic to various intracellular compartments. The internalization can lead to extended signaling or to receptor inactivation. The regulation of c-Met internalization and trafficking and the role of CD44v6 in these processes is a major topic in our group.

Role of CD44 in development

Another topic is the study of the relevance of CD44 and its interaction with c-Met in vivo. CD44 proteins appear to play essential roles in a variety of physiological processes, including tissue development, neuronal axon guidance, hematopoiesis and numerous immune functions. Furthermore, the identification of its co-receptor function for Met suggested further importance of CD44 during embryonal development and in the adult organism. It was therefore surprising that in contrast to Met, CD44 knockout mice were viable (see Figure 2). As a possible interpretation we assume that in the CD44 knockout mice functions of CD44 proteins are substituted by other proteins. In agreement with this assumption, we identified a protein that overtakes the function of CD44 in the CD44 knockout mice. Furthermore we have now produced mice containing CD44 sequences flanked by loxP sites that will allow us to inactivate CD44 in a time and tissue-specific manner. These analyses will help us to test whether there exists a time-window when CD44 can be substituted during embryogenesis and whether inactivation of CD44 in different tissues will give a phenotype.

_{Updated: October 5, 2009}