Chapter 4 Adhesion Proteins Meet Receptors

Receptors tyrosine kinases (RTKs) and cell adhesion molecules (CAMs) present on the cell surface sense the surrounding environment and influence the fate of cells. For a long time, it was believed that these molecules were working independently and that the sole binding of a ligand was enough to activate the RTK. It is now apparent that there is, in fact, a very tight connection between RTKs and CAMs and that they work in concert. The CAMs influence the activation, the signaling, or the internalization of the RTKs. Some CAMs have similar functions and are therefore interchangeable. CD44 isoforms exemplify the flexibility of these interactions as they can collaborate with several RTKs and can also be substituted by other CAMs with similar functions. In several instances, CAMs not only control the activation of the receptor by presenting the ligand but also regulate the downstream signaling by organizing a signalosome complex. Furthermore, the functions of the CAMs can be controlled by the cellular environment and the binding to their ligands.

Introduction

Receptors present on the cell surface, such as receptor tyrosine kinases (RTKs), enable the cells to communicate with their environment and to transfer signals to the intracellular machinery. They recognize signals that regulate proliferation, migration, differentiation, or apoptosis, nearly all functions that are required in a “living cell.” The recognition signal is, in most instances, a ligand that binds to the receptor and leads to its activation. In the case of RTKs, ligand binding often induces dimerization and transphosphorylation of the cytoplasmic tail, including the tyrosine kinase domain. The phosphorylated tyrosines then act as docking sites for a number of signaling molecules (reviewed in Schlessinger, 2000).

This assumption, that the binding of the ligand is the only trigger for receptor activation turned out, at least in several instances, to be too simplistic. A considerable contribution to the activation process comes from cell adhesion molecules (CAMs) that act as coreceptors. The functions that are provided by CAMs are very diverse and span from the presentation of the ligand, the prevention or the induction of internalization to the induction, or amplification of signaling. The collaboration with CAMs contributes to broaden the diversity of the responses that can be achieved by the receptors. The purpose of this chapter is to give an updated picture of several collaborations between CAMs and RTKs. A schematic representation of these interactions is given in Fig. 1.

The first RTKs that have been shown to be dependent on molecules other than their ligands were members of the fibroblast growth factor receptor (FGFR) family. The ligands for FGFRs belong to a family that includes 22 members (Ornitz and Itoh, 2001). FGFs can only activate FGFRs in the presence of additional molecules, either proteins that are modified by heparan sulfate (heparan sulfate proteoglycans, HSPGs) or even the sugar moiety, heparin, alone. Additional “heparin dependent” growth factors such as vascular endothelial growth factor (VEGF), heparin‐binding epidermal growth factor (HB‐EGF), and hepatocyte growth factor (HGF) were also identified.

The notion of “heparin dependency” came from the observation that cells defective in the synthesis of heparan sulfate (HS) were impaired in their signaling response to the respective growth factors. Moreover, signaling was restored by providing an exogenous source of heparin‐like polysaccharides. This addition leads to high affinity binding of the growth factors to the RTKs and, as demonstrated first for FGFs, to biological effects such as cell differentiation and proliferation (Rapraeger et al., 1991, Yayon et al., 1991).

Crystal structure analysis revealed that FGF, FGFR, and heparin form a ternary complex that might fit to two models: an asymmetric model in which the complex is composed of FGFs, FGFRs, and heparin in a ratio of 2:2:1 (Pellegrini et al., 2000) or even 4:4:1 (Harmer et al., 2006) and a symmetric model where two molecules of each are included in a complex (Schlessinger et al., 2000). Further studies are required to elucidate whether these different complexes are species specific and/or whether they have different functions.

Signaling by heparin‐dependent growth factors can also be promoted by cell surface proteoglycans of the glypican or syndecan family (Steinfeld et al., 1996). Glypicans and syndecans are the two main families of cell surface HSPGs. Glypicans comprise six members in vertebrates. They are GPI (glycophosphatidylinositol)‐anchored membrane proteins that play decisive roles in embryonic development where they are important for the formation of developmental gradients. Although there is ample evidence that they trigger growth factor activation, these data are indirect and the precise mechanism of action is still lacking (reviewed in Song and Filmus, 2002).