Figure 1. Regulation of signaling cascades by hyaluronan-CD44 interaction.

Hyaluronan synthases produce and extrude hyaluronan, which may be retained by the synthase or released into the pericellular milieu. The extruded hyaluronan interacts multivalently with CD44 to induce and/or stabilize signaling domains within the plasma membrane. These signaling domains contain receptor tyrosine kinases (ErbB2 and EGFR), other signaling receptors (TGFβR1) and non-receptor kinases (Src family) that drive oncogenic pathways, e.g. the MAP kinase and PI3 kinase/Akt cell proliferation and survival pathways, as well as various transporters that participate in drug resistance and malignant cell properties (15, 34). Various adaptor proteins such as Vav2, Grb2 and Gab-1 mediate interaction of CD44 with upstream effectors, e.g. RhoA, Rac1 and Ras, that drive these pathways (11, 34). In other cases carbohydrate side groups on variant regions of CD44, e.g. heparan sulfate chains, bind regulatory factors and co-activate receptor tyrosine kinases, e.g. the c-Met receptor (31). Hyaluronan-CD44 interactions also induce cytoskeletal changes that promote cell motility and invasion. In this case actin filaments are joined to the cytoplasmic tail of CD44 via members of the ezrin-radixin-moiesin (ERM) family or ankyrin (11, 31). Proteoglycans and associated factors attached to pericellular hyaluronan may also influence these activities (13, 23). This diagram emphasizes cell autonomous activities influenced by hyaluronan produced by tumor cells. Hyaluronan produced by stromal cells may have overlapping or different activities but the relative contributions of stromal and tumor-derived hyaluronan are not yet clear (6).