RECEPTORS - REGULATORS OF SIGNALING TO THE CYTOSKELETON

Hyaluronan (HA) is a ubiquitous component of the extracellular matrix (ECM) and occurs transiently in both the cell nucleus and cytoplasm. I t has been shown to promote cell motility, adhesion, and proliferation and thus it has an important role in such processes as morphogenesis, wound repair, inflammation, and metastasis. These processes require m assive cell movement and tissue reorganization and are always accompan ied by elevated levels of HA. Many of the effects of HA are mediated t hrough cell surface receptors, three of which have been molecularly ch aracterized, namely CD44, RHAMM, and ICAM-1. Binding of the HA ligand to its receptors triggers signal transduction events which, in concert with other ECM and cytoskeletal components, can direct cell trafficki ng during physiological and pathological events. The HA mediated signa ls are transmitted, at least in part, by the activation of protein pho sphorylation cascades, cytokine release, and the stimulation of cell c ycle proteins. A variety of extracellular signals regulate the express ion of both HA and the receptors necessitating that HA-receptor signal ling is a tightly controlled process. Regulated production of soluble forms of the receptors, alternately spliced cell surface isoforms, and glycosylation variants of these receptors can dramatically modulate H A binding, ligand specificity, and stimulation of the signalling pathw ay. When these processes are deregulated cell behaviour becomes uncont rolled leading to developmental abnormalities, abnormal physiological responses, and tumorigenesis. The elucidation of the molecular mechani sms regulating HA-mediated events will not only contribute greatly to our understanding of a variety of disease processes but will also offe r many new avenues of therapeutic intervention. (C) 1996 Wiley-Liss, I nc.