Signaling Properties of Hyaluronan Receptors*

In 1979, hyaluronan was demonstrated to bind specifically and with high affinity to intact cells (1), and in 1980, it was shown to enhance cell motility on two-dimensional culture surfaces where the hydrodynamic properties of hyaluronan were not necessary to open spaces for cells to move into (2). These two demonstrations raised the possibility that hyaluronan had the potential to directly modify cell behavior. In 1989, hyaluronan was shown to promote protein tyrosine phosphorylation cascades (3) that were later proven to be required for hyaluronan-mediated motility on planar culture surfaces (4). Since then, small amounts (nanograms) of hyaluronan have been shown to activate a variety of protein tyro- sine and serine/threonine kinases. These include the non-receptor protein tyrosine kinase Src (5, 6), HER2/Neu receptor (7), focal adhesion kinase (4, 8–10), protein kinase C (11, 12), and MAP 1 kinases (9, 10). Likely as a consequence of regulating these kinases, hyaluronan promotes expression of specific cytokines and proteins involved in extracellular matrix remodeling ( e.g. Ref. 13). The study of murine cardiac cells derived from hyaluronan synthase 2 (HAS2) knockout mice has provided the most convincing evidence for a signaling capability of hyaluronan (14). HAS2 (cid:1) / cardiac cells do not undergo an endothelial-mesenchymal transfor-