Functional organization of extracellular hyaluronan, CD44, and RHAMM

The integral membrane protein CD44 is constitutively expressed in most tissues, and is the primary cell surface receptor for hyaluronan (HA). HA is the key scaffolding organizer of proteoglycans and receptors in the extracellular matrix. CD44 is expressed as cell type‐specific and context‐specific alternatively spliced isoforms with variable glycosylation and interreceptor interactions. CD44 plays a critical role in the organization and patterning of domains in the cell membrane, achieved through linking the cortical actin cytoskeleton with the pericellular HA matrix. This functional and spatial organization of CD44 and HA maintains a protective and homeostatic cellular microenvironment. Tissue injury and cellular stress result in HA fragmentation and unconventional export of the CD44 coreceptor, RHAMM, which collectively alter the homeostatic organization of CD44/HA. The resulting interplay among HA, HA fragments, CD44 and RHAMM triggers cellular responses such as cell motility that contribute to tissue repair, and disease processes. Here we review current understanding of the structural biology of HA, CD44, and RHAMM, and provide an overview of their known functional organization and patterning at the cell surface. Changes in their surface organization act as sensors for detecting danger, and are critical to the understanding of consequent intracellular signaling and response mechanisms to cellular stress.