Regulation of the Functional Activity and Ligand Binding Specificity of the Adhesion Protein CD44

CD44 is a widely distributed cell surface glycoprotein that has been shown to play an important role in a large number of adhesion-dependent cellular processes including lymphopoiesis and myelopoiesis, lymphocyte recirculation, tumour metastasis, and monocyte/macrophage activation. At present, however, the molecular mechanisms that regulate the functional activity and ligand binding specificity of this important molecule remain poorly defined. In particular, although CD44 has been shown to function as a major cell surface receptor for the glycosaminoglycan hyaluronan, not all CD44-positive cell lines are able to bind this particular ligand. As discussed in this review, several non-mutually exclusive regulatory mechanisms may be involved. Thus alternative splicing may generate a large number of differentially expressed CD44 isoforms with distinct ligand binding specificities. In addition, the functional activity of these various molecules may be further regulated via changes in their conformation and/or glycosylation, or by altering their distribution in the plane of the membrane.