CD44 IN INFLAMMATION AND METASTASIS

CD44 is a major cell surface receptor for the glycosaminoglycan, hyalu ronan (HA). CD44 binds HA specifically, although certain chondroitin-s ulfate containing proteoglycans may also be recognized. CD44 binding o f HA is regulated by the cells in which it is expressed. Thus, CD44 ex pression alone does not correlate with HA binding activity. CD44 is su bject to a wide array of post-translational carbohydrate modifications , including N-linked, O-linked and glycosaminoglycan side chain additi ons. These modifications, which differ in different cell types and cel l activation states, can have profound effects on HA binding function and are the main mechanism of regulating CD44 function that has been d escribed to date. Some glycosaminoglycan modifications also affect lig and binding specificity, allowing CD44 to interact with proteins of th e extracellular matrix, such as fibronectin and collagen, and to seque ster heparin binding growth factors. It is not yet established whether the HA binding function of CD44 is responsible for its proposed invol vement in inflammation. It has been shown, however, that CD44/HA inter actions can mediate leukocyte rolling on endothelial and tissue substr ates and that CD44-mediated recognition of HA can contribute to leukoc yte activation. Changes in CD44 expression (mainly up-regulation, occa sionally down-regulation, and frequently alteration in the pattern of isoforms expressed) are associated with a wide Variety of cancers and the degree to which they spread; however, in other cancers, the CD44 p attern remains unchanged. Increased expression of CD44 is associated w ith increased binding to HA and increased metastatic potential in some experimental tumor systems; however, in other systems increased HA bi nding and metastatic potential are not correlated. CD44 may contribute to malignancy through changes in the regulation of HA recognition, th e recognition of new ligands and/or other new biological functions of CD44 that remain to be discovered.