In Search of the Carbohydrate Structures on CD44 Critical for Hyaluronic Acid Binding-Roles of Sialylation and Sulfation

CD44 is a transmembrane adhesion molecule involved in cell-cell and cell-extracellular matrix interactions. It contains a functional hyaluronic acid-binding domain and serves as a major cell surface receptor for hyaluronic acid. It mediates recruitment of various types of cells and their motility in interstitial tissues of numerous organs. Cell adhesion mediated by CD44 has generally been assumed to enhance inflammatory response and cancer progression. Recent findings using CD44-deficient mice indicated that CD44 may not be an indispensable molecule for embryonic development and maintenance of life, but it remains clear that CD44 plays an important role in many pathological processes through its binding activity to hyaluronic acid. Glycosylation of CD44 is known to have a prominent effect on its hyaluronic acid binding activity. Usually CD44 expressed at the cell surface does not constitutively bind hyaluronic acid, and some activation process is necessary to attain effective hyaluronic acid binding. Recent findings indicated that specific changes in glycosylation of CD44 induced in stimulated cells play an essential role in the activation of hyaluronic acid binding. Two kinds of specific changes in its carbohydrate side chains were identified to be induced in stimulated cells, and figure heavily in the activation of hyaluronic acid binding; one is desialylation by an endogenous sialidase, and the other is enhancement of 6-sulfation in glycans carried by CD44.