Signal transduction via CD44: Role of plasma membrane microdomains

CD44 is the principal cell surface receptor for extracellular matrix glycos aminoglycan hyaluronan. CD44-hyaluronan mediated cell adhesion is important in several pathophysiological processes such as inflammation and metastati c spread of cancer cells, It has been recently recognized that CD44 also fu nctions as a signaling receptor in a variety of cell types. Cell stimulatio n by monoclonal anti-CD44 antibody or natural CD-44 ligands activate severa l signaling pathways that culminate in cell proliferation, cytokine secreti on, chemokine gene expression and cytolytic effector functions. One of the earliest signaling events following stimulation via CD44 is tyrosine phosph orylation of intracellular proteins substrates, and CD44 mediated cellular activation could be abolished by protein tyrosine kinase (PTK) inhibitors. The Src-family non-receptor PTKs such as Lck, Fyn, Lyn and Hck were shown t o be coupled to CD44 via sphingolipid-rich microdomains (lipid rafts) of th e plasma membrane. Studies on T cell receptor and IgE receptor mediated sig naling in lymphocytes and mast cells have consolidated the notion that micr odomains consist of signaling platforms where components of multiple signal ing pathways are assembled. Co-isolation of CD44 with microdomains strongly suggests that CD44 generates cellular activation signals utilizing the sig naling machinery of the plasma membrane microdomains.