Interaction between CD44 and the cytoskeleton

CD44 isoforms belong to a family of glycoproteins known to comprise a variable extracellular domain, a single spanning 23 amino acid transmembrane domain and a 70 amino acid cytoplasmic domain. These molecules are expressed in a wide variety of tissues and cells. In humans CD44 is encoded by a single gene on chromosome lip which contains 19 exons. Most often, alternative splicing occurs between exons 5 and 15, leading to an insertion in tandem of one or more variant exons (vl-vlO, or exons 6 through exons 14 in human cells) within the membrane proximal region of the extracellular domain. The variable primary amino acid sequence of different CD44 isoforms is further modified by-extensive N- and O-glycosylations and glycoamino-glycan (GAG) additions. CD44 isoform expression has been shown to be closely correlated with malignancy of lymphoid cells.

The most common hematopoietic form, CD44s (CD44 standard form), contains exons 1-4 (N-ter-minal 150 amino acids - extracellular domain), exons 5, 15 and 16 (membrane proximal 85 amino acids), exon 17 (transmembrane domain), and a portion of exons 17 and 19 (C-terminal 70 amino acids - cytoplasmic domain). The extracellular domain of CD44s binds specifically to certain extracellular matrix (ECM) molecules such as hyaluronic acid (HA) - the major extracellular glycosaminogly-can found in mammalian ECM. CD44s-HA interaction has been shown to induce intracellular signal transduction events, cell aggregation, cell proliferation, cell migration and cell adhesion. The cytoplasmic domain of CD44s (approximately 70 amino acids long) is conserved in most of the CD44 isoforms and is clearly involved in the binding of cytoskeletal proteins such as ankyrin. The ankyrin binding site(s) is expressed at a very early stage in the biosynthesis of CD44. Furthermore, the binding interaction between CD44 and ankyrin is highly specific and regulated by several factors including protein kinase C-mediated phosphorylation, palmityol-ation and GTP binding. The fact that ankyrin preferentially accumulates underneath lymphocyte CD44 capped structures suggests that the formation of an ankyrin-CD44 complex is related to ligand-induced lymphocyte activation.

Furthermore, the ankyrin-binding domain of murine and human CD44 has been mapped using deletion mutation analyses followed by expressing in the eukaryotic cell systems. The results of these experiments indicate that the ankyrin-binding domain resides in the cytoplasmic domain of CD44 (i.e. amino acids 306-320 in mouse CD44, and amino acids 304-318 in human). Most importantly, CD44's ankyrin-binding domain is required for HA-mediated binding, cell adhesion and signal transduction.

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