A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor (original) (raw)

2003, Journal of Clinical Investigation

Introduction CD44 is a cell surface glycoprotein involved in multiple cellular functions, including cell matrix interactions, cell migration, programmed cell death (apoptosis), or, conversely, cell survival and proliferation. Additionally, CD44 isoforms were shown to exert some of their functions through docking and presentation of cytokines, chemokines, growth factors, and enzymes to their relevant cell surface receptors or substrates (1, 2). Hyaluronic acid is the principal ligand of CD44 (3), but other cell surface or ECM components, such as osteopontin, fibrinogen, fibronectin, collagen, and laminin, can interact with this glycoprotein, as well (1). This multifunctionality of CD44 is possible due to the tremendous structural variability of this receptor, derived from its highly complex genetic construction. Theoretically, hundreds of CD44 isoforms can be generated by alternative splicing (4) of ten (mouse) or nine (human) variant exons, designated v1 to v10, inserted in different combinations between the two constant regions consisting of five exons at one end of the molecule and four at the other (1-3). The number of CD44 variants (CD44v) identified so far, however, is limited to a few dozen, detected mostly on epithelial cells, keratinocytes, activated leukocytes, and many types of tumor cells (2). Direct splicing of constant exon 5 to constant exon 16 (thereby skipping all the variant exons) generates the standard CD44 (CD44s), ubiquitously expressed on mesenchymal cells and on all types of hematopoietic cells (1-3). While alternative splicing is a most efficient means of enriching the genetic information stored in a single gene, posttranslational modifications by glycosylation and glycosaminoglycan (GAG) attachments further modify the CD44 protein, allowing greater expansion of its variability and functions (1-3). Indeed, it has been found that heparan sulfate (HS) attached to the v3 exon of v3-containing