CD44 is encoded by a single gene, but multiple isoforms of CD44 are generated by alternative RNA splicing. The gene for CD44 contains 20 exons, 12 of which are expressed by the most common form of CD44, referred to as standard or hematopoietic CD44. The nonvariant exons encode for an extracellular domain, a transmembrane domain, and an intracellular domain. Isoforms of CD44 are generated by the insertion of alternative exons (V1–V11) at a single site within the membrane-proximal portion of the extracellular domain (for reviews see Naor et al., 1997
; Ponta et al., 2003
). The predominant 72–amino acid cytoplasmic domain can also be replaced by an alternatively spliced shorter form. Differential posttranslational modifications, including glycosylation and the attachment of glycosaminoglycans, generate additional structural diversity of CD44.
The regulation of the affinity of cell adhesion molecules is prerequisite for regulating cell–cell and cell–matrix interactions mediated by broadly expressed receptors that are exposed continuously to their ligands. Most primary cells express CD44 but in a low affinity state that does not exhibit a capacity to bind to HA. Cellular activation can induce a transition of CD44 to a high affinity state that mediates binding to HA. Transition from the “inactive” low affinity state to the “active” high affinity state of CD44 on leukocytes can be induced by the ligation of antigen receptors, and on leukocytes and epithelial and other mesenchymal cells by soluble factors including cytokines (Levesque et al., 1997
; Cichy and Puré, 2000
; Brown et al., 2001
). A variety of mechanisms have been implicated in the transition from inactive to active forms of CD44, including variant exon usage, receptor oligomerization, glycosylation, and sulfation (for review see Ponta et al., 2003
). However, to date, no data are available to indicate how these posttranslational modifications alter either the configuration of the receptor, its three-dimensional structure, or its molecular interactions with other moieties to modify the affinity of the receptor for HA. Functional activation of CD44, as opposed to regulation of receptor solely at the level of transcription, presumably provides for more efficient recruitment of CD44–HA interactions in mediating cell–cell and cell–matrix interactions as required, for example, after exposure to an inflammatory stimulus. In contrast to normal primary cells, many tumor-derived cells express CD44 in a high affinity state with capacity to mediate constitutive binding to HA (for review see Naor et al., 1997
). In addition to being a receptor for HA, CD44 can interact with several ECM proteins, such as fibronectin and collagens, growth factors, cytokines and chemokines, as well as metalloproteinases (for reviews see Naor et al., 1997
; Ponta et al., 2003
), but less is known about the regulation of the interactions of these ligands with CD44.
Transmembrane CD44 serves multiple roles, including mediating the metabolism of HA (Kaya et al., 1997
), in the regulation of tumor invasiveness and in the modulation of inflammatory cell function. Alterations in CD44 expression and structure have been documented in many types of cancer and are related to tumor dissemination (for reviews see Naor et al., 1997
; Ponta et al., 2003
). Moreover, targeted deletion of CD44 prevented dissemination of some tumors (Weber et al., 2002
). Most of the known effects of CD44 on cell adhesion, migration, and metastasis are intimately associated with its capacity to promote cell attachment to HA (for review see Naor et al., 1997
). Recent findings suggest that CD44 might also promote metastasis through its association with other molecules. For example, CD44 provides a docking site for MMP-9 on the surface of melanoma and carcinoma cells (Yu and Stamenkovic, 1999
) and thus can indirectly contribute to pericellular proteolysis to regulate tumor cell motility, growth factor activation, angiogenesis, as well as survival mechanisms. Furthermore, it was recently demonstrated that CD44-mediated localization of MMP-9 to the surface of some tumor cell lines results in the activation of TGF-β and promotion of tumor invasion and angiogenesis (Yu and Stamenkovic, 2000
). Interestingly, increased levels of soluble CD44 (sCD44) have been detected in plasma from patients with some tumors (Okamoto et al., 2002
). This may reflect the increase in proteolytic activity and matrix remodeling that is associated with tumor growth and metastasis.
CD44 does not appear to play a critical role in the immune system under homeostatic conditions. However, inflammation is associated with increased expression of cell surface CD44 on hematopoietic cells. Activation of T cells augments CD44-mediated HA binding and contributes to targeting of T cells to inflammatory sites (DeGrendele et al., 1997
). Based on the detection of elevated numbers of circulating T cells expressing activated CD44 in conditions of chronic inflammation, it has been suggested that functional activation of CD44 on lymphocytes may contribute to chronic inflammatory diseases (Estess et al., 1998
). A critical role for CD44 in inflammation is supported by studies using anti-CD44 antibodies and CD44-deficient mice. Administration of anti-CD44 antibodies to mice retarded cutaneous delayed-type hypersensitivity (Camp et al., 1993
) and protected mice against experimental arthritis (Mikecz et al., 1995
). In addition, anti-CD44 antibodies protected mice from the pathology associated with acute infection with Toxoplasma gondii
(Blass et al., 2001
). Although minimal defects were noted in unchallenged CD44-deficient animals (Schmits et al., 1997
), inflammatory responses in CD44-deficient mice are significantly altered compared with wild-type mice. For example, the extent of atherosclerotic lesions in hypercholesterolemic (apolipoprotein E–deficient, apoE−/−
) mice that were also deficient in CD44 was markedly reduced when compared with apoE−/−
mice expressing CD44 (Cuff et al., 2001
). Reduced atherogenesis was associated with the inhibition of macrophage recruitment and inhibition of macrophage and vascular smooth muscle cell activation in atherosclerotic lesions. Furthermore, the deletion of one particular isoform, CD44v7, protected against experimental colitis (Wittig et al., 2000
). Targeted disruption of CD44, in contrast, resulted in impaired resolution of the inflammatory response after bleomycin-induced lung injury, resulting in death (Teder et al., 2002
). CD44 deficiency under these conditions resulted in excessive accumulation of HA in bronchoalveolar lavage fluid, impaired clearance of apoptotic neutrophils, and a defect in TGF-β activation. Together, these data suggest that CD44 is pivotal to the progression of inflammation and fibrosis.