Mini-Review |
Address correspondence to Joanna Cichy, Jagiellonian University, Faculty of Biotechnology, ul. Gronostajowa 7, 30-387 Kraków, Poland. Tel.: 48-12-252 6135. Fax: 48-12-252 6902. E-mail: Cichy{at}mol.uj.edu.pl; or Ellen Puré, The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104. Tel.: (215) 898-1570. Fax: (215) 898-3937. E-mail: Pure{at}wistar.upenn.edu
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Abstract |
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Key Words: CD44; proteolytic processing; extracellular matrix; cell adhesion; presenilin
Cell surface adhesion receptors anchor cells to their surroundings, regulate cell mobility, and provide cells with critical sensors of their environment. Cell adhesion molecules are subject to regulation at multiple levels, including transcription, alternative RNA splicing, and posttranslational modifications such as phosphorylation, glycosylation, and sulfation. Proteolytic processing has also emerged as a key mechanism underlying the regulation of several cell surface adhesion molecules, including members of the selectin and cadherin families.
CD44 is a broadly distributed transmembrane glycoprotein that plays a critical role in a variety of cellular behaviors, including adhesion, migration, invasion, and survival. CD44 mediates cellcell and cellmatrix interactions in a large part through its affinity for hyaluronan (HA),* a glycosaminoglycan constituent of extracellular matrices, but also potentially through its affinity for other ligands such as osteopontin, collagens, and matrix metalloproteinases (MMPs). A soluble form of CD44 has been detected in the circulation and other body fluids. In this review, we focus on the mounting evidence that limited proteolysis liberates functional fragments of both the cytoplasmic (intracellular) domain as well as the extracellular domain of CD44. Furthermore, we review recent evidence that CD44 released from cells can accumulate as an integral component of cell-associated matrices. We also address the issue of the derivation of soluble CD44 that accumulates in the fluid phase under pathologic conditions that are associated with increased proteolytic activity and matrix remodeling. Based on current evidence, we propose that CD44 can exist in three distinct physical phases, as a transmembrane cell surface receptor, an integral component of the matrix, and in a fluid phase, each with the potential for being functionally significant (Table I).
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Structure and function of transmembrane CD44 |
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The regulation of the affinity of cell adhesion molecules is prerequisite for regulating cellcell and cellmatrix 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 CD44HA interactions in mediating cellcell and cellmatrix 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-ß 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 Edeficient, 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-ß activation. Together, these data suggest that CD44 is pivotal to the progression of inflammation and fibrosis.
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Potential mechanisms for shedding of CD44 from the cell surface |
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Endogenous metalloproteinases and serine proteinases have been implicated in the shedding of CD44 based on abrogation of its release by selective pharmacologic inhibitors. In contrast, selective inhibition of serine proteinases in some cell systems augments the release of CD44, suggesting that serine proteinases may control the activity of another class of enzymes involved in the processing of CD44 (Okamoto et al., 1999). Cell surface localization as well as activation and inhibition profiles suggest that the ADAM (a disintegrin and metalloprotease) family of enzymes may be involved in CD44 shedding, but at least one particular ADAM family member, TACE (TNF- converting enzyme), has been excluded as playing a role in the processing of CD44 (Shi et al., 2001). Membrane type 1 and membrane type 3 metalloproteinases (MT1-MMP and MT3-MMP, respectively), on the other hand, have been shown to be capable of mediating the processing for CD44. Coexpression of CD44 and either MT1-MMP or MT3-MMP, but not MT2-, MT4-, and MT5-MMPs, resulted in shedding of CD44 in human breast carcinoma cells (Kajita et al., 2001).
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Consequences of the release of CD44 from the cell surface |
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CD44 accumulates as an integral component of the matrix |
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Proteolysis liberates the intracellular cytoplasmic domain of CD44 from the membrane |
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Concluding remarks |
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Acknowledgments |
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Submitted: 18 February 2003
Revised: 7 April 2003
Accepted: 10 April 2003
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References |
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