1 The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
2 Cambridge Antibody Technology, Milstein Building, Granta Park, Cambridge, CB1 6GH, UK
* Author for correspondence (e-mail: clare.isacke{at}icr.ac.uk)
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Summary |
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Key words: CD44, Hyaluronan, ERM, Ezrin, Phosphorylation, Proteolytic cleavage
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Introduction |
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For an adhesion receptor to mediate its affects, it must not only bind to its extracellular ligand(s) but must also engage the cytoskeleton and co-ordinate signalling events to enable the cell to respond to changes in the environment. In the case of CD44, depending on the cell type, engagement of hyaluronan can result in cell rolling, cell migration or cell chemotaxis, as well as in hyaluronan internalization or assembly of a hyaluronan-rich pericellular matrix. In turn, these events can modulate cell proliferation, cell survival and differentiation, and remodelling of the extracellular matrix. Moreover, it is clear from these studies that CD44, and in particular the alternatively spliced CD44 isoforms, has roles that are independent of hyaluronan binding. Given this plethora of cell-type-dependent responses, it has proved difficult to define specific pathways downstream of CD44. However, a clearer picture of the mechanism by which CD44 interacts with the intracellular machinery is emerging, and we now have clues as to how these events might underpin aspects of disease progression. Here, we particularly focus on the roles of the transmembrane and cytoplasmic domains in these processes.
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Structure and sequence conservation of CD44 |
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A recent search of the DNA databases revealed CD44 orthologues from eleven mammalian and two avian species, and these share an overall 47-93% amino acid identity relative with the human sequence. The regions sharing most identity are the Link, transmembrane and cytoplasmic domains. Alignment of these sequences shows that the transmembrane domain is essentially invariant. The cytoplasmic domain is also highly conserved except for a small insertion towards the C-terminus in the aves (Fig. 1C). This high degree of sequence conservation predicts that transmembrane and cytoplasmic domains are crucial for CD44 function. Accordingly, several post-translational modification sites and protein interaction domains have been mapped (Fig. 1D). We discuss these below.
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Post-translational modifications of the CD44 transmembrane and cytoplasmic domains |
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Palmitoylation
CD44 is reversibly palmitoylated (Bourguignon et al., 1991; Guo et al., 1994
), the prospective acylation sites being Cys286 and/or Cys295 (Fig. 1D). Clearly defined acylation motifs for integral membrane proteins have not been defined, and the roles of this modification in such proteins also remain unclear (reviewed by Bijlmakers and Marsh, 2003
). In the case of CD44, acylation has been reported to impair anti-CD3-mediated signal transduction in lymphocytes (Guo et al., 1994
) and enhance the association of CD44 with ankyrin (Bourguignon et al., 1991
). Given the location of these cysteine residues in the CD44 sequence, palmitoylation might also play a role in partitioning CD44 into membrane subdomains and/or in regulating its association with ERM proteins.
Modification by proteolytic processing
It has long been recognized that the extracellular domain of CD44 is subject to regulated proteolytic cleavage (reviewed by Cichy and Pure, 2003). CD44 cleavage can be blocked by inhibitors of matrix metalloproteinases (MMPs) and ADAMs (a disintegrin and metalloproteinase) (Bazil and Strominger, 1994
; Okamoto et al., 1999a
; Shi et al., 2001
), and membrane-type (MT1)-MMP and MT3-MMP have been shown to release soluble CD44 (Kajita et al., 2001
; Mori et al., 2002
). However, recent work has revealed that further proteolytic processing occurs within the residual CD44 transmembrane and cytoplasmic domains (Fig. 2). Saya and colleagues demonstrated that CD44 cleavage can generate two cell-associated CD44 species (
25 kDa and
12 kDa) in addition to the secreted extracellular domain fragment (Murakami et al., 2003
; Okamoto et al., 1999a
; Okamoto et al., 2001
; Okamoto et al., 1999b
). The
25 kDa species corresponds to the residual membrane-bound C-terminal fragment (CTF), whereas the major product isolated from the
12 kDa band is a CD44 intracellular domain (ICD) fragment resulting from a cleavage just inside the CD44 transmembrane domain (Okamoto et al., 2001
) (Fig. 1D). Most recently, presenilin-1/
-secretase was shown to mediate this, cleaving after Ala280 and Ile287 in the transmembrane domain (Fig. 1D) (Lammich et al., 2002
; Murakami et al., 2003
). Moreover, the ICD fragment appears to be derived sequentially from the CTF since incubation with membrane-permeable protease inhibitors increased the accumulation of the
25 kDa band and prevented the appearance of the
12 kDa band (Okamoto et al., 2001
).
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The generation of the soluble ICD fragment represents a new example of what has been termed regulated intramembrane proteolysis (RIP) (Brown et al., 2000). Targets of this activity include both Notch and the amyloid precursor protein (APP), and intriguing parallels can be drawn with CD44. Notch and APP are both cleaved by presenilin-1/
-secretase to generate cytoplasmic fragments that can translocate to the nucleus and promote transcription (Cao and Sudhof, 2001
; Steiner and Haass, 2000
). Additionally, APP proteolysis also results in the extracellular release of the Aß peptides that are involved in amyloid plaque generation. Using a dual-epitope-tagged CD44 construct, it was shown that transmembrane cleavage resulted in the secretion of an analogous peptide (Lammich et al., 2002
). The function of this CD44ß-like peptide is not known, but it might promote the clearance of transmembrane domains from the plasma membrane. Significantly, it has been demonstrated that the released CD44-ICD fragment translocates to the nucleus and stimulates transcription via a phorbol ester response element and that one of its target genes is the gene encoding CD44 itself (Okamoto et al., 2001
).
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Functional requirement of the transmembrane and cytoplasmic domains |
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Hyaluronan internalization
Early studies (Culty et al., 1992) demonstrated that, in macrophages, chondrocytes and transformed fibroblasts, CD44 can mediate uptake of hyaluronan and that a significant proportion of the internalized ligand is degraded within the cell. More recently, increasing evidence indicates that CD44-mediated internalization of hyaluronan and its subsequent degradation are physiologically important (reviewed by Knudson et al., 2002
). For example, in transgenic studies where CD44 was downregulated in basal keratinocytes, the resulting skin and corneal lesions were associated with abnormal hyaluronan accumulation (Kaya et al., 1997
; Kaya et al., 1999
). Similarly, decreased CD44 expression correlates with excess hyaluronan accumulation in CD44-null mice in models of lung injury and inflammation (Teder et al., 2002
) and in patients with lichen sclerosus et atrophicus (LSA) (Kaya et al., 2000
), solitary cutaneous myxomas (Calikoglu et al., 2002
) and myxoid dermatofibroma (Calikoglu et al., 2003
).
The mechanism of CD44-hyaluronan internalization is not known but it is clear that the CD44 cytoplasmic domain interacts with components of the cell-trafficking machinery. Within the cytoplasmic domain, a dihydrophobic Leu331/Val332 motif is required for delivery of CD44 to the lateral plasma membrane of polarized epithelial cells (Sheikh and Isacke, 1996) (Fig. 1D). The requirement for a dihydrophobic motif for basolateral targeting has previously been identified in lysosomal integral membrane protein (LIMP)-II, tyrosinase and major histocompatibility complex (MHC) class II invariant chain and, like these, CD44 has an acidic residue in the 4 position relative to the dihydrophobic motif (Heilker et al., 1999
). In these other receptors, this dihydrophobic motif also mediates rapid internalization from the plasma membrane by clathrin-dependent endocytosis. However, CD44 appears to be excluded from clathrin-coated pits (Isacke, 1994
) and internalizes hyaluronan by a non-clathrin, non-caveolae-dependent mechanism, which is followed by CD44 recycling (Tammi et al., 2001
). This suggests that the CD44 cytoplasmic domain contains additional information that prevents recruitment into the coated pits and allows, at least in some cell types, ligand-associated receptor to interact with non-clathrin internalization machinery.
Recent analysis of hyaluronan internalization in primary cultures of articular chondrocytes show that these cells have abundant levels of CD44 transcripts containing exon 19, which results in the expression of the tailless CD44 isoform. Selective downregulation of this isoform results in enhanced hyaluronan internalization and a reduction in the size of the hyaluronan-rich cell-associated matrix, indicating that tailless CD44 acts as a dominant-negative inhibitor of the long-tail isoforms by competing for ligand binding, but lacks the information required for internalization (Jiang et al., 2001).
Interaction with the cytoskeleton
Cell migration, as opposed to cell rolling, requires active rearrangements of the cytoskeleton. In cultured cells, CD44 is strongly localized to the microvilli and regions of actin polymerization, such as membrane ruffles, which suggests that it associates with the actin cytoskeleton. Because the CD44 cytoplasmic domain does not contain any actin-binding sites, this interaction is indirect and mediated by cytoskeleton-associated proteins. The best characterized of these are the ERM proteins and the related protein merlin. These form a subfamily within the band 4.1 superfamily and function as regulatable linkers between transmembrane proteins and the actin cytoskeleton (for reviews, see Bretscher et al., 2002; Gautreau et al., 2002
; Mangeat et al., 1999
; Turunen et al., 1998
). The CD44 binding region for ERM proteins (Legg and Isacke, 1998
; Yonemura et al., 1998
), merlin (Morrison et al., 2001
) and band 4.1 proteins (Yonemura et al., 1998
) consists of two clusters of basic amino acids (292RRRCGQKKK300) next to the CD44 transmembrane domain (Fig. 1D). Additionally, ERM proteins can also interact with similar basic regions in other transmembrane receptors, such as members of the intercellular adhesion molecule (ICAM) family (Heiska et al., 1998
; Helander et al., 1996
; Serrador et al., 1998
), CD43 (leukosialin) (Yonemura et al., 1998
), syndecan-2 (Granes et al., 2000
) and L-selectin (Ivetic et al., 2002
).
Structurally, the ERM proteins consist of a 300 amino acid FERM (band 4.1, ERM) domain present at the N-terminus, which forms a three-lobed cloverleaf structure, followed by an
-helical central region and a C-terminal domain that contains an F-actin-binding site. When the ERM proteins are in their closed, inactive form, the C-terminal domain binds across lobes 2 and 3, blocking both the binding of F-actin to the C-terminal domain and binding of the FERM domain to transmembrane receptors. Activation of ERM proteins is mediated by phosphorylation and binding to membrane phospholipids (for reviews, see Bretscher et al., 2002
; Gautreau et al., 2002
; Mangeat et al., 1999
; Turunen et al., 1998
), and structural studies have demonstrated that phospholipids bind to the basic cleft between lobes 1 and 3, releasing the C-terminal domain (Hamada et al., 2000
; Pearson et al., 2000
). In this open active conformation, the ERM C-terminal domain can associate with actin, whereas transmembrane receptors can bind to a shallow groove in lobe 3 of the FERM domain (Hamada et al., 2003
). Activation of the more distantly related ERM family member merlin is also regulated by phosphorylation, but it is the dephosphorylated form of merlin that binds to CD44. The merlin C-terminal domain lacks an actin-binding site and consequently a CD44-merlin complex cannot associate directly with the cytoskeleton (Morrison et al., 2001
; Ponta et al., 2003
).
This ability of the ERM/merlin proteins to switch between an active and inactive conformation, together with the competition between the ERM proteins and merlin for CD44 binding, provides a mechanism to make and break the CD44-cytoskeletal association. A further level of regulation involves phosphorylation of the CD44 cytoplasmic domain. The PKC-triggered switch from Ser325 phosphorylation to Ser291 phosphorylation (Legg et al., 2002) (Fig. 1D and Fig. 3) results in the dissociation of ezrin. Moreover, phosphorylation at Ser291 is required for directional migration of cells in a phorbol ester gradient (Legg et al., 2002
).
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Given the importance of this phosphorylation switching in CD44-mediated chemotaxis, dephosphorylation of these residues is probably tightly controlled. The phosphatases responsible have not been identified, but the presence of a conserved binding site at the CD44 C-terminus for PDZ (PSD-95/Dlg/ZO-1)-domain-containing proteins (Fig. 1D) is of interest. The four terminal amino acids (KIGV in mammals and KSGV in aves; Fig. 1C) conform to the consensus for binding sites for class I and class II PDZ proteins (Hung and Sheng, 2002). Although no specific interaction has been assigned to this motif in CD44, PDZ-binding sites in other receptors, such as the syndecans, have been shown to interact with PDZ-domain adaptor proteins, which in turn can associate with protein phosphatases (reviewed by Bass and Humphries, 2002
). Deletion of the syndecan-4 C-terminal amino acids produces a receptor that is hyperphosphorylated in resting cells and exhibits impaired dephosphorylation following stimulation with fibroblast growth factor 2 (Horowitz et al., 2002
). How these phosphorylation/dephosphorylation events are regulated in CD44 has yet to be determined but it is clear that hyaluronan, and in particular hyaluronan fragments, are promigratory (for reviews, see Noble, 2002
; Toole et al., 2002
) and that binding to CD44 can stimulate several downstream signalling pathways (see below), including activation of PKC
(Slevin et al., 2002
). Moreover, the ERM proteins themselves act as scaffolding molecules to focus signalling molecules at the cell cortex (Bretscher et al., 2002
). For example, ezrin associates with PKC (Ng et al., 2001
), thereby providing a potential mechanism by which phosphorylation of CD44 and association with the cytoskeleton can be tightly regulated.
Other mechanisms also modulate association of CD44 with the cytoskeleton or promote cytoskeletal rearrangements. For example, it has been reported that CD44 can directly associate with members of the Rho-family GTPases, their exchange factors and adaptor molecules (reviewed by Turley et al., 2002). The nature of these interactions has yet to be established, but association with RhoA can promote the binding of the membrane-cytoskeleton linker protein ankyrin to a specific motif within the CD44 cytoplasmic domain (Fig. 1D) and this plays a role in hyaluronan-dependent cell migration and anchorage-independent growth (Bourguignon et al., 1999
). In addition, the highly conserved transmembrane domain of CD44 (Fig. 1B) is known to partition the receptor into detergent-insoluble glycosphingolipid-enriched plasma membrane domains (lipid rafts) (Neame et al., 1995
; Perschl et al., 1995a
), and this association has been reported to stabilize the interaction of CD44 with the actin cytoskeleton (Oliferenko et al., 1999
). Importantly, there is evidence that the partitioning of CD44 into lipid rafts can be regulated. The proportion of receptor found in these complexes is cell-type dependent (Neame et al., 1995
), and CD44 can be displaced from the rafts by expression of E-cadherin, which results in a consequent downregulation of hyaluronan binding and tumour cell invasion (Xu and Yu, 2003
). It is tempting to speculate that palmitoylation of the CD44 transmembrane and cytoplasmic tail provides a regulatable mechanism for the association with lipid rafts, although this has yet to be determined experimentally.
Coordination of signalling responses
From early studies it was evident that, in addition to its ability to engage the cytoskeleton, CD44 can also transduce intracellular signalling events leading to alterations in gene expression in response to ligand binding or crosslinking with specific antibodies (for reviews, see Ponta et al., 2003; Pure and Cuff, 2001
). Like all of the major classes of adhesion receptor, CD44 lacks intrinsic kinase activity and must therefore associate with other proteins to modulate signalling.
Indeed, many intracellular signalling components form complexes with the CD44 cytoplasmic tail, the most widely reported being Rho-family GTPases and associated molecules (see above) and members of the Src family of non-receptor tyrosine kinases (reviewed by Turley et al., 2002). CD44 co-immunoprecipitates with Src, Lyn, Lck, Fyn and Hck, and antibody-induced activation of CD44, at least in some cell types, stimulates tyrosine phosphorylation of these kinases and their substrates (Bates et al., 2001
; Bourguignon et al., 2001
; Ilangumaran et al., 1998
; Roscic-Mrkic et al., 2003
; Taher et al., 1996
). However, as in the case of Rho-family GTPases and associated components, the mechanism of this interaction with CD44 is not known. Src-family kinases are modified by acylation, and these modifications facilitate their targeting to lipid rafts. CD44 is similarly partitioned by its transmembrane domain (see above). Consequently, these components might not interact directly but might instead be co-immunoprecipitated owing to their co-localization in lipid rafts (Ilangumaran et al., 1998
).
Currently, stronger evidence for a signalling role for CD44 comes from its ability to act as a co-receptor. In this respect, two distinct but somewhat overlapping categories of co-receptor function have been described. First, CD44 can bind growth factors and cytokines (Bennett et al., 1995; Jones et al., 2000
; Roscic-Mrkic et al., 2003
; Sherman et al., 1998
; Tanaka et al., 1993
; Weber et al., 1996
) or MMPs that can process growth factors to their active form (reviewed by Isacke and Yarwood, 2002
). Thus, CD44 can indirectly promote signalling events by modulating the activity, affinity or localized concentration of signalling factors. Second, CD44 can associate with and modify the function of growth factor receptors and also members of the MT-MMP family. For example, CD44 acts as a co-receptor for the ErbB family of receptor tyrosine kinases and for the c-Met receptor, and these associations are essential for activation of receptor kinase activity and the regulation of diverse cellular processes, including cell survival, proliferation and differentiation (Bourguignon et al., 1997
; Orian-Rousseau et al., 2002
; Sherman et al., 2000
; van der Voort et al., 1999
; Yu et al., 2002
). These interactions could simply reflect association of the receptor extracellular domains that alters the conformation of the receptor tyrosine kinase, but current evidence indicates a more complex scenario. ErbB4 forms a complex with its ligand, heparin-binding epidermal growth factor (HBEGF), matrilysin (MMP7) and alternatively spliced CD44 isoforms containing the v3 exon (Yu et al., 2002
). In this complex, HBEGF precursor bound to heparin sulphate-modified CD44 is cleaved by MMP7 thereby activating ErbB4. It is not known whether the CD44 transmembrane and cytoplasmic domains play a role in this process, although recruitment of CD44 to lipid rafts and/or association of the cytoplasmic domain with the actin cytoskeleton may well be important for promoting heterologous receptor interactions. Indeed, the CD44 cytoplasmic domain and in particular the ERM-binding site is required for the c-Met ligand scatter factor/hepatocyte growth factor (SF/HGF) to induce activation of the MEK and Erk kinases downstream of its high-affinity receptor (Orian-Rousseau et al., 2002
).
CD44 can also associate on the cell surface with MT1-MMP (Mori et al., 2002) and, as described above, is a target for this protease, which results in cleavage of the CD44 extracellular domain. This cleavage can facilitate cell migration and reorganization of the extracellular matrix (reviewed by Cichy and Pure, 2003
) but, in addition, is a prerequisite for further proteolysis of the cell-associated CTF to release the ICD, which can then translocate to the nucleus and regulate gene transcription (Fig. 2) (Okamoto et al., 2001
). This form of CD44 signalling has only been shown in vitro thus far, but evidence for its physiological importance comes from the demonstration that CD44 CTFs are upregulated in breast, lung, colon and ovarian carcinomas (Okamoto et al., 2002
). Although the range and nature of transcriptional targets for the CD44 ICD has yet to be fully investigated, at least one known target is the gene encoding CD44 itself (Okamoto et al., 2001
). Because the newly synthesized CD44 may have altered splicing and glycosylation, this regulated CD44 cleavage and stimulation of intracellular signalling provides a potentially important mechanism for altering the repertoire of CD44 molecules presented at the plasma membrane (Kawano et al., 2000
).
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Conclusions and perspectives |
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References |
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