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CD44

CD44 acted as a competitor for the binding of several miRNAs, namely miR-328, miR-512-3p, miR-491, and miR-671, and prevented them from targeting other matrix-encoding mRNAs, including collagen type 1α1 (Col1α) and FN1 (Rutnam & Yang, 2012).

From: Advances in Genetics, 2014

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T Cells

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Extracellular Matrix

Cancer Stem Cell

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CD44

David Naor, in Encyclopedia of Immunology (Second Edition), 1998

Distribution

Standard CD44 (Figure 1) is a ubiquitous molecule expressed on many types of cells of lymphohematopoietic origin, including erythrocytes, T and B lymphocytes, natural killer cells, macrophages, Kupffer cells, dendritic cells and granulocytes. However, CD44s is also expressed on other cells, such as fibroblasts and cells of the central nervous system. After immunologic activation, T lymphocytes and other leukocytes transiently upregulate CD44v, particularly those containing V6 exon products. A CD44 variant, expressing exons V8 to V10 (CD44V8–10, also known as epithelial CD44 or CD44E), is preferentially expressed on epithelial cells. The longest CD44 isoform, CD44V3–10, was detected in keratinocytes (Figure 1c).

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The Origin of Meningiomas

Serdar Baki Albayrak, Peter M. Black, in Meningiomas, 2010

Expression of CD44

CD44 is a widely distributed cell surface marker and cell adhesion molecule. The insertion of alternatively spliced exons into the CD44 mRNA creates various isoforms of CD44, each involved in diverse biologic functions. Suzuki and colleagues demonstrated the differential expression of CD44 in various meningioma subtypes.49 In this study, only the secretory meningiomas appeared to express variant forms of CD44, favoring tumor cell differentiation to epithelial type, whereas meningothelial, fibrous, and malignant meningiomas express the standard form of CD44. Further, several other studies in the literature revealed convincing evidence that the overexpression of CD44 was often associated with increased migration ability and anaplasia in meningioma cells.49,50 Sainio and colleagues demonstrated the co-localization of NF2 gene–encoded merlin protein with CD44 and noted the interaction of CD44 and cytoskeleton via ezrin, radixin, and moesin proteins which are structurally related to merlin protein. Similarly, Morrison and colleagues presented additional evidence regarding the role of merlin-mediated contact inhibition of cell growth through interactions with CD44 in schwannoma cell lines.

We observed co-localization of CD44 with the proliferation marker Ki-67 in paraffin-embedded slides and in vitro under an IF microscope.

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Inflammation in Systemic Immune Diseases

Chhanda Biswas, in Immunity and Inflammation in Health and Disease, 2018

18.14 Enhanced CD44-ERM/ROCK (Rho Associated Protein Kinase) Pathway in SLE Manifestation

CD44 is a cell surface glycoprotein and participates in cell-cell interaction, cell adhesion and migration. CD44 gene is highly conserved and can produce various isoforms owing to alternate splicing. CD44 splice variants containing variable exons are designated CD44v. CD44 is referred to as HCAM (homing cell adhesion molecule). Activation of CD44 is initiated by binding to the common ligand hyaluronic acid (HA). The adhesion and migration property by CD44 involves the participation of ERM protein complex (Ezrin/radixin/moesin). The phosphorylation of ERM by ROCK promotes recruitment of ERM to the intracellular domain of CD44, and the downstream signaling by CD44/ERM/ROCK pathway facilitates adhesion and migration of T-cells. Exhibition of higher expression level of CD44, particularly CD44v3 and CD44v6 and pERM is observed in both CD4+ and CD8+ T-cells isolated from SLE patients. Also increased levels of HA and CD44 are observed in damaged kidney of SLE patients and lupus-prone mouse models. Further in a lupus-prone mouse model pharmacologic inhibition of ROCK proves to reduce pERM, and thus the intensity of lupus. These studies do suggest that altered output by CD44/ERM/ROCK pathway do have an association in the SLE pathogenesis (Isgro et al., 2013; Comte et al., 2015).

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Role of Hyaluronan and CD44 in Melanoma Progression

Carl Gebhardt, ... Jan C. Simon, in Hyaluronan in Cancer Biology, 2009

CD44 Influences MM Proliferation

CD44 is a transcript of a single gene containing 20 exons. Since 10 of these exons are regulated by alternative splicing, multiple isoforms of CD44 exist. In addition to alternative splicing, CD44 is subject to different degrees of posttranslational modifications, such as glycosylation, sulfation, and phosphorylation, resulting in CD44 isoforms ranging from 85 to 200 kDa (reviewed in Ponta et al., 2003). The expression of standard CD44 and variant isoforms of CD44 has been discussed as prognostic marker in the course of MM (Dietrich et al., 1997; Manten-Horst et al., 1995). Taking together the expression studies and the findings that CD44 is the principal mediator of HA induced melanoma cell proliferation, one can conclude that the CD44–HA interaction promotes melanoma development (Ahrens et al., 2001a). Consequently, Ahrens and co-workers report, that (1) the expression of CD44 is increased during melanoma progression; (2) CD44 is the principal HA surface receptor on melanoma cells; and (3) HA induced increase of melanoma proliferation is mainly dependent on CD44–HA interactions. The observed increase of the proliferative capacity of melanoma cells after HA binding is partly due to a stimulation of autocrine, secreted TGF-β1 and bFGF, thus showing for the first time a direct impact of HA on growth factor release in MM (Fig. 17.2).



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FIGURE 17.2. HA induces MM proliferation via membrane bound CD44; solCD44 is able to block this effect. HA binds to membrane CD44 (mCD44) and induces MM proliferation. This is mediated partly by autocrine secreted bFGF and TGFβ1. Shedded/soluble CD44 (solCD44) blocks this autocrine proliferative loop and inhibits MM cell proliferation. (See Page 11 in Color Section at the back of the book).

In addition to the already mentioned post-translational modifications and the alternative splicing, the extracellular portion of CD44 can be cleaved by proteases from the cell surface thus generating a soluble form of CD44 (solCD44) (Ahrens et al., 2001b; Friedl et al., 1997; Okamoto et al., 2001). More than one protease seems to be involved in the shedding of CD44 from the cell surface, among which MT1-MMP (MMP14) is the best studied occurring in pancreatic tumor cell lines. Which protease is involved in CD44 cleavage in melanomas is currently under investigation (Kajita et al., 2001; Nakamura et al., 2004). The released CD44 is able to affect cellular behavior in several ways. (1) solCD44 is able to block the HA induced increase in proliferation of MM (Fig. 17.2) and importantly the HA binding ability of solCD44 is crucial for this effect, since solCD44 with mutations in the HA binding domain is not able to block the HA induced proliferation of MM (Ahrens et al., 2001b) and mammary carcinoma cells (Peterson et al., 2000). (2) CD44 cleavage regulates cell migration (Goebeler et al., 1996; Kajita et al., 2001), since enhanced shedding of CD44 by MT1-MMP induces cell migration in pancreatic tumor cell lines (Kajita et al., 2001) and highly aggressive MM shed significant amounts of CD44 compared to MM with lower tumorigenicity (Goebeler et al., 1996).

Interestingly, cytokines like oncostatin M and TGFβ are able to attenuate the shedding process itself and the subsequent capacity of HA binding by the soluble CD44 molecule (Cichy et al., 2005). These findings obtained with human lung squamous carcinoma cell line HTB58 might indicate that the local cytokine environment may also determine the effect exerted by the shed solCD44.

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Origins of Osteoclasts

Deborah L. Galson, G. David Roodman, in Osteoimmunology, 2011

CD44

CD44 is a type I transmembrane protein and member of the cartilage link protein family. Several CD44 ligands have been identified. CD44 is a major cell surface receptor for hyaluronan, a component of the extracellular matrix, and it also interacts with osteopontin (OPN), collagen, and laminin. Kania et al. [95] determined that CD44, a cell surface glycoprotein known to function as an adhesion receptor, also is involved in osteoclast differentiation. They demonstrated that antibodies against CD44 inhibited osteoclast formation in mouse bone marrow co-cultures stimulated with 1,25(OD)2D3, but did not inhibit the bone resorption activity of mature osteoclasts. However, de Vries et al. [96] reported that CD44−/− mice do not have an osteopetrotic phenotype in vivo. Further, in vitro analysis of bone marrow cells from CD44−/− and WT mice demonstrated that they formed equal numbers of osteoclasts on bone and the resorption capacity was also similar. This group did not find that CD44-blocking antibodies altered osteoclastogenesis induced by RANKL plus M-CSF. This discrepancy with the previous report may be due to different pathways utilized during osteoclastogenesis. It is possible that in vivo there are compensating signals for the loss of CD44.

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IMMUNOLOGY OF THE PIG

In Handbook of Vertebrate Immunology, 1998

CD44

CD44 is an adhesion molecule that is involved in lymphocyte homing, T-cell activation, and intercellular interactions. Porcine CD44 was first identified in a soluble form in intestinal efferent lymph using the anti-human CD44 monoclonal antibody, Hermes-1 (Yang et al., 1993). It was characterized as 48 000 to 70 000 kDa soluble and 90 000 kDa membrane bound molecule. Porcine CD44 was subsequently purified and both polyclonal and monoclonal antibodies were generated (Yang et al., 1993). Both types of antibodies were widely species cross-reactive. The monoclonal antibodies failed to stain porcine erythrocytes but did stain all mononuclear cells compared with the situation in humans, where red cells do express CD44. It is possible that porcine red cells also express CD44 but a distinct isoform of it (Yang et al., 1993). The level of CD44 appeared to correlate with homing capacity of the particular lymphocyte populations (Yang et al., 1993).

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T Cell Activation

Tak W. Mak, Mary E. Saunders, in The Immune Response, 2006

III. CD44

CD44 is an acidic cell surface adhesion protein that is broadly expressed, including in the membranes of B cells, granulocytes, monocytes, and erythrocytes as well as on many thymocytes and mature T cells. CD44 occurs naturally in at least 20 different transmembrane isoforms that are derived from the alternative splicing of 12 exons of the 20-exon CD44 gene. Preferential expression of various isoforms in certain tissues has been observed, with the appearance of some CD44 isoforms being associated with the inhibition of tumor metastasis. In general, CD44 molecules have seven sites available for N-linked and O-linked glycosylation. CD44 has been shown to bind to hyaluronic acid, heparin sulfate, collagen, and fibronectin (all components of the extracellular matrix) and several cytoskeletal proteins. In T cells, CD44 primarily mediates adhesion to the endothelium, promoting lymphocyte rolling during extravasation through the HEV at the site of an inflammatory response. Consistent with this role, CD44 expression is induced by the pro-inflammatory cytokine TNF and is transiently upregulated on T cells during an immune response. This increase in CD44 expression may also help to retain activated T cells within a lymph node by facilitating binding to extracellular proteins acting as structural components of the node.

Knockout mice deficient for CD44 do not show a significant reduction in the total numbers of leukocytes in the peripheral blood or of hematopoietic progenitors in the liver. However, the distribution of hematopoietic progenitors is abnormal, and granuloma formation (see Chs. 15 and 22), which requires the migration of monocytes and macrophages, is defective. No evidence has been obtained from CD44−/− mice, which suggests an absolute requirement for CD44 in either T cell costimulation or thymocyte maturation.

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Genetics of lupus

Leah Kottyan, ... John B. Harley, in Rheumatology (Sixth Edition), 2015

CD44

The CD44 gene spans nearly 100 kb and contains 20 exons that encode a cell surface glycoprotein expressed on most immune cells. Expression of CD44 is complicated by complex splice variations that result in hundreds of protein isoforms (reviewed in4). Immunologically, CD44 plays critical roles in tumor metastasis, hematopoiesis, apoptosis, lymphocyte activation, and immune cell recirculation and homing.70-72 On the cell surface, CD44 forms heterodimers that bind to a wide variety of ligands that have been directly linked to autoimmunity, including hyaluronic acid, collagens, and matrix metalloproteinases.73,74

Variants of CD44 were first implicated in SLE as an extension of linkage.75 More recently, a large multi-ancestral fine mapping study produced a genomewide association with variants in a haplotype directly upstream of CD44 that appear to influence the expression of CD44.76 The causal variants for the CD44 association with SLE disease risk remain unknown.

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HSC Niche

Samiksha Wasnik, ... David J. Baylink, in Biology and Engineering of Stem Cell Niches, 2017

3.2.2.3 CD44 Glycoproteins

CD44 glycoproteins are encoded by a single gene and have been reported to regulate HSC homing in BM. CD44 was earlier known as a homing receptor for lymphocytes, expressed by hematopoietic and non-hematopoietic cells. The transmembrane CD44 protein allows the binding of HSC to osteopontin (OPN) to implement homing in BM. Roles of CD44 in migration and homing have been widely studied in both malignant and normal cells in humans; however, in the case of murine trafficking, there exists a contradiction. Depletion or neutralization of CD44 with specific antibodies or intravenous injection of hyaluronidase shows adverse effects of homing of HPCs in BM; however, in CD44 knockout mice, this system seems to remain intact. Hyaluronic acid (HA) is the major ligand of CD44 and an important matrix component of the BM niche.68 The primitive HSCs exclusively synthesize and express HA. Apart from giving the mechanical support to the niche, HA regulates cell adhesion and migration, as well as more specifically regulates homing of HSCs in an endosteal niche.69 The HA-CD44 interactions also cooperate with SDF-1 gradient for the trafficking of human CD34+ HSC to BM.70

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Activation of the Immune System

Toshiyuki Tanaka, in Encyclopedia of Immunobiology, 2016

The Hyaluronan Receptor CD44 (Pgp-1)

CD44, a class I transmembrane glycoprotein, is the principal cell-surface receptor for the extracellular matrix glycosaminoglycan hyaluronan (Ponta et al., 2003). On neutrophils and some lymphocytes, CD44 also binds E-selectin (Zarbock et al., 2011; Figure 4). To bind E-selectin, neutrophil-derived CD44 must be decorated by sialylated, α1,3-fucosylated, N-linked glycans (Katayama et al., 2005). CD44 contains an extracellular domain with a hyaluronan-binding link domain at the N-terminus, followed by a mucin-like stalk region that is subject to N- and O-linked glycosylation and chondroitin-sulfate modification. CD44 is expressed on most vertebrate cells, including hematopoietic-lineage, endothelial, and epithelial cells. CD44 is important in mobilizing leukocytes to sites of infection and inflammation, and it mediates rolling interactions with activated endothelial cells (DeGrendele et al., 1997; Baaten et al., 2012). CD44 binds collagen, fibronectin, and laminin, and has chondroitin–sulfate side chains that contribute to this binding (Jalkanen and Jalkanen, 1992).



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Figure 4. CD44 structure. CD44 is a cell-surface receptor for hyaluronan. On neutrophils and some lymphocytes, CD44 also binds E-selectin. The extracellular CD44 region consists of an N-terminal hyaluronan-binding link domain followed by a mucin-like region that is subjected to N-linked () glycosylation and variable chondroitin-sulfate () additions. CD44 variants (CD44v) are formed by the insertion of various combinations of variant exons. CD44 interactions with ERM-family members via its cytoplasmic tail link CD44 and other signaling proteins to the actin cytoskeleton.

Alternative splicing in the extracellular region generates multiple isoforms of CD44, and cells can simultaneously express multiple isoforms (Figure 4). The standard and most abundant form of CD44 (CD44s, also called hematopoietic CD44) lacks all variant exons. Hematopoietic cells express CD44s, but its glycosylated form varies depending on the cell's activation and differentiation status. CD44 variants (CD44v) are created by the insertion of various combinations of variant exos.

CD44 interacts with ERM-family membrane-cytoskeletal linker proteins through its cytoplasmic domain (Figure 4). CD44 also interacts with several intracellular signaling molecules, including Src-family kinases, Rho GTPase, and protein kinase C