Alternative titles; symbols
HGNC Approved Gene Symbol: CD44
Cytogenetic location: 11p13 Genomic coordinates (GRCh38): 11:35,139,171-35,232,402 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p13 | [Blood group, Indian system] | 609027 | 3 |
CD44 is an integral cell membrane glycoprotein with a postulated role in matrix adhesion lymphocyte activation and lymph node homing (Aruffo et al., 1990).
Telen et al. (1983) used a murine monoclonal antibody (A3D8) to identify an erythrocyte antigen inhibited by the In(Lu) gene. Telen et al. (1984) showed that the A3D8 antigenic property resides on an 80-kD red cell membrane protein which is present in only trace amounts in In(Lu) Lu(a-b-) red cells (INLU; 111150). Haynes (1986) had evidence that the A1G3 and A3D8 monoclonal antibodies bind to different epitopes on the same 80-kD molecule. The monoclonal antibody A3D8 recognized an antigen officially called MDU3, for 'monoclonal Duke University, 3,' or CD44. Telen (1992) knew of no evidence that the INLU and CD44 (MDU3) genes are the same.
By screening cDNA libraries prepared from hemopoietic cell lines, Stamenkovic et al. (1989) isolated CD44 clones. Immunoprecipitation of CD44 from transfected COS cells and cultured cell lines detected cell-specific expression of an 80- to 90-kD protein and a 160-kD protein. Several minor forms of 52 to 200 kD were variably present in different cell types. RNA blot analysis revealed transcripts of 1.6, 2.2, and 5.0 kb in hemopoietic cell lines. RNA blot analysis of carcinoma cell lines revealed 3 patterns of expression: the first, exemplified by melanoma cell lines, was identical to the hemopoietic cell pattern associated with the 80- to 90-kD isoform; the second, exemplified by a colon carcinoma cell line, showed transcripts of 2.0, 2.6, and 5.6 kb associated with the 160-kD isoform; and the third, exemplified by another colon carcinoma cell line, was a composite of the first 2 patterns. All primary carcinoma specimens examined showed prevalent CD44 transcripts of either hemopoietic or composite type. The CD44 cDNA encodes a 361-amino acid protein with a 20-residue secretory signal peptide, a 248-residue extracellular N-terminal domain with multiple N- and O-linked glycosylation sites, a 21-amino acid transmembrane domain, and a 72-residue hydrophilic cytoplasmic domain. The mature protein has a calculated molecular mass of 37 kD. Sequence analysis suggested homology with chicken and rat cartilage link proteins (HAPLN1; 115435).
Stefanova et al. (1989) demonstrated that the lymphocyte homing receptor is identical to the human leukocyte surface glycoprotein called CDw44, on the basis of studies at the Third International Workshop on Human Leukocyte Differentiation Antigens. It also appears to be identical to the Pgp-1 glycoprotein of Omary et al. (1988).
A table of all the CD antigens was provided by Schlossman et al. (1994) with a list of the common names, the size in kilodaltons, and the nature of the protein (adhesion, myeloid, platelet, and B cell, T cell, etc.).
Screaton et al. (1992) found that the CD44 gene contains 19 exons spanning 50 kb of genomic DNA. They identified 10 alternatively spliced exons within the extracellular domain, including 1 exon that had not previously been reported. In addition to the inclusion or exclusion of whole exons, additional diversity was generated through the utilization of internal splice donor and acceptor sites within 2 of the exons. A variation in the cytoplasmic domain was shown to result from the alternative splicing of 2 exons. Thus the genomic structure of CD44 is remarkably complex, and alternative splicing is the basis of its structural and functional diversity.
Nedvetzki et al. (2003) noted that human CD44 isoforms are generated from 9 variant exons (v2 to v10) inserted in different combinations between 2 constant regions consisting of 5 exons at the N terminus and 4 exons at the C terminus (constant exon 19 is noncoding). Direct splicing of constant exon 5 to constant exon 16, thereby skipping the variant exons, generates the standard CD44 isoform.
Francke et al. (1983) showed that the antigens defined by monoclonal antibodies A3D8 and A1G3 are determined by genes on 11p.
The mouse monoclonal antibody Hermes-3 recognizes the 85- to 95-kD human lymphocyte homing receptor. Using mouse-human T-lymphocyte hybrids and hybrids of Chinese hamster ovary cells with human amniotic fibroblasts, Ala-Kapee et al. (1989) found that Hermes-3 expression, as demonstrated by indirect immunofluorescence and immunoprecipitation, was determined by 11pter-p13. Forsberg et al. (1989) refined the assignment of the lymphocyte homing receptor gene to 11pter-p13 by study of Chinese hamster-human cell hybrids in which the human parent cells had various deletions of human chromosome 11. Although CD44 may have function as a lymphocyte homing receptor, the gene that maps to chromosome 11 is distinct from the lymph node homing receptor located on chromosome 1 (153240) (Seldin, 1990). In the mouse, the corresponding gene has been referred to as Ly-24.
Cianfriglia et al. (1992) mapped a drug-sensitivity marker, MC56, to 11pter-p13. Identity of the protein to the CD44 antigen, suggested on other grounds, was supported by the map location.
Aruffo et al. (1990) demonstrated that CD44 is the main cell surface receptor for hyaluronate. Mature lymphocytes in the circulation migrate selectively from the bloodstream to different lymphatic tissues through specialized high endothelial venules (HEV). Molecules on the surface of lymphocytes called homing receptors interact specifically with HEV and play a central role in the migration.
Splice variants of the glycoprotein CD44 may be associated with metastases and therefore may be useful in the early detection of metastatic potential in surgical biopsy specimens, as well as in the early diagnosis of cancer in screening programs, assessment of remaining disease, and early detection of recurrence (Matsumura and Tarin, 1992). Mayer et al. (1993) found that expression of CD44, which is not found in normal gastric mucosa and is found in only 49% of primary tumors, was associated with distant metastases at time of diagnosis and with tumor recurrence and increased mortality from gastric cancer.
Weber et al. (1996) noted that the CD44 gene encodes a transmembrane protein that is expressed as a family of molecular isoforms generated from alternative RNA splicing and posttranslational modifications. Certain CD44 isoforms that regulate activation and migration of lymphocytes and macrophages may also enhance local growth and metastatic spread of tumor cells. One ligand of CD44 is hyaluronic acid, binding of which to the NH2-terminal domain of CD44 enhances cellular aggregation and tumor cell growth. (Krainer et al. (1991) referred to CD44 as a 'hyaladherin' -- see 601269.) Weber et al. (1996) demonstrated that another ligand is osteopontin (166490). Osteopontin induces cellular chemotaxis but not homotypic aggregation of cells, whereas the inverse is true for the interaction between CD44 and hyaluronate. The alternative responses to CD44 ligation may be exploited by tumor cells to allow OPN-mediated metastatic spread and hyaluronate-dependent growth in newly colonized tissues in the process of tumor metastasis.
Sherman et al. (1998) investigated the role of CD44 proteins in early limb development. Members of this family of transmembrane glycoproteins are expressed by cells of the limb bud, including those of the apical ectodermal ridge (AER). Distinct CD44 variants are generated from a single gene by alternative RNA splicing of up to 10 variant exons and by extensive posttranslational modifications. The amino acid sequences encoded by these variant exons are located in the extracellular portion of the protein near the transmembrane domain. A standard form of CD44 lacking these variant sequences is expressed by numerous cell types and is the smallest CD44 protein. It carries no variant exon sequences. Splice variants are expressed in only a limited number of tissues and in certain tumors. Signals from the AER of the developing vertebrate limb, including fibroblast growth factor-8 (600483), can maintain limb mesenchymal cells in proliferative state. Sherman et al. (1998) reported that a specific CD44 splice variant is crucial for the proliferation of these mesenchymal cells. Epitopes carried by this variant colocalize temporally and spatially with FGF8 in the AER throughout early limb development. A splice variant containing the same sequence expressed on model cells binds both FGF4 (164980) and FGF8 and stimulates mesenchymal cells in vitro. Sherman et al. (1998) found that when applied to the AER, an antibody against a specific CD44 epitope blocked FGF presentation and inhibited limb outgrowth. Therefore, CD44 is necessary for limb development and functions in a novel growth factor presentation mechanism likely relevant to other physiologic and pathologic situations in which a cell surface protein presents a signaling molecule to a neighboring cell.
Cywes and Wessels (2001) demonstrated that CD44-dependent group A Streptococcus binding to polarized monolayers of human keratinocytes induced marked cytoskeletal rearrangements manifested by membrane ruffling and disruption of intercellular junctions. Transduction of the signal induced by group A Streptococcus binding to CD44 on the keratinocyte surface involved Rac1 (602048) and the cytoskeleton linker protein ezrin (123900), as well as tyrosine phosphorylation of cellular proteins. Studies of bacterial translocation in 2 models of human skin indicated that cell signaling triggered by interaction of the group A Streptococcus capsule with CD44 opened intercellular junctions and promoted tissue penetration by group A Streptococcus through a paracellular route. Cywes and Wessels (2001) concluded that their results support a model of host cytoskeleton manipulation and tissue invasion by an extracellular bacterial pathogen.
Nedvetzki et al. (2003) identified a CD44 variant, designated CD44vRA, in synovial fluid aspirated from 23 of 30 patients with rheumatoid arthritis (RA; 180300). Sequence analysis showed that the CD44vRA isoform contains an intron-derived CAG trinucleotide inclusion 5-prime to constant exon 5 within the CD44v3-v10 isoform. Functional expression studies in human cells showed that the CD44vRA variant interacted with FGF2 (134920) via the heparan sulfate on exon v3 in a way that enhanced binding and activation of soluble FGFR1 (136350) to a greater extent than CD44v3-v10. Synovial fluid cells from RA patients bound soluble FGFR1 more intensively than control cells. Nedvetzki et al. (2003) postulated that activation of FGFR1 may play a role in the RA inflammatory process.
In a mouse hindlimb model of arteriogenesis, van Royen et al. (2004) found that Cd44 expression increased strongly during collateral vessel growth in wildtype mice and that arteriogenesis was severely impaired in Cd44 -/- mice. The defective arteriogenesis was accompanied by reduced leukocyte trafficking to sites of collateral artery growth and reduced expression of FGF2 and platelet-derived growth factor-B protein (PDGFB; 190040). In 14 consecutive patients with single-vessel coronary artery disease, van Royen et al. (2004) found that the maximal expression of CD44 on activated monocytes was reduced in patients with poor collateralization compared to patients with good collateralization. Van Royen et al. (2004) concluded that CD44 plays a pivotal role in arteriogenesis.
By analyzing a human breast cancer cell line transduced with a micro RNA (miRNA) expression library, Huang et al. (2008) found that human miR373 (611954) and miR520C (615908) stimulated cell migration and invasion in vitro and in vivo. Using expression array analysis, they found that the migration phenotype of miR373- and miR520C-expressing cells depended on suppression of CD44. Upregulation of miR373 correlated inversely with CD44 expression in breast cancer metastasis samples. The authors noted that increased expression of the most common CD44 isoform correlates with overall survival of breast cancer patients.
Godar et al. (2008) found that p53 (TP53; 191170) negatively regulated CD44 expression in normal human mammary epithelial cells by binding to a noncanonical p53-binding sequence in the CD44 promoter. Inhibition of CD44 enabled the cells to respond to stress-induced, p53-dependent cytostatic and apoptotic signals that would have otherwise been blocked by CD44. In the absence of p53, CD44 promoted growth in a highly tumorigenic mammary epithelial cell line. In both normal and tumorigenic cell lines, p63 (TP63; 603273) positively regulated CD44 expression.
Smigiel et al. (2014) noted that FOXP3 (300292)-positive regulatory T cells (Tregs) depend on IL2 (147680) for maintaining tolerance and preventing autoimmunity. They showed that mouse central Tregs (cTregs), which express low levels of Cd44 and high levels of Cd62l (SELL; 153240) (i.e., Cd44-lo/Cd62l-hi), were quiescent and long-lived. In contrast, mouse effector Tregs (eTregs), which are Cd44-hi/Cd62l-lo, differentiated from cTregs and underwent rapid proliferation that was balanced by a high rate of apoptotic cell death. Although eTregs expressed lower levels of Cd25 (IL2RA; 147730), they responded well to Il2. cTregs gained access to paracrine Il2 through their expression of Ccr7 (600242), whereas eTregs populating nonlymphoid tissues expressed low Ccr7, did not access Il2-prevalent regions in vivo, and were insensitive to Il2 blockade. eTregs were maintained by signaling through Icos (604558). Smigiel et al. (2014) concluded that there is a fundamental homeostatic subdivision in Treg populations based on their localization and signaling mechanisms in different environments.
Valentine et al. (2011) found that expression of full-length recombinant FKBPL (617076) inhibited HMEC-1 normal human endothelia cell migration, tubule formation, and microvessel formation in vitro and in vivo. Exogenous administration of purified FKBPL also inhibited HMEC-1 cell migration in a dose-dependent manner in a scratch-wound assay. Truncation analysis revealed an antiangiogenic domain in FKBPL between amino acids 34 and 58. A synthetic peptide spanning this region, called AD01, showed similar antiangiogenic activity in vitro and in vivo in xenografts in mice. Homology between AD01 and the CD44 dimerization domain of CD74 (142790) suggested that AD01 interacts with cell surface CD44. Both full-length recombinant FKBPL and AD01 inhibited cell migration of tumor cell lines in a CD44-dependent manner.
Yakkundi et al. (2015) found that morpholino-mediated knockdown of Fkbpl in zebrafish embryos reduced vessel formation. Vessel disruption was rescued by co-knockdown of Cd44, supporting dependence of Fkbpl on Cd44.
Pascual et al. (2017) described a subpopulation of CD44(bright) cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 (173510) and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosted the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 caused almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36+ metastasis-initiating cells correlated with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impaired metastasis, at least in human melanoma- and breast cancer-derived tumors. Pascual et al. (2017) concluded that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
The Indian blood group (609027) comprises 2 antigens, In(a) and In(b), which reside on CD44. By RT-PCR analysis of cDNA extracted from In(a+b-)-transformed B lymphocytes, Telen et al. (1996) identified the CD44 polymorphism that causes the In(b-) phenotype. The polymorphism results in an arg46-to-pro change (R46P; 107269.0001), removing the basically charged amino acid at the C terminus of the hyaluronan (HA)-binding motif of CD44. In previous studies using chimeric proteins, arg46 was shown to be crucial for HA binding by CD44 (Yang et al., 1994). However, Telen et al. (1996) demonstrated that the R46P change does not reduce HA binding to CD44.
Schmits et al. (1997) generated mice deficient in all known isoforms of Cd44 by targeting exons encoding the invariant N-terminal region of the molecule. Mice were born in mendelian ratio without any obvious developmental or neurologic deficits. Hematologic impairment was evidenced by altered tissue distribution of myeloid progenitors with increased levels of colony-forming unit-granulocyte-macrophage in bone marrow and reduced numbers in spleen. Fetal liver colony-forming unit-spleen and granulocyte colony-stimulating factor mobilization assays, together with reduced colony-forming unit-granulocyte-macrophage in peripheral blood, suggested that progenitor egress from the bone marrow was defective. Mice also developed exaggerated granuloma responses to Cryotosporidium parvum infection. Tumor studies showed that SV40-transformed Cd44-deficient fibroblasts were highly tumorigenic in nude mice, whereas reintroduction of Cd44 expression into these fibroblasts resulted in a dramatic inhibition of tumor growth.
Teder et al. (2002) studied the role of Cd44 in lung inflammation by using the Cd44-deficient mice generated by Schmits et al. (1997). After intratracheal administration of bleomycin, 75% of Cd44-deficient mice died by day 14. They developed unremitting inflammation, characterized by impaired clearance of apoptotic neutrophils, persistent accumulation of hyaluronan fragments at the site of the tissue injury, and impaired activation of transforming growth factor beta-1 (190180). This phenotype was partially reversed by reconstitution with Cd44+ cells, thus demonstrating a critical role for this receptor in resolving lung inflammation.
Using immunohistochemistry, Leemans et al. (2003) confirmed that Cd44-high cells accumulated in mouse lungs following intranasal infection with Mycobacterium tuberculosis. Cd44 -/- mice, however, had a 50% reduction in pulmonary macrophages 2 weeks after infection, although the absolute numbers of leukocytes were unchanged. By 5 weeks after infection, a significant reduction in Cd4 (186940)-positive lymphocyte numbers was observed in mutant mice. At both time points, the Cd44-deficient mice displayed disorganized granulomas containing predominantly polymorphonuclear neutrophils rather than well-demarcated granulomas consisting of lymphocytes and macrophages. Splenocytes were more numerous in mice lacking Cd44, and they secreted significantly more Ifng (147570) in response to antigen-specific stimulation than splenocytes of wildtype mice. Flow cytometric analysis showed that human CD44 bound to M. tuberculosis, and Cd44 -/- mouse macrophages contained fewer bacteria than wildtype macrophages. The mutant mice allowed greater replication of M. tuberculosis in lung and liver and had reduced survival compared with wildtype mice. Leemans et al. (2003) proposed that CD44 mediates resistance to mycobacterial infection by promoting binding and phagocytosis by macrophages and by recruiting these cells to the site of infection.
TNF (191160) is a major inducer of chronic inflammation, and its overexpression leads to chronic inflammatory arthritis. Hayer et al. (2005) crossed Cd44 -/- mice with mice transgenic for human TNF and found that destruction of joints and progressive crippling was far more severe in Cd44 -/- transgenic mice than in transgenic mice expressing Cd44. Cd44 -/- transgenic mice exhibited increased systemic bone resorption due to an increase in the number, size, and activity of osteoclasts. Bone formation and osteoblast differentiation were not affected. Cd44 -/- osteoclasts had an enhanced response to TNF that was associated with increased activation of p38 (MAPK14; 600289). Hayer et al. (2005) concluded that CD44 is a critical inhibitor of TNF-induced joint destruction and inflammatory bone loss.
Krause et al. (2006) found that mice lacking Cd44 were as susceptible as wildtype mice to murine chronic myeloid leukemia (CML; 608232) after challenge with BCR-ABL virus. However, bone marrow cells from Cd44 -/- mice transduced with the virus showed defective homing to recipient bone marrow, resulting in decreased engraftment and reduced CML-like disease. In contrast, Cd44 was dispensable for induction of B-lymphoblastic leukemia-like disease. Krause et al. (2006) concluded that CD44 is required for leukemic stem cells that initiate CML.
Jin et al. (2006) found that treatment with activating monoclonal antibodies to CD44 markedly reduced leukemic repopulation in nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice challenged with human acute myeloid leukemia (AML; 601626) cells. Absence of leukemia following serial tumor transplantation experiments in mice demonstrated direct targeting of AML leukemic stem cells (LSCs). Treatment of engrafted mice with anti-CD44 reduced the number of Cd34 (142230)-positive/Cd38 (107270)-negative primitive stem cells and increased the number of Cd14 (158120)-positive monocytic cells. Anti-CD44 treatment also diminished the homing capacity of SCID leukemia-initiating cells to bone marrow and spleen. Jin et al. (2006) concluded that CD44 is a key regulator of AML LSCs, which require a niche to maintain their stem cell properties. They suggested that CD44 targeting may help eliminate quiescent AML LSCs.
The Indian blood group (609027) comprises 2 antigens, In(a) and In(b), which reside on CD44. By RT-PCR analysis of cDNA extracted from In(a+b-)-transformed B lymphocytes, Telen et al. (1996) identified the CD44 polymorphism that causes the In(b-) phenotype. The G-to-C change at nucleotide 252 results in an arg46-to-pro change (R46P), removing the basically charged amino acid at the C terminus of the hyaluronan (HA)-binding motif of CD44. In previous studies using chimeric proteins, arg46 was shown to be crucial for HA binding by CD44 (Yang et al., 1994). However, Telen et al. (1996) demonstrated that the R46P change does not reduce HA binding to CD44.
The SNP for the Indian blood group polymorphism is rs369473842 (Gassner et al., 2018).
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