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Gene Review

CD44  -  CD44 molecule (Indian blood group)

Homo sapiens

Synonyms: CD44 antigen, CD44R, CDW44, CDw44, CSPG8, ...
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Disease relevance of CD44

  • Streptococcus pyogenes (also known as group A Streptococcus, GAS), the agent of streptococcal sore throat and invasive soft-tissue infections, attaches to human pharyngeal or skin epithelial cells through specific recognition of its hyaluronic acid capsular polysaccharide by the hyaluronic-acid-binding protein CD44 (refs 1, 2) [1].
  • Immunochemical and RNA blot data have supported the existence of two forms of CD44: a hematopoietic form expressed by cells of mesodermal origin (and by some carcinoma cell lines) and an epithelial form weakly expressed by normal epithelium but highly expressed by carcinomas [2].
  • Binding studies with melanoma transfectants expressing CD44H, CD44E, or with soluble immunoglobulin fusions of CD44H and CD44E (CD44H-Rg, CD44E-Rg) showed that although both CD44 isoforms can bind HA, CD44H binds HA more efficiently than CD44E [3].
  • Human neonatal foreskin keratinocytes (HFKs) and QG56 lung squamous carcinoma cells express an alternatively spliced form of the CD44 core protein (termed CD44E) that contains an additional 132 amino acids in the carbohydrate attachment region of the extracellular domain [4].
  • We identified a molecular complex involving proteins of both the host, CD44 the hyaluronan receptor, and Shigella, the invasin IpaB, which partitions during infection within specialized membrane microdomains enriched in cholesterol and sphingolipids, called rafts [5].
  • CD44 is expressed in most human cell types and is implicated in myeloid leukemia pathogenesis [6].
  • We found that CD44(+) cells displayed clustered growth and they did not colocalize with CD133(+) cells within colorectal cancer [7].

Psychiatry related information on CD44

  • The localization of CD44 was investigated immunohistochemically in postmortem human brain tissue of control subjects and patients with Alzheimer's disease [8].
  • Plasma concentrations of reputed tumor-associated soluble CD44 isoforms (v5 and v6) in smokers are dose related and decline on smoking cessation [9].
  • The staining intensity of CD44 in liver specimens obtained from patients with ALD who were active in alcohol consumption were significantly higher when compared with patients with ALD after abstinence [10].
  • METHODS: Using a polymerase chain reaction protocol with short reaction times, we amplified, sequenced and quantified CD44 mRNA transcripts from 52 samples of NSCLC to determine the splicing patterns of alternatively included exons and the proportion of each CD44 mRNA transcript [11].

High impact information on CD44

  • This defines the consensus fold for the Link module superfamily, which includes CD44, cartilage link protein, and aggrecan [12].
  • To test whether microvillous presentation is critical for contact formation ("tethering"), we transfected lymphoid cells with chimeras of L-selectin and CD44, an adhesion molecule that is excluded from microvilli [13].
  • The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44 [14].
  • Using a monoclonal antibody (MAb1.1ASML) raised against a surface glycoprotein of the metastasizing rat pancreatic carcinoma cell line BSp73ASML, cDNA clones have been isolated that encode glycoproteins with partial homology to CD44, a presumed adhesion molecule [15].
  • The data indicate that Ly-22 is an allelic determinant on the LHR resulting from a single amino acid interchange within the EGF domain [16].

Chemical compound and disease context of CD44


Biological context of CD44


Anatomical context of CD44


Associations of CD44 with chemical compounds

  • MIP-1 beta was immobilized by binding to proteoglycan: a conjugate of heparin with bovine serum albumin and cellular proteoglycan CD44 were both effective [26].
  • The observed integrin-independent adhesion was mediated by CD44/hyaluronate interactions as it was inhibited by anti-CD44 mAb 5F12 and by hyaluronidase [25].
  • CD44-negative Namalwa cells transfected with CD44vRA cDNA or with CD44v3-v10 (CD44vRA wild type) cDNA bound FGF-2 to an equal extent via their associated heparan sulfate chains [27].
  • In resting cells, CD44 is constitutively phosphorylated at a single serine residue, Ser325 [28].
  • A subset of lymphocyte CD44 molecules is modified by covalent linkage to chondroitin sulfate (Jalkanen, S., M. Jalkanen, R. Bargatze, M. Tammi, and E. C. Butcher. 1988. J. Immunol. 141:1615-1623) [29].
  • CD34(+) populations use alpha4beta1, beta2 integrins and CD44 receptors to bind to the ligands VCAM-1/fibronectin, ICAM-1, and hyaluronic acid expressed on sinusoidal vessels in tissue sections and to primary human HSEC [30].
  • The presence of chondroitin and dermatan sulfate on CD44 standard and variant isoforms facilitates fibrin recognition [31].

Physical interactions of CD44

  • Dentin matrix protein 1 (DMP1) has been known for a number of years to bind to CD44 and ArgGlyAsp sequence-dependent integrins [32].
  • We further show that the cell surface proteoglycan CD44 plays an auxiliary role in the binding of epithelial cells to CD48 and that this interaction involves the glycosaminoglycan binding site of CD44 [33].
  • Here we present evidence that CD44 co-immunoprecipitates with EGFR and ErbB2 in the glioma cell lines U87MG and SMA560 [34].
  • Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4-mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes [35].
  • Conversely, CD44 bound HA very weakly when exons V8-V10 were replaced with a CD34 mucin domain, which is heavily modified by O-linked glycans [3].

Enzymatic interactions of CD44


Co-localisations of CD44


Regulatory relationships of CD44

  • The CD44 adhesion molecule in HUVEC was also found to be upregulated through TNF-R55 [40].
  • In this study, our results suggest that the calcium signaling pathway, in particular calmodulin (CaM) and CaM-dependent protein kinase II (CaMK-II), is involved in TNF-alpha- but not LPS-induced CD44 expression [41].
  • Taken together, these results suggest a predominant role of JNK in LPS-induced CD44 expression in monocytic cells [42].
  • We also present evidence that blockade of metalloproteinase-disintegrin ADAM10 (a disintegrin and metalloproteinase 10) by RNA interference suppresses CD44 cleavage induced by its ligation [43].
  • Recent results have indicated that adhesion molecules such as CD44 and integrin alphavbeta3 are involved in positioning activated matrix metalloproteinase molecules on the cell surface of invasive tumor cells [44].

Other interactions of CD44


Analytical, diagnostic and therapeutic context of CD44

  • PCR analysis using primers that flank the inserted region present within CD44R1 identified an additional CD44 isoform, designated CD44R2, that contains only the last 69 amino acids present within the unique region of CD44R1 [24].
  • Molecular cloning of CD44R1 and CD44R2, two novel isoforms of the human CD44 lymphocyte "homing" receptor expressed by hemopoietic cells [24].
  • Using flow cytometry we showed that EC from the vasculature of human solid tumors display an enhanced expression of CD44 as compared to EC from normal tissue [49].
  • Homing was blocked by anti-CD44 monoclonal antibodies (mAbs) or by soluble HA, and it was significantly impaired after intravenous injection of hyaluronidase [17].
  • CD44-stimulated human B cells express transcripts specifically involved in immunomodulation and inflammation as analyzed by DNA microarrays [46].


  1. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Cywes, C., Wessels, M.R. Nature (2001) [Pubmed]
  2. The hematopoietic and epithelial forms of CD44 are distinct polypeptides with different adhesion potentials for hyaluronate-bearing cells. Stamenkovic, I., Aruffo, A., Amiot, M., Seed, B. EMBO J. (1991) [Pubmed]
  3. Regulation of CD44 binding to hyaluronan by glycosylation of variably spliced exons. Bennett, K.L., Modrell, B., Greenfield, B., Bartolazzi, A., Stamenkovic, I., Peach, R., Jackson, D.G., Spring, F., Aruffo, A. J. Cell Biol. (1995) [Pubmed]
  4. Human keratinocytes express a new CD44 core protein (CD44E) as a heparan-sulfate intrinsic membrane proteoglycan with additional exons. Brown, T.A., Bouchard, T., St John, T., Wayner, E., Carter, W.G. J. Cell Biol. (1991) [Pubmed]
  5. Initial steps of Shigella infection depend on the cholesterol/sphingolipid raft-mediated CD44-IpaB interaction. Lafont, F., Tran Van Nhieu, G., Hanada, K., Sansonetti, P., van der Goot, F.G. EMBO J. (2002) [Pubmed]
  6. The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation. Peterson, L.F., Wang, Y., Lo, M.C., Yan, M., Kanbe, E., Zhang, D.E. Leukemia (2007) [Pubmed]
  7. CD44 is of functional importance for colorectal cancer stem cells. Du, L., Wang, H., He, L., Zhang, J., Ni, B., Wang, X., Jin, H., Cahuzac, N., Mehrpour, M., Lu, Y., Chen, Q. Clin. Cancer Res. (2008) [Pubmed]
  8. Morphological diversities of CD44 positive astrocytes in the cerebral cortex of normal subjects and patients with Alzheimer's disease. Akiyama, H., Tooyama, I., Kawamata, T., Ikeda, K., McGeer, P.L. Brain Res. (1993) [Pubmed]
  9. Plasma concentrations of reputed tumor-associated soluble CD44 isoforms (v5 and v6) in smokers are dose related and decline on smoking cessation. Scott, D.A., Stapleton, J.A., Palmer, R.M., Wilson, R.F., Sutherland, G., Coward, P.Y., Gustavsson, G., Odell, E.W., Poston, R.N. Cancer Epidemiol. Biomarkers Prev. (2000) [Pubmed]
  10. Immunohistochemical study of hyaluronate receptor (CD44) in alcoholic liver disease. Urashima, S., Tsutsumi, M., Ozaki, K., Tsuchishima, M., Shimanaka, K., Ueshima, Y., Takase, S. Alcohol. Clin. Exp. Res. (2000) [Pubmed]
  11. CD44 splicing pattern is associated with disease progression in pulmonary adenocarcinoma. Lee, L.N., Kuo, S.H., Lee, Y.C., Chang, Y.L., Chang, H.C., Jan, I.S., Yang, P.C. J. Formos. Med. Assoc. (2005) [Pubmed]
  12. Solution structure of the link module: a hyaluronan-binding domain involved in extracellular matrix stability and cell migration. Kohda, D., Morton, C.J., Parkar, A.A., Hatanaka, H., Inagaki, F.M., Campbell, I.D., Day, A.J. Cell (1996) [Pubmed]
  13. A central role for microvillous receptor presentation in leukocyte adhesion under flow. von Andrian, U.H., Hasslen, S.R., Nelson, R.D., Erlandsen, S.L., Butcher, E.C. Cell (1995) [Pubmed]
  14. The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44. Naujokas, M.F., Morin, M., Anderson, M.S., Peterson, M., Miller, J. Cell (1993) [Pubmed]
  15. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Günthert, U., Hofmann, M., Rudy, W., Reber, S., Zöller, M., Haussmann, I., Matzku, S., Wenzel, A., Ponta, H., Herrlich, P. Cell (1991) [Pubmed]
  16. The mouse lymph node homing receptor is identical with the lymphocyte cell surface marker Ly-22: role of the EGF domain in endothelial binding. Siegelman, M.H., Cheng, I.C., Weissman, I.L., Wakeland, E.K. Cell (1990) [Pubmed]
  17. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Avigdor, A., Goichberg, P., Shivtiel, S., Dar, A., Peled, A., Samira, S., Kollet, O., Hershkoviz, R., Alon, R., Hardan, I., Ben-Hur, H., Naor, D., Nagler, A., Lapidot, T. Blood (2004) [Pubmed]
  18. Expression of CD44 is repressed in neuroblastoma cells. Shtivelman, E., Bishop, J.M. Mol. Cell. Biol. (1991) [Pubmed]
  19. CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins. Fujisaki, T., Tanaka, Y., Fujii, K., Mine, S., Saito, K., Yamada, S., Yamashita, U., Irimura, T., Eto, S. Cancer Res. (1999) [Pubmed]
  20. Multiple variants of the human lymphocyte homing receptor CD44 generated by insertions at a single site in the extracellular domain. Jackson, D.G., Buckley, J., Bell, J.I. J. Biol. Chem. (1992) [Pubmed]
  21. Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor beta receptor I in metastatic breast tumor cells. Bourguignon, L.Y., Singleton, P.A., Zhu, H., Zhou, B. J. Biol. Chem. (2002) [Pubmed]
  22. TNF-alpha induction of CD44-mediated leukocyte adhesion by sulfation. Maiti, A., Maki, G., Johnson, P. Science (1998) [Pubmed]
  23. A human lymphocyte homing receptor, the hermes antigen, is related to cartilage proteoglycan core and link proteins. Goldstein, L.A., Zhou, D.F., Picker, L.J., Minty, C.N., Bargatze, R.F., Ding, J.F., Butcher, E.C. Cell (1989) [Pubmed]
  24. Molecular cloning of CD44R1 and CD44R2, two novel isoforms of the human CD44 lymphocyte "homing" receptor expressed by hemopoietic cells. Dougherty, G.J., Landorp, P.M., Cooper, D.L., Humphries, R.K. J. Exp. Med. (1991) [Pubmed]
  25. T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis. Lazaar, A.L., Albelda, S.M., Pilewski, J.M., Brennan, B., Puré, E., Panettieri, R.A. J. Exp. Med. (1994) [Pubmed]
  26. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Tanaka, Y., Adams, D.H., Hubscher, S., Hirano, H., Siebenlist, U., Shaw, S. Nature (1993) [Pubmed]
  27. A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor. Nedvetzki, S., Golan, I., Assayag, N., Gonen, E., Caspi, D., Gladnikoff, M., Yayon, A., Naor, D. J. Clin. Invest. (2003) [Pubmed]
  28. A novel PKC-regulated mechanism controls CD44 ezrin association and directional cell motility. Legg, J.W., Lewis, C.A., Parsons, M., Ng, T., Isacke, C.M. Nat. Cell Biol. (2002) [Pubmed]
  29. Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. Jalkanen, S., Jalkanen, M. J. Cell Biol. (1992) [Pubmed]
  30. Adhesion of human haematopoietic (CD34+) stem cells to human liver compartments is integrin and CD44 dependent and modulated by CXCR3 and CXCR4. Crosby, H.A., Lalor, P.F., Ross, E., Newsome, P.N., Adams, D.H. J. Hepatol. (2009) [Pubmed]
  31. Biomolecular characterization of CD44-fibrin(ogen) binding: distinct molecular requirements mediate binding of standard and variant isoforms of CD44 to immobilized fibrin(ogen). Alves, C.S., Yakovlev, S., Medved, L., Konstantopoulos, K. J. Biol. Chem. (2009) [Pubmed]
  32. Dentin matrix protein 1 enhances invasion potential of colon cancer cells by bridging matrix metalloproteinase-9 to integrins and CD44. Karadag, A., Fedarko, N.S., Fisher, L.W. Cancer Res. (2005) [Pubmed]
  33. A ligand for human CD48 on epithelial cells. Ianelli, C.J., Edson, C.M., Thorley-Lawson, D.A. J. Immunol. (1997) [Pubmed]
  34. EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. Tsatas, D., Kanagasundaram, V., Kaye, A., Novak, U. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. (2002) [Pubmed]
  35. The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion. Siegelman, M.H., Stanescu, D., Estess, P. J. Clin. Invest. (2000) [Pubmed]
  36. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. Kajita, M., Itoh, Y., Chiba, T., Mori, H., Okada, A., Kinoh, H., Seiki, M. J. Cell Biol. (2001) [Pubmed]
  37. Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin-containing cytoskeleton. Sainio, M., Zhao, F., Heiska, L., Turunen, O., den Bakker, M., Zwarthoff, E., Lutchman, M., Rouleau, G.A., Jääskeläinen, J., Vaheri, A., Carpén, O. J. Cell. Sci. (1997) [Pubmed]
  38. CD44 associates with EGFR and erbB2 in metastasizing mammary carcinoma cells. Wobus, M., Rangwala, R., Sheyn, I., Hennigan, R., Coila, B., Lower, E.E., Yassin, R.S., Sherman, L.S. Appl. Immunohistochem. Mol. Morphol. (2002) [Pubmed]
  39. Cytochemical localization of hyaluronic acid in human synovium with special reference to its possible process of degradation. Asari, A., Kuriyama, S., Kominami, E., Uchiyama, Y. Arch. Histol. Cytol. (1995) [Pubmed]
  40. Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. Mackay, F., Loetscher, H., Stueber, D., Gehr, G., Lesslauer, W. J. Exp. Med. (1993) [Pubmed]
  41. Differential involvement of calmodulin-dependent protein kinase II-activated AP-1 and c-Jun N-terminal kinase-activated EGR-1 signaling pathways in tumor necrosis factor-alpha and lipopolysaccharide-induced CD44 expression in human monocytic cells. Mishra, J.P., Mishra, S., Gee, K., Kumar, A. J. Biol. Chem. (2005) [Pubmed]
  42. Differential regulation of CD44 expression by lipopolysaccharide (LPS) and TNF-alpha in human monocytic cells: distinct involvement of c-Jun N-terminal kinase in LPS-induced CD44 expression. Gee, K., Lim, W., Ma, W., Nandan, D., Diaz-Mitoma, F., Kozlowski, M., Kumar, A. J. Immunol. (2002) [Pubmed]
  43. Engagement of CD44 promotes Rac activation and CD44 cleavage during tumor cell migration. Murai, T., Miyazaki, Y., Nishinakamura, H., Sugahara, K.N., Miyauchi, T., Sako, Y., Yanagida, T., Miyasaka, M. J. Biol. Chem. (2004) [Pubmed]
  44. Matrix metalloproteinases in human melanoma. Hofmann, U.B., Westphal, J.R., Van Muijen, G.N., Ruiter, D.J. J. Invest. Dermatol. (2000) [Pubmed]
  45. Moesin interacts with the cytoplasmic region of intercellular adhesion molecule-3 and is redistributed to the uropod of T lymphocytes during cell polarization. Serrador, J.M., Alonso-Lebrero, J.L., del Pozo, M.A., Furthmayr, H., Schwartz-Albiez, R., Calvo, J., Lozano, F., Sánchez-Madrid, F. J. Cell Biol. (1997) [Pubmed]
  46. CD44-stimulated human B cells express transcripts specifically involved in immunomodulation and inflammation as analyzed by DNA microarrays. Högerkorp, C.M., Bilke, S., Breslin, T., Ingvarsson, S., Borrebaeck, C.A. Blood (2003) [Pubmed]
  47. RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement. Roscic-Mrkic, B., Fischer, M., Leemann, C., Manrique, A., Gordon, C.J., Moore, J.P., Proudfoot, A.E., Trkola, A. Blood (2003) [Pubmed]
  48. Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans. Kansas, G.S., Muirhead, M.J., Dailey, M.O. Blood (1990) [Pubmed]
  49. CD44 is involved in tumor angiogenesis; an activation antigen on human endothelial cells. Griffioen, A.W., Coenen, M.J., Damen, C.A., Hellwig, S.M., van Weering, D.H., Vooys, W., Blijham, G.H., Groenewegen, G. Blood (1997) [Pubmed]
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