CD44

The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on Chromosome 11.[5] CD44 has been referred to as HCAM (homing cell adhesion molecule), Pgp-1 (phagocytic glycoprotein-1), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.

CD44
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD44, CDW44, CSPG8, ECMR-III, HCELL, HUTCH-I, IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp1, CD44 molecule (Indian blood group)
External IDsOMIM: 107269 MGI: 88338 HomoloGene: 508 GeneCards: CD44
Gene location (Human)
Chr.Chromosome 11 (human)[1]
Band11p13Start35,138,870 bp[1]
End35,232,402 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

960

12505

Ensembl

ENSG00000026508

ENSMUSG00000005087

UniProt

P16070

P15379

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 11: 35.14 – 35.23 MbChr 2: 102.81 – 102.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tissue distribution and isoforms

CD44 is expressed in a large number of mammalian cell types. The standard isoform, designated CD44s, comprising exons 1–5 and 16–20 is expressed in most cell types. CD44 splice variants containing variable exons are designated CD44v. Some epithelial cells also express a larger isoform (CD44E), which includes exons v8–10.[6]

Function

CD44 participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis.

CD44 is a receptor for hyaluronic acid and can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). CD44 function is controlled by its posttranslational modifications. One critical modification involves discrete sialofucosylations rendering the selectin-binding glycoform of CD44 called HCELL (for Hematopoietic Cell E-selectin/L-selectin Ligand).[7] (see below)

Transcripts for this gene undergo complex alternative splicing that results in many functionally distinct isoforms; however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis. Splice variants of CD44 on colon cancer cells display sialofucosylated HCELL glycoforms that serve as P-, L-, and E-selectin ligands and fibrin, but not fibrinogen, receptors under hemodynamic flow conditions pertinent to the process of cancer metastasis.[8][9]

CD44 gene transcription is at least in part activated by beta-catenin and Wnt signalling (also linked to tumour development).

HCELL

The HCELL glycoform was originally discovered on human hematopoietic stem cells and leukemic blasts,[7][10][11][12] and was subsequently identified on cancer cells.[9][13][14][15][16] HCELL functions as a "bone homing receptor", directing migration of human hematopoietic stem cells and mesenchymal stem cells to bone marrow.[11] Ex vivo glycan engineering of the surface of live cells has been used to enforce HCELL expression on any cell that expresses CD44.[17] CD44 glycosylation also directly controls its binding capacity to fibrin and immobilized fibrinogen.[8][18]

Clinical significance

The protein is a determinant for the Indian blood group system.

  • CD44, along with CD25, is used to track early T cell development in the thymus.
  • CD44 expression is an indicative marker for effector-memory T-cells. Memory cell proliferation (activation) can also be assayed in vitro with CFSE chemical tagging.

In addition, variations in CD44 are reported as cell surface markers for some breast and prostate cancer stem cells. In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics[19] and has been seen as an indicator of increased survival time in epithelial ovarian cancer patients.[20]

Endometrial cells in women with endometriosis demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells.[21]

CD44 variant isoforms are also relevant to the progression of head and neck squamous cell carcinoma.[22][23]

Monoclonal antibodies against CD44 variants include bivatuzumab for v6.

CD44 in cancer

CD44 is a multistructural and multifunctional cell surface molecule involved in cell proliferation, cell differentiation, cell migration, angiogenesis, presentation of cytokines, chemokines, and growth factors to the corresponding receptors, and docking of proteases at the cell membrane, as well as in signaling for cell survival. All these biological properties are essential to the physiological activities of normal cells, but they are also associated with the pathologic activities of cancer cells. Experiments in animals have shown that targeting of CD44 by antibodies, antisense oligonucleotides, and CD44-soluble proteins markedly reduces the malignant activities of various neoplasms, stressing the therapeutic potential of anti-CD44 agents.

High levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia.[24] Furthermore, because alternative splicing and posttranslational modifications generate many different CD44 sequences, including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor-specific agents may be a realistic therapeutic approach.[25]

In many cancers (renal cancer and non-Hodgkin's lymphomas are exceptions), a high level of CD44 expression is not always associated with an unfavorable outcome.[26] On the contrary, in some neoplasms CD44 upregulation is associated with a favorable outcome. This is true of prostate cancer, where the transcript variant CD44v5 (includes the fifth 'v5' exon) is associated with better prognosis (increased time to recurrence following surgery).[27][26] In prostate cancer, the exclusion of the v5 exon through alternative splicing was associated with the presence of RNA binding protein KHDRBS1 and became included in the presence of increased YTHDC1 or metadherin expression.[27]

In other cases different research groups analyzing the same neoplastic disease reached contradictory conclusions regarding the correlation between CD44 expression and disease prognosis, possibly due to differences in methodology. These problems must be resolved before applying anti-CD44 therapy to human cancers.[26]

Interactions

CD44 has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000026508 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000005087 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Spring FA, Dalchau R, Daniels GL, Mallinson G, Judson PA, Parsons SF, Fabre JW, Anstee DJ (May 1988). "The Ina and Inb blood group antigens are located on a glycoprotein of 80,000 MW (the CDw44 glycoprotein) whose expression is influenced by the In(Lu) gene". Immunology. 64 (1): 37–43. PMC 1385183. PMID 2454887.
  6. Goodison S, Urquidi V, Tarin D (Aug 1999). "CD44 cell adhesion molecules". Molecular Pathology. 52 (4): 189–96. doi:10.1136/mp.52.4.189. PMC 395698. PMID 10694938.
  7. Oxley SM, Sackstein R (Nov 1994). "Detection of an L-selectin ligand on a hematopoietic progenitor cell line". Blood. 84 (10): 3299–306. doi:10.1182/blood.V84.10.3299.3299. PMID 7524735.
  8. Alves CS, Burdick MM, Thomas SN, Pawar P, Konstantopoulos K (Apr 2008). "The dual role of CD44 as a functional P-selectin ligand and fibrin receptor in colon carcinoma cell adhesion". American Journal of Physiology. Cell Physiology. 294 (4): C907–16. doi:10.1152/ajpcell.00463.2007. PMID 18234849.
  9. Hanley WD, Burdick MM, Konstantopoulos K, Sackstein R (Jul 2005). "CD44 on LS174T colon carcinoma cells possesses E-selectin ligand activity". Cancer Research. 65 (13): 5812–7. doi:10.1158/0008-5472.CAN-04-4557. PMID 15994957.
  10. Sackstein R, Dimitroff CJ (Oct 2000). "A hematopoietic cell L-selectin ligand that is distinct from PSGL-1 and displays N-glycan-dependent binding activity". Blood. 96 (8): 2765–74. doi:10.1182/blood.V96.8.2765. PMID 11023510.
  11. Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP, Wohlgemuth R (Feb 2008). "Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone". Nature Medicine. 14 (2): 181–7. doi:10.1038/nm1703. PMID 18193058. S2CID 5095656.
  12. Dimitroff CJ, Lee JY, Rafii S, Fuhlbrigge RC, Sackstein R (Jun 2001). "CD44 is a major E-selectin ligand on human hematopoietic progenitor cells". The Journal of Cell Biology. 153 (6): 1277–86. doi:10.1083/jcb.153.6.1277. PMC 2192031. PMID 11402070.
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  16. Thomas SN, Zhu F, Schnaar RL, Alves CS, Konstantopoulos K (Jun 2008). "Carcinoembryonic antigen and CD44 variant isoforms cooperate to mediate colon carcinoma cell adhesion to E- and L-selectin in shear flow". The Journal of Biological Chemistry. 283 (23): 15647–55. doi:10.1074/jbc.M800543200. PMC 2414264. PMID 18375392.
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  18. Alves CS, Yakovlev S, Medved L, Konstantopoulos K (Jan 2009). "Biomolecular characterization of CD44-fibrin(ogen) binding: distinct molecular requirements mediate binding of standard and variant isoforms of CD44 to immobilized fibrin(ogen)". The Journal of Biological Chemistry. 284 (2): 1177–89. doi:10.1074/jbc.M805144200. PMC 2613610. PMID 19004834.
  19. Li F, Tiede B, Massagué J, Kang Y (Jan 2007). "Beyond tumorigenesis: cancer stem cells in metastasis". Cell Research. 17 (1): 3–14. doi:10.1038/sj.cr.7310118. PMID 17179981.
  20. Sillanpää S, Anttila MA, Voutilainen K, Tammi RH, Tammi MI, Saarikoski SV, Kosma VM (Nov 2003). "CD44 expression indicates favorable prognosis in epithelial ovarian cancer". Clinical Cancer Research. 9 (14): 5318–24. PMID 14614016.
  21. Griffith JS, Liu YG, Tekmal RR, Binkley PA, Holden AE, Schenken RS (Apr 2010). "Menstrual endometrial cells from women with endometriosis demonstrate increased adherence to peritoneal cells and increased expression of CD44 splice variants". Fertility and Sterility. 93 (6): 1745–9. doi:10.1016/j.fertnstert.2008.12.012. PMC 2864724. PMID 19200980.
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  24. Quere R, Andradottir S, Brun A, Zubarev R, Karlsson G, Olsson K, Magnusson M, Cammenga J, Karlsson S (Mar 2010). "High levels of the adhesion molecule CD44 on leukemic cells generate acute myeloid leukemia relapse after withdrawal of the initial transforming event". Leukemia. 25 (3): 515–526. doi:10.1038/leu.2010.281. PMC 3072510. PMID 21116281.
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  27. Luxton, Hayley J.; Simpson, Benjamin S.; Mills, Ian G.; Brindle, Nicola R.; Ahmed, Zeba; Stavrinides, Vasilis; Heavey, Susan; Stamm, Stefan; Whitaker, Hayley C. (2019-08-23). "The Oncogene Metadherin Interacts with the Known Splicing Proteins YTHDC1, Sam68 and T-STAR and Plays a Novel Role in Alternative mRNA Splicing". Cancers. 11 (9): 1233. doi:10.3390/cancers11091233. ISSN 2072-6694. PMC 6770463. PMID 31450747.
  28. Bourguignon LY, Singleton PA, Zhu H, Diedrich F (Aug 2003). "Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression". The Journal of Biological Chemistry. 278 (32): 29420–34. doi:10.1074/jbc.M301885200. PMID 12748184.
  29. Chen X, Khajeh JA, Ju JH, Gupta YK, Stanley CB, Do C, Heller WT, Aggarwal AK, Callaway DJ, Bu Z (Mar 2015). "Phosphatidylinositol 4,5-bisphosphate clusters the cell adhesion molecule CD44 and assembles a specific CD44-Ezrin heterocomplex, as revealed by small angle neutron scattering". The Journal of Biological Chemistry. 290 (10): 6639–52. doi:10.1074/jbc.M114.589523. PMC 4358296. PMID 25572402.
  30. Midgley AC, Rogers M, Hallett MB, Clayton A, Bowen T, Phillips AO, Steadman R (May 2013). "TGF-β1-stimulated fibroblast to myofibroblast differentiation is mediated by HA-facilitated EGFR and CD44 co-localization in lipid rafts". The Journal of Biological Chemistry. 288 (21): 14824–38. doi:10.1074/jbc.M113.451336. PMC 3663506. PMID 23589287.
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  33. Aruffo A, Stamenkovic I, Melnick M, Underhill C, Seed B (Jul 1990). "CD44 is the principal cell surface receptor for hyaluronate". Cell. 61 (7): 1303–13. doi:10.1016/0092-8674(90)90694-A. PMID 1694723. S2CID 8217636.
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