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CD44 molecule (Indian blood group)

PDB rendering based on 1poz.
Available structures
1poz, 1uuh, 2i83
Identifiers
Symbols CD44; CDW44; CSPG8; ECMR-III; HCELL; IN; LHR; MC56; MDU2; MDU3; MGC10468; MIC4; MUTCH-I; Pgp1
External IDs OMIM107269 MGI88338 HomoloGene508 GeneCards: CD44 Gene
RNA expression pattern
PBB GE CD44 204490 s at tn.png
PBB GE CD44 212063 at tn.png
PBB GE CD44 204489 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 960 12505
Ensembl ENSG00000026508 ENSMUSG00000005087
UniProt P16070 P15379
RefSeq (mRNA) NM_000610 NM_001039150
RefSeq (protein) NP_000601 NP_001034239
Location (UCSC) Chr 11:
35.12 - 35.21 Mb
Chr 2:
102.61 - 102.7 Mb
PubMed search [1] [2]

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.[1]

Contents

Function

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, as exemplified by the ability of sialyfucosylated glycoforms of CD44 to bind P-, L-, and E-selectin under shear flow conditions.[2][3][4] CD44 glycosylation also directly controls its binding capacity to fibrin and immobilized fibrinogen. [5] [6] Furthermore, specialized sialofucosylated glycoform of CD44 called HCELL is found natively on human hematopoietic stem cells, and is a highly potent E-selectin and L-selectin ligand. HCELL functions as a "bone homing receptor", directing migration of human hematopoietic stem cells and mesenchymal stem cells to bone marrow.[7]

This protein participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. 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 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. CD44 gene transcription is at least in part activated by beta-catenin and Wnt signalling (also linked to tumour development).

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.[8] and has been seen as an indicator of increased survival time in epithelial ovarian cancer patients.[9]

Interactions

CD44 has been shown to interact with FYN,[10] ARHGEF1,[11] Src,[12] Lck,[13][10] Fibronectin,[14] selectins,[2][3][4] and fibrin and immobilized fibrinogen.[5][6]

References

  1. ^ 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. PMID 2454887. 
  2. ^ a b Hanley WD, Napier SL, Burdick MM, Schnaar RL, Sackstein R, Konstantopoulos K. (Dec 2005). "Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells". FASEB J 20 (2): 337-9. PMID 16352650. 
  3. ^ a b Napier SL, Healy ZR, Schnaar RL, Konstantopoulos K (Feb 2007). "Selectin ligand expression regulates the initial vascular interactions of colon carcinoma cells: the roles of CD44v and alternative sialofucosylated selectin ligands". J Biol Chem 282 (6): 3433-41. PMID 17135256. 
  4. ^ a b 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". J Biol Chem 283 (23): 15647-55. PMID 18375392. 
  5. ^ a b 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". Am J Physiol Cell Physiol 294 (4): C907-16. PMID 18234849. 
  6. ^ a b 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)". J Biol Chem 284 (2): 1177-89. PMID 19004834. 
  7. ^ Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP, Wohlgemuth R (February 2008). "Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone". Nat. Med. 14 (2): 181–7. doi:10.1038/nm1703. PMID 18193058. 
  8. ^ Li F, Tiede B, Massagué J, Kang Y (January 2007). "Beyond tumorigenesis: cancer stem cells in metastasis". Cell Res. 17 (1): 3–14. doi:10.1038/sj.cr.7310118. PMID 17179981. 
  9. ^ Sillanpää S, Anttila MA, Voutilainen K, Tammi RH, Tammi MI, Saarikoski SV, Kosma VM (November 2003). "CD44 expression indicates favorable prognosis in epithelial ovarian cancer". Clin. Cancer Res. 9 (14): 5318–24. PMID 14614016. http://clincancerres.aacrjournals.org/content/9/14/5318.long. 
  10. ^ a b Ilangumaran S, Briol A, Hoessli DC (May 1998). "CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes". Blood 91 (10): 3901–8. PMID 9573028. 
  11. ^ Bourguignon LY, Singleton PA, Zhu H, Diedrich F (August 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". J. Biol. Chem. 278 (32): 29420–34. doi:10.1074/jbc.M301885200. PMID 12748184. 
  12. ^ Bourguignon LY, Zhu H, Shao L, Chen YW (March 2001). "CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration". J. Biol. Chem. 276 (10): 7327–36. doi:10.1074/jbc.M006498200. PMID 11084024. 
  13. ^ Taher TE, Smit L, Griffioen AW, Schilder-Tol EJ, Borst J, Pals ST (February 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". J. Biol. Chem. 271 (5): 2863–7. PMID 8576267. 
  14. ^ Jalkanen S, Jalkanen M (February 1992). "Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin". J. Cell Biol. 116 (3): 817–25. PMID 1730778. 

Further reading

  • Konstantopoulos K, Thomas SN (2009). "Cancer cells in transit: the vascular interactions of tumor cells". Annu Rev Biomed Eng 11: 177-202. PMID 19413512. 
  • Sackstein R (May 2004). "The bone marrow is akin to skin: HCELL and the biology of hematopoietic stem cell homing". J. Invest. Dermatol. 122 (5): 1061–9. doi:10.1111/j.0022-202X.2004.09301.x. PMID 15140204. 
  • Günthert U (1994). "CD44: a multitude of isoforms with diverse functions.". Curr. Top. Microbiol. Immunol. 184: 47–63. PMID 7508842. 
  • Yasuda M, Nakano K, Yasumoto K, Tanaka Y (2003). "CD44: functional relevance to inflammation and malignancy.". Histol. Histopathol. 17 (3): 945–50. PMID 12168806. 
  • Sun CX, Robb VA, Gutmann DH (2003). "Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation.". J. Cell. Sci. 115 (Pt 21): 3991–4000. doi:10.1242/jcs.00094. PMID 12356905. 
  • Assimakopoulos D, Kolettas E, Patrikakos G, Evangelou A (2003). "The role of CD44 in the development and prognosis of head and neck squamous cell carcinomas.". Histol. Histopathol. 17 (4): 1269–81. PMID 12371152. 
  • Ponta H, Sherman L, Herrlich PA (2003). "CD44: from adhesion molecules to signalling regulators.". Nat. Rev. Mol. Cell Biol. 4 (1): 33–45. doi:10.1038/nrm1004. PMID 12511867. 
  • Martin TA, Harrison G, Mansel RE, Jiang WG (2004). "The role of the CD44/ezrin complex in cancer metastasis.". Crit. Rev. Oncol. Hematol. 46 (2): 165–86. doi:10.1016/S1040-8428(02)00172-5. PMID 12711360. 

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