CD44 Pgp-1(lymphocyte homing receptor & phagocytic glycoprotein 1),HCAM,gp85, ECMR III(extracellular matrix receptor type III), Hermes antigen, Ly-24(mouse), HUTCH-1, Lu(in-related)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Hematopoietic Cell
Nonhematopoietic Cell
Epithelial Cell
Endothelial Cell
Mesenchymal Cell
Lymphoid Cell
Myeloid Cell
Erythroid Cell
T Cell
Kidney
Skeletal muscle
Bone Marrow
Plasma Cell
Leukocyte
Erythrocyte
Lymphocyte
Endothelium
Skin
Testis
Hepatocyte
Nervous system
90 / 90
180 / 180
200 / 200

Expression
The predominant isoform of CD44 is expressed without variable exons CD44H or CD44s.  It is widely expressed on the surface of most cell types, leukocytes and erythrocytes.  Very few types of tissue or cells lack CD44.  It is expressed on epithelial, endothelial, mesothelial and mesenchymal cells, and in the nervous system.  Cells and tissues that lack CD44 include platelets, hepatocytes, certain lymphoid cell lines, cardiac muscle, kidney tubular epithelium, testis and portions of the skin.  CD44H is a major isoform expressed on lymphoid, myeloid and erythroid cells.  Expression is increased on activated and memory/effector T cells.  CD44 isoforms encoded by additional variable exons CD44v are widely expressed on epithelial cells but are only present at low levels on leukocytes, with the exception of a subpopulation of bone marrow plasma cells. Activation of lymphocytes and monocytes leads to a transient increase in the expression of CD44v isoforms.  Soluble forms of CD44 can be detected in body fluids.  They are generated by proteolytic shedding and perhaps alternative splicing to exons containing stop codons.



Structure
MOLECULAR FAMILY NAME: Belongs to the hyaladherin family.

CD44 is a single-pass type-1 341 aa glycoprotein.  It contains a 248 aa extracellular domain which contains 6 cysteine residues that have a potential to form a globular domain and multiple potential N- and O-linked glycosylation sites and sites for addition of chondroitin or heparin sulfate, a 21 aa transmembrane and a 72 aa intracellular cytoplasmic domain containing 6 serine residues which are potential phosphorylation sites.  The N-terminal has significant homology to cartilage link and proteoglycan core proteins known to interact with hyaluronan.  Alternative splicing of the CD44 gene can generate a large number of CD44 isoforms, all of which are heavily glycosylated.  In humans, all other CD44 isoforms, CD44v, are generated by the insertion of various combinations of at least 9 exons units, v2-v10, after Thr202 in the mucin-like region, adding up to 380 aa to the extracellular portion.  These variable exons also encode mucin-link sequences of ~30% Ser/Thr residues).  In addition to carrying O- and N-linked oligosaccharides, proteoglycan isoforms of CD44 have been identified with the co-valently linked glycosaminoglycans (GAGs), chondroitin sulfate (CS) and heparan sulfate (HS).  One or more of the partial consensus sequences for GAG-modification (SG) in CD44H are modified by CS on lymphocytes.  However, a full consensus sequence SGxG encoded by the v3 exon appears to be the primary site for HS modification in CD44v isoforms. The cytoplasmic domain is phosphorylated on serine/threonine residues.  There are 2 alleles of CD44 differing at 1 residue which constitute the India (In) blood group antigens In a Arg26 and In b Pro26.

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Lymphocyte 90 kDa
180-200 kDa


glycosylated
after glycosaminoglycan
modification

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  The standard form of CD44 is generated by exons 1-5, 15-17 and 19 due to alternate splicing of 1 gene containing 19 exons in humans and 20 exons in mice spanning approximately 50 kb of DNA.

POST-TRANSLATIONAL MODIFICATION

The extracellular domain of the mature protein, resulting from the cleavage of a putative 20 aa signal peptide of CD44, contains 6 cysteine residues that potentially forms a single globular domain.  There are multiple potential sites for N- and O-linked glycosylation, and several sites for CS modification.  There are 4 of 6 serine residues in the cytoplasmic domain, S271, S303, S305 and S317, that are potential sites for phosphorylation.

Ligands
The membrane-distal link module of CD44 binds the extracellular matrix (ECM) GAG hyaluronan (HA). The ability of CD44 to bind HA is highly regulated.  For example, leukocytes expressing CD44 do not bind HA constitutively but are able to bind following activation.  Molecular mechanism implicated in regulating binding include clustering, altered glycosylation, differential use of exons, and interactions with the cytoskeleton.  CD44 has also been reported to bind the ECM proteins collagen, fibronectin and laminin.  These interactions are probably mediated by CS carried by CD44.  Similarly, CD44 molecules carrying HS can bind growth factors such as basic fibroblast growth factor.  HS may also mediate reported interactions between CD44 and chemokines such as macrophages inflammatory protein 1b.  CD44 is a receptor for the chemotactic cytokine osteopontin.  The cytoplasmic domain interacts with the actin cytoskeleton through associations with ankyrin and members of the ezrin, radixin and moesin (ERM) family.  CD44 also associates with and may activate the cytoplasmic tyrosine kinase Lck.

LIGANDS AND MOLECULES ASSOCIATED WITH CD44
Molecule Comment
Hyaluronan Extracellular ligand
MIP1[b] Potential ligand via the proteoglycan chain
Osteopontin
Ankyrin Intercellular association
Fibronectin




Function
CD44 binds hyaladherin (HA) and a number of other tissue macromolecules, mediates cell adhesion and transduces activation signals to the cell.  It also interacts with other ligands, such as osteopontin, collagens and matrix metalloproteinases.  CD44 participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis and tumor metastasis.  CD44 contributes to the adhesion of leukocytes to endothelial cells, stromal cells and ECM.  These interactions appear to be mediated by CD44 binding to HA associated with cells and ECM, although alternative ligands may exist.  CD44 appears to mediate extravasation of activated and memory/effector lymphocytes, rather than na├»ve lymphocytes, into sites of inflammation rather than to primary or secondary typhoid tissues.  Expression of the v6 exon in the rat confers metastatic potential on tumor cell lines.  The same exon is expressed in activated lymphocytes in vivo and antibodies specific for this exon inhibit the immune response in vivo. Expression of the v3 exon in human B lymphoma cells increases their metastatic potential.  This effect does not appear to result from enhanced HA adhesion but does require an intact HS GAG consensus sequence SGxG, consistent with a role for growth factor or chemokine binding to HS.  CD44 may transduce signals to cells following interactions with ECM or with soluble ligands such as osteopontin.  CD44 is involved in leukocyte attachment to and rolling on endothelial cells, homing to peripheral lymphoid organs and to sites of inflammation and leukocyte aggregation. Signaling through CD44 induces cytokine release and T cell activation. The ability of CD44 to bind its ligands and growth factors changes with pattern of glycosylation.

BIOCHEMICAL ACTIVITY

CD44 serves as a recyclable receptor for HA, which is internalized by endocytosis and catabolized.  CD44 may also anchor epithelial cells to HA in the basement membranes and to maintain polar orientation.

DISEASE RELEVANCE AND FUNCTION OF CD44 IN INTACT ANIMAL

CD44 mAbs inhibit inflammation in mouse models of arthritis.  CD44/HA interactions also have a possible role in tumor metastasis and uterine smooth muscle tumors.  Variant isoforms are involved in plasma cell adhesion to bone marrow stromal cells and in the multiple myeloma disease process.  CD44 is a prognostic markers in non-Hodgkin's lymphoma, gastric and colonic tumors and breast cancer.  S. pyogenes produces a hyaluronic acid that can bind CD44, thus enabling the organism to adhere to and invade tissues.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD44: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD44
Molecule Comment
Protein kinase C

ADDITIONAL INSIGHTS

A structure for hyaladherins is now available, with the interesting similarity to C type lectins.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 960P16070
MouseA34424P15379M27129
RatP26051M61875
Antibodies
25.32   View Reactivity
BAG40A   View Reactivity
BAT31A   View Reactivity
CACTB40A   View Reactivity
CACTB45A   View Reactivity
CACTB48A   View Reactivity
CVS18   View Reactivity
DF1485   View Reactivity
F10-44-2   View Reactivity
G44-26   View Reactivity
GB34A   View Reactivity
GB50A   View Reactivity
H22A   View Reactivity
LT36A   View Reactivity
LT41A   View Reactivity
PORC24A   View Reactivity
W4/86   View Reactivity
YKIX337.8.7   View Reactivity

Revised June 25, 2008


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