CD44 is an integral cell membrane glycoprotein with a postulated role in matrix adhesion lymphocyte activation and lymph node homing.

The nucleotide sequence of CD44 cDNAs predicts a 37-kD polypeptide with homology to cartilage link protein (115435) in a phylogenetically conserved amino-terminal domain.

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.

The mouse monoclonal antibody Hermes-3 recognizes the 85-95 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.

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).

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).

Francke et al. (1983) showed that the antigens defined by monoclonal antibodies A3D8 and A1G3 are determined by genes on 11p.

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--'monoclonal Duke University, 3,' or CD44.

Telen (1992) knew of no evidence that the INLU and CD44 (MDU3) genes are the same.

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.

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.

Screaton et al. (1992) found that the CD44 gene contains 19 exons spanning some 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.

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 expression 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.

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.).

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.