Consists of 20 exons spanning a length of 60 kb. The first five and the last five exons are constant; Exons 1-5 and Exons 15-19 encode the N-terminal (extracellular) and C-terminal (extracellular, transmembrane, and cytoplasmic) domains respectively, and share homologous domains among all the CD44 family members. The ten exons (Exons 5a-14) located between these regions are, however, subjected to alternative splicing, resulting in the generation of CD44 variants.

742 amino acids.
Apart from alternative splicing, further diversity arises from post-translational modifications with N- and O-glycosylation and glycosaminoglycanation by heparan sulphate or chondroitin sulphate to generate multiple CD44 isoforms (at least 20 are known) of different molecular sizes (85-230 kDa).
Other post-translational modifications include cleavage by specific proteinases (possibly matrix metalloproteinases) in the extracellular matrix (ECM), (de)phosphorylation (activation of protein kinase C results in dephosphorylation of Ser-706, a constitutive phosphorylation site, and the phosphorylation of Ser-672).
N-terminal segment interacts with hyaluronan and other glycosaminoglycans, collagen, laminin and fibronectin. C-terminal segment interacts with ANK, ERM proteins (VIL2, RDX and MSN), and NF2.

Standard CD44 (CD44s), which is the smallest CD44 molecule (85-95kDa), lacks the entire variable region. It is a single-chain molecule containing several domains: a distal extracellular domain (N-terminal containing the ligand-binding sites), a membrane-proximal region, a transmembrane domain, and a cytoplasmic domain. High interspecies homology among CD44 isoforms is exhibited through these basic domains (with the exception of the membrane-proximal region). As CD44s is mostly expressed on cells of lymphohaematopoietic origin, it is also known as haematopoietic CD44 (CD44H).
The CD44 variant isoforms (CD44v) are identified by the presence of variant exon(s). These CD44 variant isoforms can be upregulated by T lymphocytes and other leukocytes after immunological activation. Their expression patterns are tissue specific: CD44 lacking v2-v10 is the most common form on haematopoietic cells while larger CD44 splice variants dominate on certain normal and neoplastic epithelia, activated lymphocytes and malignant lymphomas. A CD44 isoform consisting of the last three exon products of the variable region (CD44V8-10) is preferentially expressed on epithelial cells, hence it is also called epithelial CD44 or CD44E. In contrast, CD44V3-10, the longest CD44 isoform that expresses eight exons of the variable region, has been observed in keratinocytes.

Membrane; single-pass type I membrane protein.

CD44 is a multifunctional receptor which plays a role in cell adhesion (cell-cell and cell-ECM interactions), cell traffic, lymph node homing, presentation of chemokines and growth factors, transmission of growth signals and signals mediating haematopoiesis and apoptosis.
Ligand-binding: The principal ligand of CD44 is HA, an important component of the ECM. CD44 is involved in the uptake and intracellular degradation of HA. Other CD44 ligands include ECM components such as collagen, fibronectin, laminin, and chondroitin sulphate. ECM-unrelated ligands include mucosal addressin, serglycin, osteopontin, and the class II invariant chain.
CD44 expression in tumours: High levels of expression of CD44 have been observed in numerous cancer cell types. Some tumours, such as gliomas, express CD44s only. In contrast, other cancers, including gastrointestinal carcinoma, bladder cancer, uterine cervical cancer, breast carcinoma and non-Hodgkins lymphomas, express CD44 variants at higher levels. In addition, results from animal studies showed that introduction of CD44s- or CD44v-specific antibodies impeded CD44-ligand interaction and led to inhibition of local tumour growth and distant metastasis. These suggest that CD44 may confer a growth advantage on some tumours and could thus be a target for cancer therapy. In addition, CD44v may be a useful diagnostic marker for some cancers, or a prognostic marker.