User:Jacob A. Ray/Sandbox 1

Function

is a highly glycosylated multifunctional cell surface receptor that is involved in cell-cell interaction and maintenance of the extracellular matrix.^[1] The primary ligand for CD44 is hyaluronan (HA), but it has also been found to interact with other molecules including osteopontin, collagens, and fibronectin. ^[2] CD44 is a single chain protein containing four distinct regions: the N-terminal HA binding Link domain^[3], a flexible variable domain, a transmembrane domain, and an intracellular signaling domain.^[4] The is an approximately 100 amino acid domain consisting of two antiparallel β-sheets, two α-helicies, and two disulfide bonds.^[5] This domain is found in most HA binding proteins, including aggrecan, versican, brevican, and tumor necrosis factor-inducible gene 6.^[6]

Evolutionary Conservation

of CD44 residues, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Residues proximal to the HA binding site tend to be the most conserved across species while residues that fall outside of the canonical Link domain are the most variable.

Isoforms

The CD44 gene encodes a total of 20 exons but only exons 1-5 (HA binding domain) and 16-20 (transmembrane domain and cytosolic region) are constitutively expressed.^[7] Exons 6-15 are variably expressed within and across cell types creating diversity in available N- and O-glycosylation sites.^[8][9] Variable exons are termed 1v-10v. Standard CD44 contains no variable regions while variants are termed CD44vX where 'vX' identifies the variable peptides expressed.

Substrate Binding

The HA binding domain of is well characterized. Interactions with tyrosine, alanine, and cysteine residues in the appear to be the most impactful.^[10]

Cancer

Due to its key role in interacting with the extracellular matreix, altered expression of CD44 in tumors is associated with an increased risk of metastasis.^[11] For example, benign human prostate cell express CD44v5, but after neoplasia they shift to express soluble CD44 which contains no variable peptides. CD44 expression on vascular endothelial cells contributes to the regulation of angiogenesis and may be leveraged by tumors to increase local blood supply.^[12]