The International Journal of Biochemistry & Cell Biology
Molecules in focusThe hyaluronan receptor, CD44
Introduction
The interaction between CD44 and hyaluronan can mediate both cell–cell and cell–extracellular matrix interactions and has been shown to be important in a variety of physiological and pathophysiological processes, including tumour metastasis, wound healing and leukocyte extravasation at sites of inflammation [1]. This review will focus on the interplay between CD44 and matrix metalloproteinases (MMPs) in facilitating and/or regulating cell migration. MMPs are a family of zinc-dependent endopeptidases that are the principle enzymes involved in the degradation of extracellular matrix components [2].
Section snippets
Structure
The 50–60 kb human CD44 gene is located on the short arm of chromosome 11 and is composed of 20 exons. Extensive alternative splicing gives rise to multiple variant isoforms of CD44 (Fig. 1). The so-called standard (CD44s) form lacks any variant exons. In CD44s the extracellular domain comprises 248 amino acids. The amino terminal region is relatively conserved among mammalian species (∼85% homology) and contains the hyaluronan binding domain while the membrane-proximal region is relatively
Synthesis and degradation
CD44 is expressed on many cell types including leukocytes, fibroblasts, epithelial cells, keratinocytes and some endothelial cells with CD44s being the most abundantly expressed isoform. Alternative splicing is precisely regulated and occurs only in particular cell types and activation states. Little is known about the mechanisms controlling CD44 expression but the frequent association of abnormal isoform patterns and levels of CD44 with malignancy and disease pathologies no doubt reflects a
Biological function
The ability of CD44 to bind hyaluronan is tightly regulated. CD44 can exist in inactive non-binding forms or an active ligand binding form. Changes in CD44 glycosylation, insertion of variant exons, clustering in the plane of the membrane and modulation by the cytoplasmic domain can all determine conversion between inactive and active forms. Chondroitin sulphate modified CD44 has additionally been reported to bind other extracellular matrix components such as collagen and fibronectin, while
Clinical role and therapeutic potential
It has been shown in animal models that introduction of reagents interfering with CD44–ligand interactions can inhibit inflammatory responses, local tumour growth and metastatic spread indicating that CD44 may be a potential target for therapeutic intervention in these disease states.
Database accession
EMBL/GenBank M69215.
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