Molecules in focus The CD44 protein family

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Abstract

The designation CD44 describes a group of type I transmembrane proteins which share N-terminal and C-terminal sequences. These molecules differ in the central extracellular domain by the use of sequences encoded by ten variant exons which may be completely absent or included in various combinations and by cell type specific addition of glycosaminoglycan and carbohydrate moieties. Expression of variant proteins is observed in normal tissues such as on keratinocytes, dendritic cells and activated lymphocytes in the adult organism and on morphogenetically active epithelium such as the apical ectodermal ridge (AER) in the embryo. Certain CD44 proteins expressed on the AER can act as low affinity fibroblast growth factor receptors and are vital for epithelial–mesenchymal cell communication. CD44 variant proteins have also been implicated in tumour growth and metastasis and we speculate that CD44 mediated growth factor presentation may also be decisive in metastasis formation. Molecular strategies designed to block growth factor presentation by CD44 may aid in the therapy of metastatic cancer.

Introduction

Prior to being given a standardised name, CD44 appeared in many guises probably reflecting its many functions. CD44 was first described by Dalchau et al.[3], as a molecule present on the surface of T-lymphocytes, granulocytes and cortical thymocytes. It was rediscovered as phagocytic glycoprotein 1 (Pgp-1), an 80 kDa polymorphic surface glycoprotein expressed in large amounts on the surface of 3T3 cells, macrophages and granulocytes. The ability of CD44 to associate with the cellular cytoskeleton and bind the extracellular matrix components fibronectin, collagen types I and IV and hyaluronan led to CD44 being described as the extracellular matrix receptor type III (ECM-III) and identified as the major receptor for hyaluronan[8]. Furthermore, binding of specific antibodies to a protein that we now know to be CD44 were shown to interfere with lymphocyte homing (Hermes 3) and with the binding of lymphocytes to high endothelial venules (HUTCH-1)[8]. Other suggested functional roles for CD44 proteins include involvement in lymphocyte activation, hematopoiesis, cell migration, nerve axon guidance, metastasis formation[9]and epithelial–mesenchymal cell communication during embryogenesis[16].

Section snippets

Structure

The CD44 gene is located on the short arm of human chromosome 11 and on mouse chromosome 2. The entire human CD44 gene covers between 50 and 60 kb of genomic DNA and contains at least 20 exons (Fig. 1(A)). Exons 1–16 including exon 5a encode the extracellular domain of the protein, exon 17 encodes a short transmembrane domain and exons 18 and 19 encode the cytoplasmic domain[8]. The cDNA sequences of the rat, murine, equine, canine, bovine, hamster and baboon CD44 genes are also known. cDNA

Expression of CD44

Two classes of CD44 specific antibodies exist which can be utilised as tools to study the expression and function of CD44 proteins. The first class encompasses all antibodies which recognise epitopes encoded by non-variant sequences and therefore detect all forms of CD44 with no distinction between CD44s and CD44v proteins (pan-CD44 antibodies). The majority of the members falling into this class recognise epitopes located in the extracellular domain and include all of the antibodies generated

Functions of CD44 proteins

One may expect that CD44 proteins through diversity of their extracellular domains interact with numerous different partners (ligands). Many ligands have been described, e.g. hyaluronate, fibronectin, collagen types I and IV, serglycin and osteopontin (for references see Ref.[9]). Unfortunately, there are at present, only a few examples for a physiological significance for the interaction between CD44 and the majority of these ligands. Such physiologically relevant interactions are supported by

The role in cancer, a hypothesis and possible therapeutic implications

We like to propose that tumour cells expressing CD44 may gain a selective advantage by binding growth factors and presenting them either to themselves or to their neighbours in the process of metastatic colony formation. This binding could be mediated by either covalently bound heparan sulphate side chains or by non-covalent recruitment of glycosaminoglycans such as heparan or chondroitin sulphate by certain CD44v proteins[14]. Tumour cells could present growth factors in a CD44 dependent

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