Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes — not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.

CD44: From adhesion molecules to signalling regulators

The circulatory and migratory properties of white blood cells have evolved to allow efficient surveillance of tissues for infectious pathogens and rapid accu­ mulation at sites of injury and infection. Lymphocytes continually patrol the body for foreign antigen by recirculating from blood, through tissue, into lymph, and back to blood. Lymphocytes acquire a predilection, based on the environment in which they first encounter foreign antigen, to home to or recirculate through that same environment (39, 40). Granulocytes and mono­ cytes cannot recirculate, but emigrate from the bloodstream in response to molecular changes on the surface of blood vessels that signal injury or infec­ tion. Lymphocytes can similarly accumulate in response to inflammatory stim­ uli. The nature of the inflammatory stimulus determines whether lymphocytes. monocytes, neutrophils, or eosinophils predominate, and thus exercises spec­ ificity in the molecular signals or "area codes" that are displayed on endothe­ lium and control traffic of particular leukocyte classes. Recent findings show that the "traffic signals" for lymphocyte recirculation and for neutrophil and monocyte localization in inflammation are strikingly similar at the molecular level. These traffic signal or area code molecules are

Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration

Publisher Summary This chapter focuses on CD44 and its interaction with extracellular matrix. CD44 is a broadly distributed family of cell surface glycoprotein that has been studied independently by many investigators in a variety of systems and under a variety of names. Two reviews clarify the diverse historical nomenclature and present the evidence that has brought this assortment of molecules and their proposed functions together under the designation CD44. Study of the structure of the single gene that encodes CD44 reveals the way the great variety of molecular forms of CD44 may be generated. CD44 is involved in lymphocyte development, during which it participates both in the earliest stages of T and B cell differentiation and in later stages of T and B cell activation in response to immunological stimuli. In these and other contexts, CD44 seems to function by mediating cell–cell or cell–substrate interactions through recognition of elements of the extracellular matrix, intercellular milieu, and pericellular layer. CD44 is expressed on cells in the early stages of hematopoiesis and has been shown to participate in at least some aspects of the hematopoietic process. In mature lymphocytes, CD44 is upregulated in response to antigenic stimuli and may participate in the effector stage of immunological responses.

CD44 and its interaction with extracellular matrix.

CD44 is a ubiquitous multistructural and multifunctional cells surface adhesion molecule involved in cell-cell and cell-matrix interactions. Twenty exons are involved in the genomic organization of this molecule. The first five and the last 5 exons are constant, whereas the 10 exons located between these regions are subjected to alternative splicing, resulting in the generation of a variable region. Differential utilization of the 10 variable region exons, as well as variations in N-glycosylation, O-glycosylation, and glycosaminoglycanation (by heparan sulfate or chondroitin sulfate), generate multiple isoforms (at least 20 are known) of different molecular sizes (85-230 kDa). The smallest CD44 molecule (85-95 kDa), which lacks the entire variable region, is standard CD44 (CD44s). As it is expressed mainly on cells of lymphohematopoietic origin, CD44s is also known as hematopoietic CD44 (CD44H). CD44s is a single-chain molecule composed of a distal extracellular domain (containing, the ligand-binding sites), a membrane-proximal region, a transmembrane-spanning domain, and a cytoplasmic tail. The molecular sequence (with the exception of the membrane-proximal region) displays high interspecies homology. After immunological activation, T lymphocytes and other leukocytes transiently upregulate CD44 isoforms expressing variant exons (designated CD44v). A CD44 isform containing the last 3 exon products of the variable region (CD44V8-10, also known as epithelial CD44 or CD44E), is preferentially expressed on epithelial cells. The longest CD44 isoform expressing in tandem eight exons of the variable region (CD44V3-10) was detected in keratinocytes. Hyaluronic acid (HA), an important component of the extracellular matrix (ECM), is the principal, but by no means the only, ligand of CD44. Other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate. Mucosal addressin, serglycin, osteopontin, and the class II invariant chain (Ii) are additional, ECM-unrelated, ligands of the molecule. In many, but not in all cases, CD44 does not bind HA unless it is stimulated by phorbol esters, activated by agonistic anti-CD44 antibody, or deglycosylated (e.g., by tunicamycin). CD44 is a multifunctional receptor involved in cell-cell and cell-ECM interactions, cell traffic, lymph node homing, presentation of chemokines and growth factors to traveling cells, and transmission of growth signals. CD44 also participates in the uptake and intracellular degradation of HA, as well as in transmission of signals mediating hematopoiesis and apoptosis. Many cancer cell types as well as their metastases express high levels of CD44. Whereas some tumors, such as gliomas, exclusively express standard CD44, other neoplasms, including gastrointestinal cancer, bladder cancer, uterine cervical cancer, breast cancer and non-Hodgkin's lymphomas, also express CD44 variants. Hence CD44, particularly its variants, may be used as diagnostic or prognostic markers of at least some human malignant diseases. Furthermore, it has been shown in animal models that injection of reagents interfering with CD44-ligand interaction (e.g., CD44s- or CD44v-specific antibodies) inhibit local tumor growth and metastatic spread. These findings suggest that CD44 may confer a growth advantage on some neoplastic cells and, therefore, could be used as a target for cancer therapy. It is hoped that identification of CD44 variants expressed on cancer but not on normal cells will lead to the development of anti-CD44 reagents restricted to the neoplastic growth.

CD44: Structure, Function and Association with the Malignant Process

The CD44 family of surface receptors regulates adhesion, movement, and activation of normal and neoplastic cells. The cytokine osteopontin (Eta-1), which regulates similar cellular functions, was found to be a protein ligand of CD44. Osteopontin induces cellular chemotaxis but not homotypic aggregation, whereas the inverse is true for the interaction between CD44 and a carbohydrate ligand, hyaluronate. The different responses of cells after CD44 ligation by either osteopontin or hyaluronate may account for the independent effects of CD44 on cell migration and growth. This mechanism may also be exploited by tumor cells to promote metastasis formation.

https://science.sciencemag.org/content/sci/271/5248/509.full.pdf

Receptor-Ligand Interaction Between CD44 and Osteopontin (Eta-1)

A variant of the glycoprotein CD44 (CD44v) that shares sequences with variants causally involved in metastasis formation is transiently expressed on B and T lymphocytes and macrophages after antigenic stimulation and in the postnatal period. Antibodies to the variant hinder in vivo activation of both B and T cells. The observation that a protein domain that is expressed on CD44 and required for the lymphatic spread of tumor cells can catalyze an essential step in the process of lymphocyte activation supports the idea that metastasizing tumor cells mimic lymphocyte behavior.

https://science.sciencemag.org/content/sci/257/5070/682.full.pdf

Participation in normal immune responses of a metastasis-inducing splice variant of CD44

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Participation in normal immune responses of a metastasis-inducing splice variant of CD44