[Frontiers in Bioscience 3, d650-656, July 1, 1998] |
THE CD44 PROTEIN FAMILY: ROLES IN EMBRYOGENESIS AND TUMOR PROGRESSION
Helmut Ponta1 and Peter Herrlich1,2
1Forschungszentrum Karlsruhe, Institute of Genetics, and 2 University of Karlsruhe, Institute of Genetics, Postfach 3640, D-76021 Karlsruhe, Germany
Received 4/27/98 Accepted 5/12/98
The major challenge in the CD44 field originates from the fact that CD44 comprises a large family of proteins, the different members of which fullfill quite different functions. Functional differences are based on structural differences due to alternative splicing to which more than 50% of the 20 exons of the CD44 gene are subjected, and to posttranslational modifications. The molecular properties linked to CD44 are not static but subject to changes. For example, the N-terminal domain of CD44 carries a basic amino acid motif which, in principle, has affinity for glycosaminoglycans. Non-activated lymphocytes express CD44s (smallest CD44 splice form) but do not bind hyaluronate (HA). Activation of lymphocytes with a tumor promoter or Concanavalin A leads to HA binding of lymphocytes (1-4). On the same line of observatives, the transfection of a CD44 splice variant into two different cell lines lead to HA binding in one, but not in the other (5)..
Examples of molecular properties provided by different CD44 splice forms are manyfold (for review see 6). Although the precise functions of individual splice forms in nearly all physiological contexts are not known, transfection experiments and the use of antibodies discriminating between different splice forms have suggested specific functions for some CD44 variants in particular physiological conditions. Most striking is a specific role of splice forms in tumor progression and in metastasis formation in rat pancreas carcinoma (7). The smallest splice form CD44s appears not to be involved in this process. Furthermore, on many human tumor cells expression of larger CD44 splice forms (CD44 variants, CD44v) is upregulated in comparison to their tissue of origin. Another striking example of a particular role of some CD44 splice forms but not of others is found in the activation of the immune system. The immune response leads to upregulation of CD44 variants that are not expressed in resting lymphocytes and dendritic cells. CD44 variant specific antibodies can abrogate the immune response (8,9). It is already evident from the current limited knowledge of the molecular properties of CD44 that a given CD44 protein fullfills more than one molecular function, e.g. in the immune system.