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The regulation of CD44-mediated adhesion to hyaluronan

University of British Columbia

Although the widely distributed cell surface glycoprotein CD44 has been shown to function as a receptor for the glycosaminoglycan hyaluronan (Aruffo et al, 1990; Miyake etal, 1990b), not all CD44 expressing cell lines are able to bind this particular ligand. This observation suggests that the hyaluronan adhesive capacity of the CD44 molecule is not determined simply by its expression on the cell surface. At present, however, the mechanisms regulating CD44 - mediated adhesion to hyaluronan remain largely undefined. Using expression cloning, a cDNA clone designated B6F1.3, was isolated that appears to "activate" the hyaluronan-binding capacity of CD44 upon transfection into the murine fibroblastoid cell line MOP8. The putative regulatory molecule encoded by this clone was found to be the murine interleukin-2 receptor γ chain (mIL-2Rγ; Cao et al., 1993). Mutation within this molecule is the mechanism causing X-linked severe combined immunodeficiency (XSCID) in humans (Noguchi et al., 1993). The human interleukin-2 receptor γ chain (hIL-2Rγ) was originally isolated as a component of functional IL-2 receptor complexes (Takeshita et al., 1992). More recent studies have demonstrated a link between this molecule and the cytokine receptors for IL-4 (Kondo et al., 1993; Russell et al., 1993) and IL-7 (Noguchi ei al., 1993; Kondo et al., 1994). Furthermore, the receptors for the cytokines IL-9 and IL-13 also are suspected to use the IL-2Rγ chain as a functional component. The expression of B6F1.3 was determined by Northern blot analysis. B6F1.3 mRNA was found at high levels on all tested murine hemopoietic cell lines and tissue types with the exception of the bone marrow cells in which little message was observed. Upregulation of CD44 does not seem to be the mechanism by which the "activation" of adhesion occurs as CD44 levels were apparently unaffected upon transfection of B6F1.3. Moreover, a cytoplasmic deletion mutant of B6F1.3 was not able to induce this adhesive event. These findings suggest a functional link between the IL-2 receptor complex and CD44, which may play a role in contributing to the XSCID phenotype in humans. We further demonstrated that stable expression of the mIL-2Rγ in MOP8 cells by retroviral-mediated gene transfer not only enhanced binding of these cells to hyaluronan but also upregulated c-jun expression without affecting cell surface levels of CD44. Transient expression of the human c-jun cDNA in MOP8 cells by a plasmid-based system using pCDM8 (Seed and Aruffo, 1987) also induced adhesion to hyaluronan, again with no alteration of CD44 expression levels. These data suggest a functional link between the proto-oncogene c-jun and the adhesion protein CD44 in the signal transduction pathways regulating cellular adhesion.

Thesis/Dissertation

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2009-01-10

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http://hdl.handle.net/2429/3543

Genetics

University of British Columbia

UBCV

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