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Molecular mechanisms regulating the ligand binding function of cd44

University of British Columbia

CD44 is a broadly distributed cell surface glycoprotein that has been shown to play an important role in many adhesion-dependent cellular processes including wound healing, lymphocyte and progenitor cell homing, and tumour metastasis. Defining the precise molecular mechanisms that regulate the ligand-binding function of CD44 is a critical step to the understanding of its role in these diverse processes. Binding of the principal ligand for CD44, hyaluronan, is a highly regulated process. Although all cells that express CD44 on their surface, present the same conserved amino terminal hyaluronan recognition motif, most do not bind this ligand constitutively. To further explore this fact, several cell lines with differing hyaluronan binding abilities were examined. These studies have demonstrated that changes in avidity achieved through increased transcription and/or aggregation in the plane of the membrane play a critical role in regulating the hyaluronan binding activity of the molecule. Correlations have been noted between the expression of certain alternatively spliced CD44 isoforms and the metastatic propensity of various histologically distinct tumour cell types. The precise mechanism by which particular CD44 isoforms contribute to the metastatic process is, however, unclear. The studies presented in this Thesis demonstrate that exon vlO containing CD44 isoforms promote cell-cell aggregation through the recognition of chondroitin sulfate presented by CD44 itself. These data help explain the differential involvement of vlO containing CD44 isoforms in tumour metastasis. Soluble CD44 proteins generated by proteolytic cleavage or aberrant intron retention have been shown to antagonize the ligand binding activity of the corresponding cell surface receptor, inducing apoptosis and inhibiting tumour growth. Interestingly, such findings appear to contradict recent studies demonstrating a correlation between the presence of high levels of soluble CD44 in the serum of cancer patients, and poor prognosis. In this Thesis, a novel naturally occurring soluble CD44 isoform generated by alternative splicing of the "constant exons", was cloned and analyzed. This molecule, designated CD44RC, markedly enhances the hyaluronan binding function of cell surface CD44. CD44RC induces the aggregation of cell surface CD44 via a mechanism that involves the recognition of chondroitin sulfate side chains.

Thesis/Dissertation

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2009-06-29

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http://hdl.handle.net/2429/9846

Pathology

University of British Columbia

UBCV

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