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CD44 signaling in T cells leading to cell spreading and its regulation by CD45 Wong, Nelson Kwan Yin


CD44 is a widely expressed adhesion molecule that has been implicated in mediating cellular signaling. In this dissertation, the signaling pathway initiated by CD44 that leads to actin rearrangement and cell spreading in T cells was studied. The results indicate that engagement of CD44 leads to actin-dependent clustering of this adhesion molecule. CD44 clustering then initiates the recruitment of signaling proteins, including the Src-family kinases (SFK) Lck and Fyn, phosphatidylinositol-3 kinase (PI3K), and non-receptor related focal adhesion kinase Pyk2. The outcome of actin rearrangement and cell spreading resultant of CD44 signaling was determined by CD45, a transmembrane tyrosine phosphatase. In the absence of CD45, elongated cell spreading and F-actin polymerization along the longitudinal axis of the cells were observed. This was accompanied by the accumulation of tyrosine phosphorylation at CD44 microclusters. Moreover, Pyk2 phosphorylation was also associated with the CD44- induced elongated cell spreading. The CD44-induced signaling pathway that leads to Pyk2 phosphorylation and elongated cell spreading involves the activities of SFK, phospholipase C (PLC), and phosphatidylinositode-3-kinase (PI3K), as well as actin polymerization and calcium mobilization. These signaling components identified are also involved in T-cell receptor (TCR)/CD3 signaling, which is initiated during T cell activation; however, the CD44 pathway was distinct. This was supported by the observations that LAT (linker for activation of T cells) phosphorylation and ERK activation were not involved in CD44 signaling, while these events are observed in TCR/CD3 signaling. In the presence of CD45, BW5147 T cells formed F-actin rings and spread round on immobilized CD44 antibody. The formation of F-actin structures in CD45+ BW5147 T cells also required Src family kinase activity. Results from confocal microscopy studies suggest that CD45 was recruited to CD44 microclusters and this was associated with the prevention of sustained Lck activation. Overall, this work shows that CD44 mediates signals that result in actin reorganization and cell spreading in T cells; however, the outcome of these events is regulated by CD45. This is likely due to the negative regulatory effect of CD45 on SFK during CD44 signaling.

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