CD44 Meets Merlin and Ezrin: Their Interplay Mediates the Pro-Tumor Activity of CD44 and Tumor-Suppressing Effect of Merlin

The hyaluronan (HA)-enriched extracellular matrix is shown to support and promote cell migration during embryogenesis, inflammation, and tumorigenesis. Moreover, HA production is often increased at the sites of tumor invasion and metastasis, and the binding affinity of CD44 for HA is often increased in proliferating and migrating cells. Many of CD44's functions are mediated through its binding to HA, including its ability to promote tumor invasion and angiogenesis. A recent study has further confirmed the functional relationship between CD44 and activation of TGF-beta signaling. An interaction between CD44 and HA has also been found to promote chemoresistance of non-small cell lung carcinoma cells. Several other reports have suggested a very different role for CD44 in influencing the growth and metastasis of certain types of cancer. The ERM proteins and merlin serve as cross-linkers between cortical actin filaments and the plasma membrane and regulate actin-cytoskeleton organization and cell motility. Various experimental results suggest that merlin serves as a tumor suppressor in a wide array of cells and that loss of merlin may play an important role in tumor progression. Studies have shown that increased expression of merlin not only inhibits cell proliferation and promotes apoptosis but also impairs cell-cell and cell-matrix adhesion, cell spreading, and cell motility. Genetic analyses in Drosophila have indicated a role for merlin in promoting endocytosis of a number of signaling receptors. The data accumulated to date suggest that merlin serves as a key point of contact between the extracellular and intracellular signaling networks, and that its function is exerted through its interaction with cell-surface adhesion receptors including, and perhaps predominantly, CD44.