Fig. 4

CD44-mediated downstream signaling pathways. CD44s and CD44v6 are shown as representative CD44 isoforms that mediate specific downstream signaling pathways. CD44v6 can recruite ezrin/radixin/moesin (ERM) proteins that promote cytosketal changes and that may interact with VEGFR contributing angiogenesis, cancer cell division, and proliferation. CD44v can act as a coreceptor for the receptor tyrosine kinase c-Met to promote cancer cell invasion. CD44s can change cytoskeleton structure mediating Snail/β-catenin translocation to the nucleus promoting transcrition of the matrix metalloproteinases (MMP) family or urokinase-type plasminogen activator (uPA) expression causing an increase in cancer cell invasion. CD44s can also enhance activation of the PI3K/AKT pathway contributing to cancer cell invasion and proliferation. CD44 modulates Src/MAPK signaling pathway leading to cancer cell division and proliferation. CD44 also causes Hypoxia-inducible factor 1α (HIF1α) binding to nuclear DNA to increase glycolysis, in turn rendering a metabolic shift in cancer cells