Hyaluronan Regulates Cell Behavior: A Potential Niche Matrix for Stem Cells
Signaling through CD44: hyaluronan binding to a receptor such as CD44 or RHAMM will cause a conformational change in the receptor. In the case of CD44, γ-secretase cleavage of the intracellular fragment can lead to phosphorylation of cellular components such as CaMK (calmodulin kinase). Clustering of the intracellular portion of CD44 with cellular proteins such as merlin, Src, and PKC leads to downstream activation of the Raf/MEK/ERK pathway, enhancing cell proliferation. Alternatively, activation with ankyrin, ERM, or Vav2/Tiam1 leads to F-actin activation and cytoskeletal rearrangement, membrane ruffling, and cell motility. Hyaluronan signaling also regulates cell migration and adhesion through interaction of PI3K and activation of the focal adhesion complex. PI3K activation by hyaluronan signaling, when incorporated with the Akt pathway, may also lead to MDR and cell survival.