Figure 3.

The involvement of HA and CD44 in cell survival and differentiation. (A) Model for the involvement of CD44v6 and Met due to autocrine TGF β1 signaling in lung fibrogenic fibroblasts. The repetitive lung injury in pulmonary fibrosis results in overexpression of TGFβ1 and TGFβ1-induced autocrine signaling that induces a sustained expression of CD44v6 and its co-receptor c-Met. This activates fibrogenic lung fibroblasts with subsequent increased collagen matrix synthesis. Therefore, TGF β1-induced CD44v6 and Met can have a crucial role for the sustained fibrogenic activation of lung fibroblasts. The CD44-phosphorylated ERM complex initiates activation of transforming growth factor-β receptor 1 and 2 (TGFβRI and II) and the downstream SMAD signaling complex, which contribute to fibrosis. (B) Model for involvement of periostin in HA-CD44-mediated cell survival and differentiation. Matricellular protein [periostin (PN)] binding to β1 or β3-integrin activates FAK, which activates downstream MAPK/Erk and PI3K/Akt to regulate cardiac valve cell growth, survival, differentiation into fibroblasts, and matrix organization (maturation). PN binding to β3-integrin also activates Has2 mRNA expression, Has2 phosphorylation, and HA synthesis. The interaction of HA with CD44, may, in turn, amplify the downstream effects of PN on heart valve cushion cell differentiation/maturation processes. (C) Cleavage of the extracellular domain is accompanied by the cleavage of the intracellular domain (ICD) by the presenilin-γ-secretase complex. The CD44 ICD acts together with CBP or p300 as a transcription factor and promotes CD44 transcription and extracellular matrix production.