Figure 7.

Schematic illustration of the IPF fibroblast pathological proliferation signaling pathway. When IPF fibroblasts interact with polymerized collagen, Akt activity is inappropriately high as a result of low PTEN activity. Akt phosphorylates and inactivates FoxO3a by promoting its translocation to the cytoplasm. Furthermore, p-FoxO3a in the nucleus cannot bind to DNA because of Ser253 phosphorylation. FoxO3a is then unable to activate its target gene p27, and proliferation is not suppressed (left). In contrast, when control fibroblasts interact with polymerized collagen, PTEN activity remains high, suppressing Akt activity. FoxO3a remains active and accumulates in the nucleus, promoting p27 expression and suppressing proliferation (right).