Figure 7. Schematic representation of the signal transduction pathways affected in PASMC lacking Abr and Bcr.

Hypoxia directly or indirectly activates a G-nucleotide exchange factor (GEF) for Rac, resulting in elevated levels of GTP-bound Rac. In the absence of Bcr or Abr, Rac is not downregulated to its inactive GDP-bound form and this causes prolonged activation of p38 MAPK and production of IL-6. The inhibitor Z62954982 prevents the generation of the GTP-bound Rac that switches these pathways on, by interfering with the binding of Rac to the GEF that is chronically switched on in hypoxia.