Figure 4.

PAR₂-dependent activation of GSK3β in normal colon stem cells. PAR₂ activation by protease-dependent cleavage can induce a β arrestin-dependent signaling pathway resulting in GSK3β activation through its de-phosphorylation by the phosphatase PP2A. This signaling pathway is controlled by the Rho kinase activated by adhesive stress. Gene transcription of integrins, metalloproteases (MMP) and their inhibitors (TIMP), is regulated by the PAR₂/GSK3β pathway. Active GSK3β counteracts stress-induced apoptosis by multiple mechanisms (see Section 3, “GSK3β and key functions of adult stem cells”). In the physiology of colon stem cells, the pro-survival signaling of PAR₂ is sexually dimorphic depending on GSK3β or on Akt.