Figure 4.

GIST and apoptosis signaling. Survival signals can activate the PtdIns(3,4,5)P₃-AKT cascade, which phosphorylates and inactivates the pro-apoptotic BCL2-family member BAD. In GIST, pro-apoptotic proteins, such as BAX, are downregulated and anti-apoptotic regulators are expressed. Anti-apoptotic proteins, including the anti-apoptotic BCL2 family members and inhibitor of apoptosis (IAP) proteins, are regulated by DIABLO/SMAC, which is mutated in GIST samples. IAPs are upregulated in GIST. XIAP/BIRC4, directly inhibits effector caspases, whereas BIRC5/survivin has indirect anti-apoptotic effects by stabilizing XIAP and inhibiting DIABLO. Apoptosis is also regulated through the mitochondrial (intrinsic) pathway. Pro-apoptotic BCL2 family proteins, including, BAX and BCL2L11/BIM, are important mediators of these signals. Activation of mitochondria promotes the release of CYCS/cytochrome C that binds APAF1 to form the apoptosome and subsequent activation of the initiator proCASP9. APAF1 interacts with the pro-apoptotic tumor suppressor FAM96A, which is downregulated in GIST.