Fig. 10. Sequence of signaling events during anoikis of primary human IECs. Loss of cell anchorage leads to the activation of long-prodomain caspase-2 and -9, followed by the rapid activation of downstream caspase-7, -3, and -6. Caspase 8 is also activated during IEC anoikis, presumably as a positive feedback mechanism during the augmentation phase of anoikis. Cytochrome c is released from mitochondria mostly during the augmentation phase of anoikis, possibly due to the cessation of FAK signaling via the phosphatidylinositol 3'-kinase (PI-3K)-Akt-Bad pathway. Apoptotic signaling eventually leads to DFF cleavage and DNA fragmentation, finalizing programmed cell death. Direct interaction of the components delineated needs to be shown in cell lines amenable to molecular/genetic manipulations.