Fig. 7. Steps in ER-stress-induced apoptosis and communication of this signaling event from the ER to the mitochondria by the PKC-Abl complex. Several steps in the transduction of ER stress signaling leading to apoptosis have been identified. (Step 1) ER stress triggers translocation of PKC to the ER where it binds to Abl and is (directly or indirectly) phosphorylatedon tyrosine residues by Abl. (Step 2) The PKC-Abl complex translocates to mitochondria in a process that depends on PKC catalytic activity. Abl is required for PKC translocation to the mitochondria and, vice versa, PKC is required for Abl translocation to this organelle. (Step 3) PKC-Abl complex activates JNK-mediated mitochondrium-dependent apoptotic cascade. The PKC-specific peptide inhibitor V1-1, inhibits PKC translocation to the ER and the subsequent interaction of PKC and Abl, thereby suppressing ER-stress-mediated apoptosis. Rottlerin, an inhibitor of PKC catalytic activity, blocks the translocation of PKC-Abl complex to mitochondria and, thus, inhibits ER-stress-induced mitochondrium-dependent apoptosis.