Figure 3. Potential ROCK targets in apoptotic signaling.

Several ROCK substrates are involved in the regulation of apoptosis. ROCK can increase MLC phosphorylation through direct effect on MLC or indirectly by inactivating MLC phosphatase (MYPT1). The increased MLC phosphorylation results in stimulation of actomyosin contractility, which regulates morphological apoptotic events during the execution phase of apoptosis including plasma membrane blebbing, nuclear disintegration and fragmentation of apoptotic cells. Under some conditions, the actin cytoskeleton rearrangement induced by ROCK activation can also be involved in the intracellular signaling involved in the initiating stages of apoptosis through the regulation of assembly of death receptor complex or loss of cell adhesion. In addition, ROCK has been shown to stimulate phosphatase and tensin homologue (PTEN) and inhibit insulin receptor substrate 1 (IRS1) signaling (broken line indicates that both positive and negative regulations of IRS1 signaling by ROCK have been reported), resulting in inactivation of Akt. Akt has important roles in promoting cell survival, possibly through inhibition of both extrinsic and intrinsic pathways. Finally, ROCK activation was found to promote apoptosis through increasing ezrin phosphorylation, which in turn led to Fas clustering and membrane expression.