Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8

Abstract

Although caspase-2 is believed to be involved in death receptor-mediated apoptosis, the exact function, mode of activation, and regulation of caspase-2 remain unknown. Here we show that protein kinase (PK) CK2 phosphorylates procaspase-2 directly at serine-157. When intracellular PKCK2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a PIDDosome-independent manner. The activated caspase-2 then processes procaspase-8 monomers between the large and small subunits, thereby priming cancer cells for TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The processed procaspase-8 that is recruited to death-inducing signaling complex by TRAIL engagement becomes fully activated, and cancer cells undergo apoptosis. PKCK2 activity is low in TRAILsensitive cancer cell lines but high in TRAIL-resistant cancer cell lines. Thus, downregulating PKCK2 activity is required for TRAIL-mediated apoptosis to occur in TRAILresistant cancer cells. Our data provide novel insights into the regulation, mode of activation, and function of caspase-2 in TRAIL-mediated apoptosis.

A Purified Extract from Clematis mandshurica Prevents Adenoviral-TRAIL Induced Apoptosis on Rat Articular Chondrocytes

“…Activated caspase-8 then activates downstream caspase members such as caspase-3, and induces continuously the cleavage of cytosolic proapoptotic protein Bid (Sprick et al, 2000;Kischkel et al, 2000;Stennicke et al, 1998). A recent study has elucidated that caspase-2 primes TRAIL-mediated apoptosis by processing procaspase-8 (Shin et al, 2005). The data of the present study also show that caspase-2 and -8 and Bid are involved in Ad-TRAIL-induced apoptosis of chondrocytes.…”

Caspases and Kinases in a Death Grip

“…CK2 phosphorylates caspase-2 at serine 157 (S157) in the region connecting the caspase recruitment domain and the large subunit, blocking the dimerization and subsequent activation of caspase-2 (Shin et al, 2005). Interestingly, the loss of S157 phosphorylation results in the autoactivation of caspase-2 in a PIDDosome-independent manner, raising the possibility that caspase-2 activation is persistently suppressed by constitutively active CK2 (Shin et al, 2005).…”

“…CK2 phosphorylates caspase-2 at serine 157 (S157) in the region connecting the caspase recruitment domain and the large subunit, blocking the dimerization and subsequent activation of caspase-2 (Shin et al, 2005). Interestingly, the loss of S157 phosphorylation results in the autoactivation of caspase-2 in a PIDDosome-independent manner, raising the possibility that caspase-2 activation is persistently suppressed by constitutively active CK2 (Shin et al, 2005). CaMKII-mediated phosphorylation of caspase-2 at serine 135 (S135) was identified using extracts from eggs of the frog Xenopus laevis , where this phosphorylation can suppress the binding of RAIDD to caspase-2 and subsequent caspase-2 activation (Nutt et al, 2005).…”

Emergence of protein kinase CK2 as a key target in cancer therapy

“…It now appears that CK2 may exert a broad impact on the apoptotic machinery by influencing the activity of diverse molecules and pathways involved in the regulation of apoptosis. A few of the examples are the PI3K/Akt pathway [29,30], survivin and other inhibitors of apoptosis proteins (IAPs) [31,32], caspases [33,34], proteins in the Bcl2 pathway, and reactive oxygen species pathways [35-39]. These various observations point to the global impact of CK2 on apoptotic activity in the cell, and further highlight the significance of this function of CK2 in cancer cell biology as discussed subsequently.…”