Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2

Abstract

The apoptotic initiator caspase-2 has been implicated in oocyte death, in DNA damage-and heat shock-induced death, and in mitotic catastrophe. We show here that the mitosis-promoting kinase, cdk1-cyclin B1, suppresses apoptosis upstream of mitochondrial cytochrome c release by phosphorylating caspase-2 within an evolutionarily conserved sequence at Ser 340. Phosphorylation of this residue, situated in the caspase-2 interdomain, prevents caspase-2 activation. S340 was susceptible to phosphatase 1 dephosphorylation, and an interaction between phosphatase 1 and caspase-2 detected during interphase was lost in mitosis. Expression of S340A non-phosphorylatable caspase-2 abrogated mitotic suppression of caspase-2 and apoptosis in various settings, including oocytes induced to undergo cdk1-dependent maturation. Moreover, U2OS cells treated with nocodazole were found to undergo mitotic catastrophe more readily when endogenous caspase-2 was replaced with the S340A mutant to lift mitotic inhibition. These data demonstrate that for apoptotic stimuli transduced by caspase-2, cell death is prevented during mitosis through the inhibitory phosphorylation of caspase-2 and suggest that under conditions of mitotic arrest, cdk1-cyclin B1 activity must be overcome for apoptosis to occur.

Mechanism of action of the multikinase inhibitor Foretinib

“…20,21 In addition, activation of caspase 2 is sought to be important for cell death that occurs during the metaphase/ anaphase in response to DNA damage. 22 We show here that Foretinib induces inhibition of JNK and degradation of Plk1 via the proteasome pathway. Activation of JNK by anisomycin in CML cells treated with Foretinib results in inhibition of MC and conversely inhibition of JNK1/2 by siRNA promotes MC.…”

“…18,22,23 In addition, it has been proposed that during MC, caspase 2 shuttled from the nucleus to the cytoplasm to induce caspase 3 activation and apoptosis. Accordingly, we established through knockdown experiments that Foretinib induces apoptosis in CML cells through activation of caspases 2, -9 and -3, caspase 2 being initiatory in this process.…”

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

“…Caspase-2, -8, and -9 are phosphorylated by Cdk1/Cyclin B1 during mitosis and these modifications inhibit pro-apoptotic activity. [40][41][42] A general feature of mitotic cells is the loss of attachment to extracellular matrix as the cytoskeleton is remodeled in preparation for spindle formation. When anchorage-dependent cells remain in a detached state for extended periods, they undergo a process termed anoikis.…”

Caspase-2 as a tumour suppressor

“…7,8 Caspase-2 activation has been shown to be regulated by phosphorylation mediated by various kinases, including calcium/calmodulin-dependent protein kinase II (Ser164), 47 protein kinase CK2 (Ser157) 48 and cyclin-dependent kinase 1 (Ser340). 49 …”