The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125.
Caspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr(125) by ERK1/2 MAPKs in response to growth factors. Here, we show that phosphorylation of this site is specific for these classical MAPKs and is not strongly induced when JNK and p38alpha/beta MAPKs are activated by anisomycin. By deletion and mutagenic analysis, we identify domains in caspase-9 and ERK2 that mediate their interaction. Binding of ERK2 to caspase-9 and subsequent phosphorylation of caspase-9 requires a basic docking domain (D domain) in the N-terminal prodomain of the caspase. Mutational analysis of ERK2 reveals a (157)TTCD(160) motif required for recognition of caspase-9 that acts independently of the putative common docking domain. Molecular modeling supports the conclusion that Arg(10) in the D domain of caspase-9 interacts with Asp(160) in the TTCD motif of ERK2. Differences in the TTCD motif in other MAPK family members could account for the selective recognition of caspase-9 by ERK1/2. This selectivity may be important for the antiapoptotic role of classical MAPKs in contrast to the proapoptotic roles of stress-activated MAPKs.[1]References
- The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. Martin, M.C., Allan, L.A., Mancini, E.J., Clarke, P.R. J. Biol. Chem. (2008) [Pubmed]
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