The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125

Morag C. Martin, Lindsey A. Allan, Erika J. Mancini, Paul R. Clarke (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    32 Citations (Scopus)

    Abstract

    Caspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr125 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 p38 alpha/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 (TTCD160)-T-157 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.

    Original languageEnglish
    Pages (from-to)3854-3865
    Number of pages12
    JournalJournal of Biological Chemistry
    Volume283
    Issue number7
    DOIs
    Publication statusPublished - 15 Feb 2008

    Keywords

    • ACTIVATED PROTEIN-KINASES
    • MAP KINASES
    • TRANSCRIPTION FACTORS
    • STRUCTURAL BASIS
    • IN-VIVO
    • CYTOCHROME-C
    • CELL-DEATH
    • IDENTIFICATION
    • SPECIFICITY
    • SUBSTRATE

    Cite this