The regulation of anoikis: MEKK-1 activation requires cleavage by caspases.
Certain cell types undergo apoptosis when they lose integrin-mediated contacts with the extracellular matrix ("anoikis"). The Jun N-terminal kinase (JNK) pathway is activated in and promotes anoikis. This activation requires caspase activity. We presently report that a DEVD motif-specific caspase that cleaves MEKK-1 specifically is activated when cells lose matrix contact. This cleavage is required for the activation of the kinase activity. When overexpressed, the MEKK-1 cleavage product stimulates apoptosis; the wild-type, full-length MEKK-1 sensitizes cells to anoikis; and a cleavage-resistant mutant of MEKK-1 partially protects cells against anoikis. The cleavage-resistant or kinase-inactive mutants also prevent caspase-7 from being activated completely. Thus, caspases can induce apoptosis by activating MEKK-1, which in turn activates more caspase activity, comprising a positive feedback loop.[1]References
- The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cardone, M.H., Salvesen, G.S., Widmann, C., Johnson, G., Frisch, S.M. Cell (1997) [Pubmed]
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