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-termin al kinase (JNK) pathway is activated in and promotes anoikis. This act ivation requires caspase activity. We presently report that a DEVD mot if-specific caspase that cleaves MEKK-1 specifically is activated when cells lose matrix contact. This cleavage is required for the activati on of the kinase activity. When overexpressed, the MEKK-1 cleavage pro duct stimulates apoptosis; the wild-type, full-length MEKK-1 sensitize s cells to anoikis; and a cleavage-resistant mutant of MEKK-1 partiall y protects cells against anoikis. The cleavage-resistant or kinase-ina ctive mutants also prevent caspase-7 from being activated completely. Thus, caspases can induce apoptosis by activating MEKK-1, which in tur n activates more caspase activity, comprising a positive feedback loop .