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.
Cardone
M H
MH
The Burnham Institute, La Jolla, California 92037, USA.
Salvesen
G S
GS
Widmann
C
C
Johnson
G
G
Frisch
S M
SM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053179:Caspase 7; D020169:Caspases; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D007686:Kidney Tubules, Distal / Q000166:cytology; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015843:Serpins / Q000494:pharmacology; D014162:Transfection; D014764:Viral Proteins
D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D017346:Protein Serine-Threonine Kinases; D053179:Caspase 7; D020169:Caspases; D003546:Cysteine Endopeptidases