Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling.
Apoptosis signal-regulating kinase 2 (ASK2) is an interaction partner of the highly related ASK1. Here, we describe a regulatory function of ASK2 in stress signaling-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Increased cleavage of caspase-3 and PARP was demonstrated by overexpression as well as knockdown of ASK2 after stress-induction by serum-starvation. We show that ectopically expressed ASK2 homo-oligomerized while endogenous ASK2 and ASK1 formed hetero-oligomers, which decreased upon serum-starvation. Co-expression of ASK2 and ASK1 stabilized these two proteins and reduced starvation-induced caspase-3 activation and degradation of PARP. Analysis of the intracellular localization of ASK2 exhibited a similar localization compared with ASK1 in the nucleus, cytoplasm, and in mitochondria. We propose that ASK2 regulates stress-induced caspase-3 and PARP cleavage in a dose-dependent manner by heteromeric complex formation with ASK1.
Ortner
Elisabeth
E
Institute of Medical Virology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland.
Moelling
Karin
K
D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D015151:Immunoblotting; D047468:Immunoprecipitation; D048848:MAP Kinase Kinase Kinase 5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
D016895:Culture Media, Serum-Free; D011065:Poly(ADP-ribose) Polymerases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C116394:MAP kinase kinase kinase 6; C482858:MAP3K5 protein, human; D053148:Caspase 3