Open AccessMEK Kinase 1, a Substrate for DEVD-Directed Caspases, Is Involved in Genotoxin-Induced Apoptosis
Author(s) -
Christian Widmann,
Pär Gerwins,
Nancy L. Johnson,
Matthew Jarpe,
Gary L. Johnson
Publication year - 1998
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.18.4.2416
Subject(s) - caspase , biology , microbiology and biotechnology , apoptosis , kinase , mitogen activated protein kinase kinase , protein kinase a , phosphorylation , caspase 3 , enzyme activator , poly adp ribose polymerase , map kinase kinase kinase , biochemistry , programmed cell death , dna , polymerase
MEK kinase 1 (MEKK1) is a 196-kDa protein that, in response to genotoxic agents, was found to undergo phosphorylation-dependent activation. The expression of kinase-inactive MEKK1 inhibited genotoxin-induced apoptosis. Following activation by genotoxins, MEKK1 was cleaved in a caspase-dependent manner into an active 91-kDa kinase fragment. Expression of MEKK1 stimulated DEVD-directed caspase activity and induced apoptosis. MEKK1 is itself a substrate for CPP32 (caspase-3). A mutant MEKK1 that is resistant to caspase cleavage was impaired in its ability to induce apoptosis. These findings demonstrate that MEKK1 contributes to the apoptotic response to genotoxins. The regulation of MEKK1 by genotoxins involves its activation, which may be part of survival pathways, followed by its cleavage, which generates a proapoptotic kinase fragment able to activate caspases. MEKK1 and caspases are predicted to be part of an amplification loop to increase caspase activity during apoptosis.