title: Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1.
abstract: MEKK1 is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates the MAPK JNK and is required for microtubule inhibitor-induced apoptosis in B cells. Here, we find that apoptosis induced by actin disruption via cytochalasin D and by the protein phosphatase 1/2A inhibitor okadaic acid also requires MEKK1 activation. To elucidate the functional requirements for activation of the MEKK1-dependent apoptotic pathway, we created mutations within MEKK1. MEKK1-deficient cells were complemented with MEKK1 containing mutations in either the ubiquitin interacting motif (UIM), plant homeodomain (PHD), caspase cleavage site or the kinase domain at near endogenous levels of expression and tested for their sensitivity to each drug. We found that both the kinase activity and the PHD domain of MEKK1 are required for JNK activation and efficient induction of apoptosis by drugs causing cytoskeletal disruption. Furthermore, we discovered that modification of MEKK1 and its localization depends on the integrity of the PHD.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Tricker
authors.forename: Afsane
authors.initials: A
authors.lastname: Arvand
authors.forename: Raymond
authors.initials: R
authors.lastname: Kwan
authors.forename: Gordon Y
authors.initials: GY
authors.lastname: Chen
authors.forename: Ewen
authors.initials: E
authors.lastname: Gallagher
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D002645:Chickens; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats
chemical_list: D050505:Mutant Proteins; D048728:MAP Kinase Kinase Kinase 1