Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1

Autor: Diane M. Ambrose, David K. Han, Edwin G. Krebs, Kevin E. Draves, Yukiko Gotoh, Jonathan Chernoff, Michael E. Wright, Edward A. Clark, Jonathan D. Graves
Rok vydání: 1998
Předmět:
Saccharomyces cerevisiae Proteins
p38 mitogen-activated protein kinases
Molecular Sequence Data
Apoptosis
Caspase 3
Cysteine Proteinase Inhibitors
Protein Serine-Threonine Kinases
Serpin
General Biochemistry
Genetics and Molecular Biology
Amino Acid Chloromethyl Ketones
Viral Proteins
Tumor Cells
Cultured
medicine
Animals
Humans
Staurosporine
Amino Acid Sequence
fas Receptor
Protein kinase A
Molecular Biology
Serpins
Caspase
Cell Line
Transformed
Mammals
Binding Sites
General Immunology and Microbiology
MAP kinase kinase kinase
biology
General Neuroscience
Intracellular Signaling Peptides and Proteins
MAP Kinase Kinase Kinases
Fas receptor
Molecular biology
Cell biology
Cysteine Endopeptidases
Caspases
Calcium-Calmodulin-Dependent Protein Kinases
biology.protein
Oligopeptides
Research Article
medicine.drug
Zdroj: The EMBO Journal. 17:2224-2234
ISSN: 1460-2075
DOI: 10.1093/emboj/17.8.2224
Popis: Mst1 is a ubiquitously expressed serine-threonine kinase, homologous to the budding yeast Ste20, whose physiological regulation and cellular function are unknown. In this paper we show that Mst1 is specifically cleaved by a caspase 3-like activity during apoptosis induced by either cross-linking CD95/Fas or by staurosporine treatment. CD95/Fas-induced cleavage of Mst1 was blocked by the cysteine protease inhibitor ZVAD-fmk, the more selective caspase inhibitor DEVD-CHO and by the viral serpin CrmA. Caspase-mediated cleavage of Mst1 removes the C-terminal regulatory domain and correlates with an increase in Mst1 activity in vivo, consistent with caspase-mediated cleavage activating Mst1. Overexpression of either wild-type Mst1 or a truncated mutant induces morphological changes characteristic of apoptosis. Furthermore, exogenously expressed Mst1 is cleaved, indicating that Mst1 can activate caspases that result in its cleavage. Kinase-dead Mst1 did not induce morphological alterations and was not cleaved upon overexpression, indicating that Mst1 must be catalytically active in order to mediate these effects. Mst1 activates MKK6, p38 MAPK, MKK7 and SAPK in co-transfection assays, suggesting that Mst1 may activate these pathways. Our findings suggest the existence of a positive feedback loop involving Mst1, and possibly the SAPK and p38 MAPK pathways, which serves to amplify the apoptotic response.
Databáze: OpenAIRE
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