Journal article
Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1
EMBO Journal, Vol.17(8), pp.2224-2234
04/01/1998
DOI: 10.1093/emboj/17.8.2224
Abstract
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. Kinasedead 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.
Details
- Title: Subtitle
- Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1
- Creators
- J D Graves - University of Washington Medical CenterY Gotoh - Boston Children's HospitalK E Draves - University of Washington Medical CenterDiane Ambrose (Author)M Wright - University of Iowa, Molecular Physiology and BiophysicsDavid K M Han (Author)Jonathan Chernoff (Author) - University of Washington Medical CenterEdward A Clark (Author) - University of Washington Medical CenterEdwin G Krebs (Author) - University of Washington Medical Center
- Resource Type
- Journal article
- Publication Details
- EMBO Journal, Vol.17(8), pp.2224-2234
- DOI
- 10.1093/emboj/17.8.2224
- ISSN
- 0261-4189
- eISSN
- 1460-2075
- Language
- English
- Date published
- 04/01/1998
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9983759100202771
Metrics
7 Record Views