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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3432-3438
PHAGOCYTES
Caspase-catalyzed cleavage and activation of Mst1 correlates with
eosinophil but not neutrophil apoptosis
Patricia M. De Souza,
Hannu Kankaanranta,
Ashour Michael,
Peter J. Barnes,
Mark A. Giembycz, and
Mark A. Lindsay
From the Department of Thoracic Medicine,
Imperial College School of Medicine at the National Heart and Lung
Institute, London, United Kingdom; EST-Biology, AstraZeneca
Pharmaceuticals, Alderley Park, Cheshire, United Kingdom; and the
Immunopharmacology Research Group, Medical School, University of
Tampere, Finland and Department of Respiratory Medicine, Tampere
University Hospital, Tampere, Finland.
We have examined the role of caspase-mediated cleavage of the
Ste20-like kinases, mammalian sterile 20-like 1 and 2 (Mst1/Mst2), in
the mechanism of human eosinophil and neutrophil apoptosis. Initial
measurements of kinase activity, using myelin basic protein (MBP) as a
substrate in "in-gel" renaturation assays, showed that constitutive
eosinophil and neutrophil apoptosis were associated temporally with the
activation of a 36-kd MBP kinase (p36 MBPK) and a 34-kd MBP kinase (p34
MBPK), respectively. A constitutively active 63-kd MBP kinase (p63
MBPK) was also detected in freshly prepared eosinophils but not
neutrophils, whose activity was transiently augmented during
spontaneous apoptosis. Immunoblotting studies demonstrated the
expression of Mst1 and Mst2 in eosinophils but not neutrophils whereas
immunoprecipitation studies identified the p63 MBPK activity as
being Mst1 and Mst2 and showed that the p36 MBPK activity
represented the N-terminal catalytic fragment of Mst1. A role for
the p36 MBPK in eosinophil cell death was supported by studies showing
increased activation upon exposure to the proapoptotic
Fas/CD95-activating antibody, CH-11, and attenuation in the presence of
the survival-promoting cytokine, interleukin-5. Furthermore, spontaneous and Fas-induced activation of p36 MBPK was inhibited by catalase and the general caspase inhibitor,
z-Asp-CH2-DCB, at concentrations that suppressed eosinophil
apoptosis. These studies therefore implicate a role for caspase-
and H2O2-mediated cleavage of the Mst1 and the
subsequent release of the 36-kd catalytic fragment in the
mechanism of eosinophil apoptosis. In contrast, neutrophil apoptosis
occurs independently of Mst1 and Mst2 but instead is correlated with
the activation of an as-yet-unidentified 34-kd MBPK.
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