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J. Biol. Chem., Vol. 276, Issue 18, 14909-14915, May 4, 2001
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From the Departments of The serine/threonine kinase Mst1, a
mammalian homolog of the budding yeast Ste20 kinase, is cleaved by
caspase-mediated proteolysis in response to apoptotic stimuli such as
ligation of CD95/Fas or treatment with staurosporine. Furthermore,
overexpression of Mst1 induces morphological changes characteristic of
apoptosis in human B lymphoma cells. Mst1 may therefore represent an
important target for caspases during cell death which serves to amplify the apoptotic response. Here we report that Mst1 has two caspase cleavage sites, and we present evidence indicating that cleavage may
occur in an ordered fashion and be mediated by distinct caspases. We
also show that caspase-mediated cleavage alone is insufficient to
activate Mst1, suggesting that full activation of Mst1 during apoptosis
requires both phosphorylation and proteolysis. Another role of
phosphorylation may be to influence the susceptibility of Mst1 to
proteolysis. Autophosphorylation of Mst1 on a serine residue close to
one of the caspase sites inhibited caspase-mediated cleavage in
vitro. Finally, Mst1 appears to function upstream of the protein
kinase MEKK1 in the SAPK pathway. In conclusion, Mst1 activity is
regulated by both phosphorylation and proteolysis, suggesting that
protein kinase and caspase pathways work in concert to regulate cell death.
Both Phosphorylation and Caspase-mediated Cleavage Contribute to
Regulation of the Ste20-like Protein Kinase Mst1 during
CD95/Fas-induced Apoptosis*
§,
,¶
Immunology,
¶ Microbiology, and ** Pharmacology, University of Washington
Medical Center, Seattle, Washington 98195 and the Institute of
Molecular and Cellular Biosciences, University of Tokyo,
Tokyo 113-8654, Japan
*
This work was supported by National Institutes of Health
Grants R01GM58487 and RO1AI44250.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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