PubMed Journals: J Biol Chem
Source: PMID: 11278283
⇦ ⇨ J Biol Chem. 2001 Jun 1;276(22):19276-85.
⇩ Epub 2001 Mar 7.
MST, a physiological caspase substrate, highly
sensitizes apoptosis both upstream and downstream
of caspase activation.
Lee KK(1), Ohyama T, Yajima N, Tsubuki S,
(1) Institute for Virus Research, Kyoto University,
Kyoto 606-8507, Japan.
The human serine/threonine kinase, mammalian
STE20-like kinase (MST), is considerably
homologous to the budding yeast kinases,
SPS1 and STE20, throughout their kinase
domains. The cellular function and physiological
activation mechanism of MST is unknown except
for the proteolytic cleavage-induced activation
in apoptosis. In this study, we show that MST1
and MST2 are direct substrates of caspase-3
both in vivo and in vitro. cDNA cloning
of MST homologues in mouse and nematode
shows that caspase-cleaved sequences are
evolutionarily conserved. Human MST1 has
two caspase-cleavable sites, which generate
biochemically distinct catalytic fragments.
Staurosporine activates MST either
caspase-dependently or independently, whereas
Fas ligation activates it only caspase-dependently.
Immunohistochemical analysis reveals that
MST is localized in the cytoplasm. During
Fas-mediated apoptosis, cleaved MST translocates
into the nucleus before nuclear fragmentation
is initiated, suggesting it functions in the
nucleus. Transiently expressed MST1 induces
striking morphological changes characteristic
of apoptosis in both nucleus and cytoplasm,
which is independent of caspase activation.
Furthermore, when stably expressed in HeLa
cells, MST highly sensitizes the cells to
death receptor-mediated apoptosis by accelerating
caspase-3 activation. These findings suggest
that MST1 and MST2 play a role in apoptosis
both upstream and downstream of caspase
DOI: 10.1074/jbc.M005109200 PMID: 11278283
[Indexed for MEDLINE]