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1 during apoptosis in Molt-4 cells
* Department of Signal Transduction, Division of Molecular and Life Science, Pohang University of Science and Technology, Kyungbuk, Pohang 790–784, Republic of Korea;
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA;
Department of Biochemistry, Faculty of Medicine and Health Science, UAE University, Al Ain, UAE; and
§ BASF Bioresearch Corporation, Worcester, Massachusetts 01605, USA
1Correspondence: Department of Signal Transduction, Division of Molecular and Life Science, Pohang University of Science and Technology, San 31 Hyoja-Dong, Nam-Gu, Kyungbuk, Pohang 790–784, Republic of Korea. E-mail: pgs{at}pop.postech.ac.kr
Apoptosis is a cell suicide mechanism that requires the activation of
cellular death proteases for its induction. We examined whether the
progress of apoptosis involves cleavage of phospholipase C-
1
(PLC-1), which plays a pivotal role in mitogenic signaling pathway.
Pretreatment of T leukemic Molt-4 cells with PLC inhibitors such as
U-73122 or ET-18-OCH3 potentiated etoposide-induced
apoptosis in these cells. PLC-1 was fragmented when Molt-4 cells
were treated with several apoptotic stimuli such as etoposide,
ceramides, and tumor necrosis factor 
. Cleavage of PLC-1 was
blocked by overexpression of Bcl-2 and by specific inhibitors of
caspases such as Z-DEVD-CH2F and YVAD-cmk. Purified
caspase-3 and caspase-7, group II caspases, cleaved PLC-1 in
vitro and generated a cleavage product of the same size as that
observed in vivo, suggesting that PLC-1 is cleaved by
group II caspases in vivo. From point mutagenesis
studies, Ala-Glu-Pro-Asp770 was identified to be a cleavage
site within PLC-1. Epidermal growth factor receptor (EGFR) -induced
tyrosine phosphorylation of PLC-1 resulted in resistance to cleavage
by caspase-3 in vitro. Furthermore, cleaved PLC-1
could not be tyrosine-phosphorylated by EGFR in vitro.
In addition, tyrosine-phosphorylated PLC-1 was not significantly
cleaved during etoposide-induced apoptosis in Molt-4 cells. This
suggests that the growth factor-induced tyrosine phosphorylation may
suppress apoptosis-induced fragmentation of PLC-1. We provide
evidence for the biochemical relationship between PLC-1-mediated
signal pathway and apoptotic signal pathway, indicating that the defect
of PLC-1-mediated signaling pathway can facilitate an apoptotic
progression.—Bae, S. S., Perry, D. K., Oh, Y. S., Choi,
J. H., Galadari, S. H., Ghayur, T., Ryu, S. H., Hannun,
Y. A., Suh, P.-G. Proteolytic cleavage of phospholipase C-1
during apoptosis in Molt-4 cells.
Key Words: PLC-1 • proteolysis • tyrosine phosphorylation
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