Abstract
Caspases are the major executioners of cell death, serving as molecular guillotines to behead many proteins required for maintenance of cellular homeostasis. Identification of caspase substrates has taken on increasing importance as we attempt to better understand the molecular mechanisms involved in regulating the struggle between life and death. Many caspase substrates have been described and include RNA binding proteins such as La and U1-70 kD, structural proteins such as keratin and nuclear lamins, and transcription factors or their regulatory proteins that include IκB, SP1, and SREBP. Kinases and other signaling proteins are perfectly suited to regulate life and death decisions in response to cellular stressors and have only recently been identified as important caspase substrates. Here we review the current status of signaling pathways that are activated, inactivated or dysregulated by proteases such as caspases and calpain to control entry into apoptosis. The emerging concept that some caspase pathways may be inhibited by cellular and viral apoptosis inhibitory proteins while other caspase pathways are preserved suggests that a subset of these kinases may exist as cleaved ‘isoforms’ in cells that are not destined to perish. By acting as executioners and as important ‘molecular sensors’ of the degree of cellular injury, the signaling proteins described in this review are strong candidates to mediate downstream events, both in condemned and in viable cells. Cell Death and Differentiation (2000) 7, 589–602
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Abbreviations
- APC:
-
antigen presenting cell
- ASK-1:
-
apoptosis signal-regulating kinase-1
- CaMK:
-
calcium/calmodulin-dependent protein kinase
- CDK:
-
cell cycle dependent kinase
- CDKI:
-
cdk inhibitor
- DNA-PKcs:
-
DNA-dependent kinase catalytic subunit
- FADD:
-
Fas-associated death domain protein
- FAK:
-
focal adhesion kinase
- FAP:
-
Fas-associated phosphatase-1
- FAT domain:
-
focal adhesion targeting domain
- FLICE:
-
Fas-associated death-domain-like IL-1beta-converting enzyme
- FLIP:
-
FLICE-inhibitory protein
- GTPase:
-
guanine triphosphatase
- HUVEC:
-
human umbilical vein endothelial cells
- IAP:
-
inhibitor of apoptosis
- IκB:
-
NF-κB inhibitory subunit
- ITAM:
-
immunoreceptor tyrosine-based activation motifs
- JNK:
-
jun N terminal kinase
- LOK:
-
lymphocyte-oriented kinase
- MAPK:
-
mitogen-activated protein kinase
- MHC:
-
major histocompatibility complex
- NF-κB:
-
nuclear factor kappa B
- PAK2:
-
p21-activated kinase 2
- PCNA:
-
proliferating cell nuclear antigen
- PI3-K:
-
phosphatidylinositol 3-kinase
- PKC:
-
protein kinase C
- Plkk1:
-
polo-like kinase 1
- PP2A:
-
protein phosphatase 2A
- RIPK:
-
receptor-interacting protein kinase
- SAPK:
-
stress-activated protein kinase
- SDS–PAGE:
-
sodium dodecyl sulfate polyacrylamide gel electrophoresis
- SH2:
-
src homology domain 2
- SRP72:
-
72 kD subunit of the signal recognition particle
- SR:
-
serine/arginine splicing factor
- SRPK:
-
SR protein kinase
- SLK:
-
Ste20-related kinase
- TCR:
-
T cell receptor
- TIL:
-
tumor infiltrating lymphocytes
- TNF:
-
tumor necrosis factor
- TNFR:
-
TNF receptor
- TRADD:
-
TNF receptor-associated death domain protein
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
- UV:
-
ultraviolet
- ZAP-70:
-
ζ-associated protein of 70 kD
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Acknowledgements
The authors thank WJ van Venrooij, WGJ Degen, GJM Pruijn, members of the Anderson laboratory, and participants of the 1999 Bertine Koperberg Conference in Nijmegen, The Netherlands for helpful comments and stimulating discussions. The authors regret failing to include the work of others that could not be referenced due to space limitations. Dr. Utz's work was supported in part by the Arthritis Foundation, National Institutes of Health Grant K08AI01521, the Arthritis National Research Foundation, the Scleroderma Foundation, Inc., and laboratory startup funding provided by Stanford University. Dr. Anderson's work was funded by the Arthritis Foundation, National Institutes of Health Grants AI33600 and CA67929, the Peabody Foundation, and the Leukemia Society of America.
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Utz, P., Anderson, P. Life and death decisions: regulation of apoptosis by proteolysis of signaling molecules. Cell Death Differ 7, 589–602 (2000). https://doi.org/10.1038/sj.cdd.4400696
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DOI: https://doi.org/10.1038/sj.cdd.4400696
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