TY  - JOUR
AU  - Crawford, E. D.
AU  - Seaman, J. E.
AU  - Barber, A. E.
AU  - David, Della
AU  - Babbitt, P. C.
AU  - Burlingame, A. L.
AU  - Wells, J. A.
TI  - Conservation of caspase substrates across metazoans suggests hierarchical importance of signaling pathways over specific targets and cleavage site motifs in apoptosis.
JO  - Cell death and differentiation
VL  - 19
IS  - 12
SN  - 1350-9047
CY  - London
PB  - Macmillan
M1  - DZNE-2020-07615
SP  - 2040-2048
PY  - 2012
AB  - Caspases, cysteine proteases with aspartate specificity, are key players in programmed cell death across the metazoan lineage. Hundreds of apoptotic caspase substrates have been identified in human cells. Some have been extensively characterized, revealing key functional nodes for apoptosis signaling and important drug targets in cancer. But the functional significance of most cuts remains mysterious. We set out to better understand the importance of caspase cleavage specificity in apoptosis by asking which cleavage events are conserved across metazoan model species. Using N-terminal labeling followed by mass spectrometry, we identified 257 caspase cleavage sites in mouse, 130 in Drosophila, and 50 in Caenorhabditis elegans. The large majority of the caspase cut sites identified in mouse proteins were found conserved in human orthologs. However, while many of the same proteins targeted in the more distantly related species were cleaved in human orthologs, the exact sites were often different. Furthermore, similar functional pathways are targeted by caspases in all four species. Our data suggest a model for the evolution of apoptotic caspase specificity that highlights the hierarchical importance of functional pathways over specific proteins, and proteins over their specific cleavage site motifs.
KW  - Animals
KW  - Apoptosis
KW  - Caenorhabditis elegans: enzymology
KW  - Caspases: metabolism
KW  - Cell Line
KW  - Drosophila: enzymology
KW  - Humans
KW  - Mass Spectrometry
KW  - Mice
KW  - Signal Transduction
KW  - Substrate Specificity
KW  - Caspases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22918439
C2  - pmc:PMC3504717
DO  - DOI:10.1038/cdd.2012.99
UR  - https://pub.dzne.de/record/141293
ER  -