Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Jan 11

PMID 33425918

Citations 26

Authors

Alexandra N Brown-Suedel

Lisa Bouchier-Hayes

Affiliations

Soon will be listed here.

Abstract

Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, but how it regulates this function is still unknown. For many years, caspase-2 has been considered an "orphan" caspase because, although it is able to induce apoptosis, there is an abundance of conflicting evidence that questions its necessity for apoptosis. Recent evidence supports that caspase-2 has non-apoptotic functions in the cell cycle and protection from genomic instability. It is unclear how caspase-2 regulates these opposing functions, which has made the mechanism of tumor suppression by caspase-2 difficult to determine. As a protease, caspase-2 likely exerts its functions by proteolytic cleavage of cellular substrates. This review highlights the known substrates of caspase-2 with a special focus on their functional relevance to caspase-2's role as a tumor suppressor.

Citing Articles

Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity.

Klemm J, Van Hazel C, Harris R Elife. 2025; 13.

PMID: 40042383 PMC: 11882144. DOI: 10.7554/eLife.101114.

Cellular communication network 1 promotes CASP2 mRNA expression but suppresses its protein translation in esophageal adenocarcinoma.

Xu R, Jiang Z, Meng X, Xing L, Aladan W, Chi B J Cell Commun Signal. 2024; 18(3):e12046.

PMID: 39524140 PMC: 11544643. DOI: 10.1002/ccs3.12046.

Centrioles are frequently amplified in early B cell development but dispensable for humoral immunity.

Schapfl M, LoMastro G, Braun V, Hirai M, Levine M, Kiermaier E Nat Commun. 2024; 15(1):8890.

PMID: 39406735 PMC: 11480410. DOI: 10.1038/s41467-024-53222-4.

The powerful antioxidant effects of plant fruits, flowers, and leaves help to improve retinal damage and support the relief of visual fatigue.

Duan H, Wang D, Zheng Y, Zhou Y, Yan W Heliyon. 2024; 10(14):e34299.

PMID: 39113954 PMC: 11305225. DOI: 10.1016/j.heliyon.2024.e34299.

Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Sakthivel D, Brown-Suedel A, Lopez K, Salgar S, Coutinho L, Keane F Sci Adv. 2024; 10(31):eadj3145.

PMID: 39093977 PMC: 11296348. DOI: 10.1126/sciadv.adj3145.

References

Tu S, McStay G, Boucher L, Mak T, Beere H, Green D . In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat Cell Biol. 2005; 8(1):72-7. DOI: 10.1038/ncb1340. View

Negrini S, Gorgoulis V, Halazonetis T . Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010; 11(3):220-8. DOI: 10.1038/nrm2858. View

Julien O, Zhuang M, Wiita A, ODonoghue A, Knudsen G, Craik C . Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles. Proc Natl Acad Sci U S A. 2016; 113(14):E2001-10. PMC: 4833263. DOI: 10.1073/pnas.1524900113. View

Hanahan D, Weinberg R . The hallmarks of cancer. Cell. 2000; 100(1):57-70. DOI: 10.1016/s0092-8674(00)81683-9. View

Lavrik I, Golks A, Baumann S, Krammer P . Caspase-2 is activated at the CD95 death-inducing signaling complex in the course of CD95-induced apoptosis. Blood. 2006; 108(2):559-65. DOI: 10.1182/blood-2005-07-007096. View

Zhao D, Jiang M, Zhang X, Hou H . The role of RICTOR amplification in targeted therapy and drug resistance. Mol Med. 2020; 26(1):20. PMC: 7011243. DOI: 10.1186/s10020-020-0146-6. View

Park H, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J . Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell. 2007; 128(3):533-46. PMC: 2908332. DOI: 10.1016/j.cell.2007.01.019. View

Harvey N, Trapani J, Fernandes-Alnemri T, Litwack G, Alnemri E, Kumar S . Processing of the Nedd2 precursor by ICE-like proteases and granzyme B. Genes Cells. 1996; 1(7):673-85. DOI: 10.1046/j.1365-2443.1996.00255.x. View

Ribe E, Jean Y, Goldstein R, Manzl C, Stefanis L, Villunger A . Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. Biochem J. 2012; 444(3):591-9. PMC: 3365438. DOI: 10.1042/BJ20111588. View

10.

van de Craen M, Declercq W, Van den brande I, Fiers W, Vandenabeele P . The proteolytic procaspase activation network: an in vitro analysis. Cell Death Differ. 1999; 6(11):1117-24. DOI: 10.1038/sj.cdd.4400589. View

11.

Peintner L, Dorstyn L, Kumar S, Aneichyk T, Villunger A, Manzl C . The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd. Cell Death Differ. 2015; 22(11):1803-11. PMC: 4648327. DOI: 10.1038/cdd.2015.31. View

12.

Gell D, Jackson S . Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res. 1999; 27(17):3494-502. PMC: 148593. DOI: 10.1093/nar/27.17.3494. View

13.

Bergeron L, Perez G, MacDonald G, Shi L, Sun Y, Jurisicova A . Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev. 1998; 12(9):1304-14. PMC: 316779. DOI: 10.1101/gad.12.9.1304. View

14.

Dawar S, Lim Y, Puccini J, White M, Thomas P, Bouchier-Hayes L . Caspase-2-mediated cell death is required for deleting aneuploid cells. Oncogene. 2016; 36(19):2704-2714. PMC: 5442422. DOI: 10.1038/onc.2016.423. View

15.

Duan H, Dixit V . RAIDD is a new 'death' adaptor molecule. Nature. 1997; 385(6611):86-9. DOI: 10.1038/385086a0. View

16.

Boatright K, Salvesen G . Mechanisms of caspase activation. Curr Opin Cell Biol. 2003; 15(6):725-31. DOI: 10.1016/j.ceb.2003.10.009. View

17.

Oliver T, Meylan E, Chang G, Xue W, Burke J, Humpton T . Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell. 2011; 43(1):57-71. PMC: 3160283. DOI: 10.1016/j.molcel.2011.06.012. View

18.

Andersen J, Johnson C, Freel C, Parrish A, Day J, Buchakjian M . Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2. EMBO J. 2009; 28(20):3216-27. PMC: 2771089. DOI: 10.1038/emboj.2009.253. View

19.

Shelton S, Dillard C, Robertson J . Activation of caspase-9, but not caspase-2 or caspase-8, is essential for heat-induced apoptosis in Jurkat cells. J Biol Chem. 2010; 285(52):40525-33. PMC: 3003351. DOI: 10.1074/jbc.M110.167635. View

20.

Boice A, Bouchier-Hayes L . Targeting apoptotic caspases in cancer. Biochim Biophys Acta Mol Cell Res. 2020; 1867(6):118688. PMC: 7155770. DOI: 10.1016/j.bbamcr.2020.118688. View