CASP2

Official Full Name

caspase 2

Organism

Homo sapiens

GeneID

835

Background

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Caspases mediate cellular apoptosis through the proteolytic cleavage of specific protein substrates. The encoded protein may function in stress-induced cell death pathways, cell cycle maintenance, and the suppression of tumorigenesis. Increased expression of this gene may play a role in neurodegenerative disorders including Alzheimer's disease, Huntington's disease and temporal lobe epilepsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

Synonyms

ICH1; MRT80; NEDD2; CASP-2; NEDD-2; PPP1R57;

Bio Chemical Class

Peptidase

Protein Sequence

MAAPSAGSWSTFQHKELMAADRGRRILGVCGMHPHHQETLKKNRVVLAKQLLLSELLEHLLEKDIITLEMRELIQAKVGSFSQNVELLNLLPKRGPQAFDAFCEALRETKQGHLEDMLLTTLSGLQHVLPPLSCDYDLSLPFPVCESCPLYKKLRLSTDTVEHSLDNKDGPVCLQVKPCTPEFYQTHFQLAYRLQSRPRGLALVLSNVHFTGEKELEFRSGGDVDHSTLVTLFKLLGYDVHVLCDQTAQEMQEKLQNFAQLPAHRVTDSCIVALLSHGVEGAIYGVDGKLLQLQEVFQLFDNANCPSLQNKPKMFFIQACRGDETDRGVDQQDGKNHAGSPGCEESDAGKEKLPKMRLPTRSDMICGYACLKGTAAMRNTKRGSWYIEALAQVFSERACDMHVADMLVKVNALIKDREGYAPGTEFHRCKEMSEYCSTLCRHLYLFPGHPPT

Open

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

A highly conserved member of the cysteine-aspartic acid protease family, caspase-2 has long fascinated scientists with its multifarious and often conflicting functions in cellular processes. Originally thought to be a pro-apoptotic protein, new data has shown its surprising ability to inhibit tumors, further complicating our knowledge of this mysterious protease.

Structural Features and Activation Mechanism

Fundamentally, caspase-2 has a structural resemblance with other initiator caspases as it has an N-terminal prodomain with a caspase activation recruitment domain (CARD). Its activation by dimerization—which takes place at the PIDDosome, a molecular complex consisting of PIDD1 and RAIDD— depends on this domain. The activation mechanism is a complex dance of protein interactions wherein PIDD1 undergoes autocatalytic processing to create PIDD-CC, which then interacts with RAIDD via death domains. This connection helps caspase-2 to be recruited and then dimerized, therefore activating it.

Though classified as an initiator caspase, caspase-2 has special qualities that distinguish it from its colleagues. Caspase-2 has no obvious enzymatic activity towards other caspases, unlike other initiator caspases that mainly activate downstream executioner caspases. Rather, it indirectly activates downstream caspases and cleaves other cellular substrates to support its activities. Its cleavage specificity intriguingly more closely matches that of executioner caspases, which presents a challenge for scientists trying to classify its function in the apoptotic cascade.

Caspase-2's Role as a Tumor Suppressor

Multiple mouse models of oncogene-driven tumors have shown caspase-2's tumor suppressor action. Both partial and whole caspase-2 deletion enhanced tumor development in the Eμ-Myc model of lymphoma. Similar results were shown in Atm-deficient animals, in which simultaneous caspase-2/ATM insufficiency greatly raised tumor incidence and lowered the average age of tumor starts. Based on MMTV/c-neu mammary tumors and Kras-driven lung cancer models, the tumor suppressor function spans epithelial cancers to haematologic malignancies.

Still mysterious, nevertheless, is the mechanism behind caspase-2's tumor control. Although its pro-apoptotic activity would imply that caspase-2-deficient tumors are more resistant to cell death, the data is contradictory depending on various models and cell types. For example, Jurkat cells lack resistance to heat shock-induced mortality but caspase-2-deficient splenocytes display such resistance. The somewhat typical phenotype of caspase-2-deficient mice further confuses our knowledge as these animals are alive and fruitful, with minimal death problems apart from extra oocytes in females.

Figure 1 illustrates how caspase-2 is activated in response to cellular stress and its role in initiating apoptosis through both mitochondrial pathways and interactions with other caspases. Figure 1. Caspase-2 activation in cell death. (Puccini J, et al., 2013)

Influence on Cell Proliferation and Genomic Stability

Beyond apoptosis, caspase-2 seems to control genomic integrity and cell growth. Particularly after DNA damage, many investigations have shown that caspase-2-deficient cells multiply quicker than their wild-type counterparts. This faster development reflects the more rapid carcinogenesis seen in many cancer models. Furthermore linked to caspase-2 loss is increased genomic instability, which shows up in many tumor models as more aneuploidy and chromosomal abnormalities.

Given its function in cell cycle control, caspase-2's association with genomic stability could be connected. Particularly in response to disturbances in mitotic spindle formation, cell death triggered by aneuploidy requires caspase-2. The absence of caspase-2 suggests a possible function in avoiding cytokinesis failure because cells become more resistant to treatments that perturb cytoskeletal dynamics and are more likely to become multinucleated.

Contradictory Roles in Different Cancer Types

The seemingly contradicting functions of caspase-2 in many cancer models emphasize even more its complexity. Although it suppresses tumors in many circumstances, in certain models—like ThMycn-induced neuroblastoma—loss of caspase-2 actually slowed tumor development. This implies that the function of the protein might be very tissue-specific and depend on the cellular environment.

Future Directions and Therapeutic Potential

Understanding the mechanisms by which caspase-2 exerts its tumor suppressor function remains a critical area of investigation. Future studies should concentrate on determining the particular substrates caspase-2 targets in many cellular environments and how these interactions support its several purposes. Furthermore, investigating the regulatory systems controlling caspase-2 activation and substrate choice can provide important light on its function in both cancer formation and normal cellular activities.

References:

Zeng M, Wang K, Wu Q, et al. Dissecting caspase-2-mediated cell death: from intrinsic PIDDosome activation to chemical modulation. Protein Cell. Published online April 27, 2024.
Brown-Suedel AN, Bouchier-Hayes L. Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond. Front Cell Dev Biol. 2020;8:610022.
Forsberg J, Zhivotovsky B, Olsson M. Caspase-2: an orphan enzyme out of the shadows. Oncogene. 2017;36(39):5441-5444.
Puccini J, Dorstyn L, Kumar S. Caspase-2 as a tumour suppressor. Cell Death Differ. 2013;20(9):1133-1139.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry