CASP2

CASP2 Background

Caspase-2 is a protein in humans that is encoded by the CASP2 gene ^[1]. Caspase-2 is the most evolutionarily conserved of all the caspases ^[2]. And caspase-2 is characterized by the feature of both initiator and executioner caspases. The substrate specificity of caspase-2 is similar to that of executioner caspases. Like executioner caspases caspase-3 and caspase-7, caspase-2 displays a strong preference for an Aspartic acid residue in the P4 position of its substrates ^[3]. On the other hand, caspase-2 shares sequence similarities with initiator caspases that all possess long pro-domains containing a protein-protein interaction domain such as a caspase recruitment domain (CARD)^[4] or a death effector domain ^[5]. Due to a CARD in the prodomain of caspase-2, it is activated analogously to the activation of initiator caspases ^[5]. Under certain cellular stresses, the inactive caspase-2 precursor undergoes dimerization and then converts into active caspase-2. Nevertheless, unlike other initiator caspases, caspase-2 activates the executioner caspases indirectly by inducing MOMP (mitochondrial outer membrane permeabilization) through cleavage and activation of the pro-apoptotic Bid ^[6][7]. Bid further incurs the release of cytochrome c from mitochondria and subsequent apoptosis. Anti-apoptotic protein Bcl-xL can inhibit apoptosis caused by caspase-2 through the prevention of MOMP ^[6][8][9]. In addition, caspase-2 may have a role in the development ^[10], tumorigenesis suppression ^[11], and aging ^[12].

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[4] Hofmann K, Bucher P, et al. The CARD domain: a new apoptotic signalling motif [J]. Trends Biochem Sci. 1997;22:155-6.
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[7] Bonzon C, Bouchier-Hayes L, Pagliari LJ, et al. et al. Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death [J]. Mol Biol Cell. 2006;17:21507.
[8] Bouchier-Hayes L, Oberst A, et al. Characterization of cytoplasmic caspase-2 activation by induced proximity [J]. Mol Cell. 2009;35:830-40.
[9] Tu S, McStay GP, Boucher LM, et al. et al. In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis [J]. Nat Cell Biol. 2006;8:72-7.
[10] Bergeron L, Perez GI, et al. Defects in regulation of apoptosis in caspase-2-deficient mice [J]. Genes Dev. 1998;12:1304-14.
[11] Ho LH, Taylor R, et al. A tumor suppressor function for caspase-2 [J]. Proc Natl Acad Sci USA. 2009;106:5336-41.
[12] Zhang Y, Padalecki et al. Caspase-2 deficiency enhances aging-related traits in mice [J]. Mech Ageing Dev. 2007;128:213-21.