The inhibitor‑of‑apoptosis (IAP) family of proteins such as X‑linked IAP (XIAP) suppress cell death by inhibiting the catalytic activity of caspases (Deveraux QL et al. 1997; Paulsen M et al. 2008). XIAP consists of three bacculoviral inhibitory repeat (BIR) domains and a C‑terminal ring finger. Biochemical and structural analyses revealed that the linker connecting BIR1 to BIR2 inhibits executioner caspase‑3 and ‑7 by positioning itself at the active site (Sun C et al. 1999; Riedl SJ et al. 2001; Huang Y et al. 2001; Chai J et al. 2001). Formation of a complex between caspase‑3 or caspase‑7 and the XIAP BIR2‑linker region appears to be driven by interactions between XIAP's Leu141 and Val146 and a hydrophobic site present on both caspases. This hydrophobic site is not found in caspase‑8 or caspase‑9, perhaps explaining the binding specificity of XIAP (Riedl SJ et al. 2001). BIR2 domain of XIAP may also contribute to inhibition of executioner caspases by interacting with additional sites on the enzymes (Scott FL et al. 2005; Abhari BA & Davoodi J 2008).
The PIDDosome promotes activation of CASP2 (caspase-2) by proteolytic cleavage, triggering apoptosis (Tinel and Tschopp 2004). The PIDDosome may also participate in the proteolytic activation of CASP3 and CASP7 (Berube et al. 2005).
Caspase-mediated cleavage of Mst3 activates its intrinsic kinase activity. Proteolytic removal of the COOH-terminal domain promotes nuclear translocation of its kinase domain. Ectopic expression of COOH-terminal truncated Mst3 results in DNA fragmentation and morphological changes characteristic of apoptosis (Huang et al., 2002). Both CASP3 and CASP7 can cleave MST3, and phosphorylation of MST3 may promote facilitate caspase-mediated cleavage (Turowec et al. 2014).
During apoptosis, activated caspase-3 (CASP3) and to a lesser degree CASP7 inactivate gasdermin D (GSDMD) by cleaving GSDMD at position D87 generating p20 (GSDMD(1-87)) and p43 (GSDMD(88-484)) fragments (Taabazuing CY et al. 2017). This cleavage site is evolutionarily conserved and lies within the N-terminal fragment (p30, GSDMD(1-275)) that forms membrane pores. Proteolysis at this site renders GSDMD incapable of activating pyroptosis (Taabazuing CY et al. 2017). This pathway does not seem to play a key role during animal development as wild-type and Gsdmd-deficient mice both develop normally.
Second mitochondria derived activator of caspase/direct inhibitor of apoptosis binding protein with low pI (SMAC, also known as DIABLO) is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis (Du C et al. 2000). Mitochondrial import and cleavage of its signal peptide are required for SMAC to gain its apoptotic activity (Du C et al. 2000). In vitro studies revealed that dimerization was required for its function, while monomerization of cytosolic mature SMAC attenuated interaction with XIAP (Chai J et al. 2000; Burke SP & Smith JB 2010). Moreover, SMAC dimer showed high stability in vitro as measured by high hydrostatic pressure, low and high temperatures, and chemical denaturation (Goncalves RB et al. 2008). Binding of SMAC (DIABLO) to the BIR3 region of X linked inhibitor of apoptosis protein (XIAP) competitively inhibits binding of XIAP to caspase 9, while binding to the BIR2 region sterically hinders the interaction of XIAP with CASP3 and CASP7 (Srinivasula SM et al. 2001; Abhari BA & Davoodi J 2008).
FGFR2 fusions have been identified in cancers such as lung, breast, thyroid and cholangiocarcinoma (Wu et al, 2013; Seo et al, 2012; Arai et al, 2013). Of all the FGF receptors, FGFR2 shows the broadest range of 3' fusion partners, including BICC1, AHCYL1, CIT, CCDC6, CASP7, AFF3, OFD1 and CCAR2. Many of these fusion partners contain dimerization domains, suggesting that the resulting fusions may demonstrate constitutive ligand-independent activation (Wu et al, 2013; Arai et al, 2013; Seo et al, 2012; reviewed in Parker et al, 2014).
Second mitochondria derived activator of caspase/direct inhibitor of apoptosis binding protein with low pI (SMAC, also known as DIABLO) regulates XIAP function and potentiates caspase-3, -7 and -9 activity by disrupting the interaction of caspases with XIAP. Residues 56-59 of SMAC (DIABLO) are homologous to the amino-terminal motif that is used by caspase-9 (CASP9) to bind to the BIR3 domain of XIAP. SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Srinivasula SM et al. 2001; Salvesen et al. 2002). The binding of SMAC to the BIR2 and BIR3 regions of XIAP creates a steric hindrance that is essential for preventing binding of XIAP linker region with effector caspases CASP3 and CASP7 thus achieving neutralization of XIAP inhibition. The strong affinity for XIAP allows SMAC (DIABLO) to displace caspase-3, -7 from the XIAP:caspase complexes (Wu G et al. 2000; Chai J et al. 2001; Huang Y et al. 2003; Abhari BA & Davoodi J 2008).