In the execution phase of apoptosis, effector caspases cleave vital cellular proteins leading to the morphological changes that characterize apoptosis. These changes include destruction of the nucleus and other organelles, DNA fragmentation, chromatin condensation, cell shrinkage and cell detachment and membrane blebbing (reviewed in Fischer et al., 2003).
View original pathway at Reactome.
Kalinowska-Herok M, Widłak P.; ''High mobility group proteins stimulate DNA cleavage by apoptotic endonuclease DFF40/CAD due to HMG-box interactions with DNA.''; PubMedEurope PMCScholia
Thomsen ND, Koerber JT, Wells JA.; ''Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.''; PubMedEurope PMCScholia
Woo EJ, Kim YG, Kim MS, Han WD, Shin S, Robinson H, Park SY, Oh BH.; ''Structural mechanism for inactivation and activation of CAD/DFF40 in the apoptotic pathway.''; PubMedEurope PMCScholia
Widlak P, Lanuszewska J, Cary RB, Garrard WT.; ''Subunit structures and stoichiometries of human DNA fragmentation factor proteins before and after induction of apoptosis.''; PubMedEurope PMCScholia
Fasulo L, Ugolini G, Visintin M, Bradbury A, Brancolini C, Verzillo V, Novak M, Cattaneo A.; ''The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis.''; PubMedEurope PMCScholia
Cirillo N, Lanza M, De Rosa A, Cammarota M, La Gatta A, Gombos F, Lanza A.; ''The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3-mediated apoptotic machinery.''; PubMedEurope PMCScholia
Qian J, Steigerwald K, Combs KA, Barton MC, Groden J.; ''Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis.''; PubMedEurope PMCScholia
Steinhusen U, Weiske J, Badock V, Tauber R, Bommert K, Huber O.; ''Cleavage and shedding of E-cadherin after induction of apoptosis.''; PubMedEurope PMCScholia
Jänicke RU, Ng P, Sprengart ML, Porter AG.; ''Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.''; PubMedEurope PMCScholia
Jung JH, Traugh JA.; ''Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141.''; PubMedEurope PMCScholia
Datta R, Kojima H, Yoshida K, Kufe D.; ''Caspase-3-mediated cleavage of protein kinase C theta in induction of apoptosis.''; PubMedEurope PMCScholia
Kamada S, Kikkawa U, Tsujimoto Y, Hunter T.; ''Nuclear translocation of caspase-3 is dependent on its proteolytic activation and recognition of a substrate-like protein(s).''; PubMedEurope PMCScholia
Byun Y, Chen F, Chang R, Trivedi M, Green KJ, Cryns VL.; ''Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis.''; PubMedEurope PMCScholia
Morishima N.; ''Changes in nuclear morphology during apoptosis correlate with vimentin cleavage by different caspases located either upstream or downstream of Bcl-2 action.''; PubMedEurope PMCScholia
Neimanis S, Albig W, Doenecke D, Kahle J.; ''Sequence elements in both subunits of the DNA fragmentation factor are essential for its nuclear transport.''; PubMedEurope PMCScholia
Mizuno K, Noda K, Araki T, Imaoka T, Kobayashi Y, Akita Y, Shimonaka M, Kishi S, Ohno S.; ''The proteolytic cleavage of protein kinase C isotypes, which generates kinase and regulatory fragments, correlates with Fas-mediated and 12-O-tetradecanoyl-phorbol-13-acetate-induced apoptosis.''; PubMedEurope PMCScholia
Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grütter MG.; ''The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.''; PubMedEurope PMCScholia
Orth K, Chinnaiyan AM, Garg M, Froelich CJ, Dixit VM.; ''The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A.''; PubMedEurope PMCScholia
Widlak P, Kalinowska M, Parseghian MH, Lu X, Hansen JC, Garrard WT.; ''The histone H1 C-terminal domain binds to the apoptotic nuclease, DNA fragmentation factor (DFF40/CAD) and stimulates DNA cleavage.''; PubMedEurope PMCScholia
Webb SJ, Nicholson D, Bubb VJ, Wyllie AH.; ''Caspase-mediated cleavage of APC results in an amino-terminal fragment with an intact armadillo repeat domain.''; PubMedEurope PMCScholia
Widlak P, Li P, Wang X, Garrard WT.; ''Cleavage preferences of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease) on naked DNA and chromatin substrates.''; PubMedEurope PMCScholia
Brancolini C, Benedetti M, Schneider C.; ''Microfilament reorganization during apoptosis: the role of Gas2, a possible substrate for ICE-like proteases.''; PubMedEurope PMCScholia
Chang J, Xie M, Shah VR, Schneider MD, Entman ML, Wei L, Schwartz RJ.; ''Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis.''; PubMedEurope PMCScholia
Lazebnik YA, Takahashi A, Poirier GG, Kaufmann SH, Earnshaw WC.; ''Characterization of the execution phase of apoptosis in vitro using extracts from condemned-phase cells.''; PubMedEurope PMCScholia
Riedl SJ, Fuentes-Prior P, Renatus M, Kairies N, Krapp S, Huber R, Salvesen GS, Bode W.; ''Structural basis for the activation of human procaspase-7.''; PubMedEurope PMCScholia
Clarke CA, Bennett LN, Clarke PR.; ''Cleavage of claspin by caspase-7 during apoptosis inhibits the Chk1 pathway.''; PubMedEurope PMCScholia
van de Water B, Tijdens IB, Verbrugge A, Huigsloot M, Dihal AA, Stevens JL, Jaken S, Mulder GJ.; ''Cleavage of the actin-capping protein alpha -adducin at Asp-Asp-Ser-Asp633-Ala by caspase-3 is preceded by its phosphorylation on serine 726 in cisplatin-induced apoptosis of renal epithelial cells.''; PubMedEurope PMCScholia
Weiske J, Schöneberg T, Schröder W, Hatzfeld M, Tauber R, Huber O.; ''The fate of desmosomal proteins in apoptotic cells.''; PubMedEurope PMCScholia
Dusek RL, Getsios S, Chen F, Park JK, Amargo EV, Cryns VL, Green KJ.; ''The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes.''; PubMedEurope PMCScholia
Sgorbissa A, Benetti R, Marzinotto S, Schneider C, Brancolini C.; ''Caspase-3 and caspase-7 but not caspase-6 cleave Gas2 in vitro: implications for microfilament reorganization during apoptosis.''; PubMedEurope PMCScholia
Chandra D, Choy G, Deng X, Bhatia B, Daniel P, Tang DG.; ''Association of active caspase 8 with the mitochondrial membrane during apoptosis: potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death.''; PubMedEurope PMCScholia
Browne SJ, MacFarlane M, Cohen GM, Paraskeva C.; ''The adenomatous polyposis coli protein and retinoblastoma protein are cleaved early in apoptosis and are potential substrates for caspases.''; PubMedEurope PMCScholia
Warby SC, Doty CN, Graham RK, Carroll JB, Yang YZ, Singaraja RR, Overall CM, Hayden MR.; ''Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus.''; PubMedEurope PMCScholia
Liu X, Zou H, Slaughter C, Wang X.; ''DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis.''; PubMedEurope PMCScholia
Bojarski C, Weiske J, Schöneberg T, Schröder W, Mankertz J, Schulzke JD, Florian P, Fromm M, Tauber R, Huber O.; ''The specific fates of tight junction proteins in apoptotic epithelial cells.''; PubMedEurope PMCScholia
Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y.; ''Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.''; PubMedEurope PMCScholia
Liu X, Zou H, Widlak P, Garrard W, Wang X.; ''Activation of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease). Oligomerization and direct interaction with histone H1.''; PubMedEurope PMCScholia
Huang CY, Wu YM, Hsu CY, Lee WS, Lai MD, Lu TJ, Huang CL, Leu TH, Shih HM, Fang HI, Robinson DR, Kung HJ, Yuan CJ.; ''Caspase activation of mammalian sterile 20-like kinase 3 (Mst3). Nuclear translocation and induction of apoptosis.''; PubMedEurope PMCScholia
Fischer U, Jänicke RU, Schulze-Osthoff K.; ''Many cuts to ruin: a comprehensive update of caspase substrates.''; PubMedEurope PMCScholia
Sahara S, Aoto M, Eguchi Y, Imamoto N, Yoneda Y, Tsujimoto Y.; ''Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation.''; PubMedEurope PMCScholia
Hanus J, Kalinowska-Herok M, Widlak P.; ''The major apoptotic endonuclease DFF40/CAD is a deoxyribose-specific and double-strand-specific enzyme.''; PubMedEurope PMCScholia
Clem RJ, Sheu TT, Richter BW, He WW, Thornberry NA, Duckett CS, Hardwick JM.; ''c-IAP1 is cleaved by caspases to produce a proapoptotic C-terminal fragment.''; PubMedEurope PMCScholia
Chen YR, Kori R, John B, Tan TH.; ''Caspase-mediated cleavage of actin-binding and SH3-domain-containing proteins cortactin, HS1, and HIP-55 during apoptosis.''; PubMedEurope PMCScholia
Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMedEurope PMCScholia
Steinhusen U, Badock V, Bauer A, Behrens J, Wittman-Liebold B, Dörken B, Bommert K.; ''Apoptosis-induced cleavage of beta-catenin by caspase-3 results in proteolytic fragments with reduced transactivation potential.''; PubMedEurope PMCScholia
Zhivotovsky B, Samali A, Gahm A, Orrenius S.; ''Caspases: their intracellular localization and translocation during apoptosis.''; PubMedEurope PMCScholia
Wen LP, Fahrni JA, Troie S, Guan JL, Orth K, Rosen GD.; ''Cleavage of focal adhesion kinase by caspases during apoptosis.''; PubMedEurope PMCScholia
Rao L, Perez D, White E.; ''Lamin proteolysis facilitates nuclear events during apoptosis.''; PubMedEurope PMCScholia
Dan I, Ong SE, Watanabe NM, Blagoev B, Nielsen MM, Kajikawa E, Kristiansen TZ, Mann M, Pandey A.; ''Cloning of MASK, a novel member of the mammalian germinal center kinase III subfamily, with apoptosis-inducing properties.''; PubMedEurope PMCScholia
Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC.; ''Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol.''; PubMedEurope PMCScholia
Wu YM, Huang CL, Kung HJ, Huang CY.; ''Proteolytic activation of ETK/Bmx tyrosine kinase by caspases.''; PubMedEurope PMCScholia
Galande S, Dickinson LA, Mian IS, Sikorska M, Kohwi-Shigematsu T.; ''SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis.''; PubMedEurope PMCScholia
Kim KW, Chung HH, Chung CW, Kim IK, Miura M, Wang S, Zhu H, Moon KD, Rha GB, Park JH, Jo DG, Woo HN, Song YH, Kim BJ, Yuan J, Jung YK.; ''Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: cleavage of the common alpha subunit during apoptosis.''; PubMedEurope PMCScholia
Stegh AH, Herrmann H, Lampel S, Weisenberger D, Andrä K, Seper M, Wiche G, Krammer PH, Peter ME.; ''Identification of the cytolinker plectin as a major early in vivo substrate for caspase 8 during CD95- and tumor necrosis factor receptor-mediated apoptosis.''; PubMedEurope PMCScholia
Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT.; ''Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis.''; PubMedEurope PMCScholia
Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD.; ''The atomic-resolution structure of human caspase-8, a key activator of apoptosis.''; PubMedEurope PMCScholia
Geng YJ, Azuma T, Tang JX, Hartwig JH, Muszynski M, Wu Q, Libby P, Kwiatkowski DJ.; ''Caspase-3-induced gelsolin fragmentation contributes to actin cytoskeletal collapse, nucleolysis, and apoptosis of vascular smooth muscle cells exposed to proinflammatory cytokines.''; PubMedEurope PMCScholia
Ghayur T, Hugunin M, Talanian RV, Ratnofsky S, Quinlan C, Emoto Y, Pandey P, Datta R, Huang Y, Kharbanda S, Allen H, Kamen R, Wong W, Kufe D.; ''Proteolytic activation of protein kinase C delta by an ICE/CED 3-like protease induces characteristics of apoptosis.''; PubMedEurope PMCScholia
Turowec JP, Zukowski SA, Knight JD, Smalley DM, Graves LM, Johnson GL, Li SS, Lajoie GA, Litchfield DW.; ''An unbiased proteomic screen reveals caspase cleavage is positively and negatively regulated by substrate phosphorylation.''; PubMedEurope PMCScholia
The caspase 3-mediated proteolytic processing of full-length Dsg2, the most widespread desmosomal cadherin, results in disappearance of Dsg2 from the cell surface and appearance of a 70-kDa fragment in the cytosol. Loss of Dsg2 from the cell surface may contribute to the progressive loss of intercellular adhesion strength during apoptosis (Cirillo et al., 2008)
Desmosomes represent one of the anchoring junctions mediating strong cell-cell contacts.Desmosomal plaque proteins including the head domain of plakophilin provide interaction sites for cytokeratin filaments (see references in Weiske et al.,2001). Proteolytic fragmentation of these proteins prevents binding of intermediate filaments and in consequence results in remodeling of the intermediate filament cytoskeleton (Weiske et al., 2001).Cleaved Plakophilin-1 appears to be impaired in supporting the formation and maintenance of desmosomes during apoptosis (Weiske et al., 2001). Caspase-3 inhibition prevents cleavage of Plakophilin-1, implicating Caspase-3 as the responsible endopeptidase (Weiske et al. 2001).
The cortical actin cytoskeletal network is lost during apoptosis. During apoptosis, increased phosphorylation of the actin capping protein alpha-adducin leads to its dissociation from the cytoskeleton. The caspase-3-mediated cleavage cleavage of alpha adducin at Asp-Asp-Ser-Asp(633)-Ala prevents its reassociation (van de Water et al, 2000).
Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing (Sebbagh et al., 2001). Cleavage and activation of ROCK-1 by caspase-3 plays has also been shown to play a crucial role in in cardiac myocyte apoptosis (Chang et al., 2006).
Gelsolin is cleaved by caspase-3 generating a constitutively active fragment that can depolymerize F-actin contributing to actin cytoskeletal collapse (Kothakota et al., 1997)
Vimentin is cleaved by several caspases during apoptosis (Morishima et al., 1999, Byun et al., 2001). This cleavage disrupts the cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Caspase-6 recognizes and cleaves C terminal side of Asp-429. Vimentin is cleaved at Asp85 by caspases-3 and -7 (Byun et al., 2001). This clevage generates a pro-apoptotic amino-terminal cleavage product (amino acids 1-85) that amplifies the cell death signal (Byun et al., 2001).
In epithelial cells, desmosomes are anchoring junctions that mediate strong cell-cell contacts. Desmosomal proteins are proteolytically targeted during apoptosis (Weiske et al., 2001). Desmogleins are a major component of the desmosome are specifically cleaved after onset of apoptosis. Cleavage of desmosomal proteins results in the disruption of the structure of desmosomes and contributes to cell rounding and disassembly of the intermediate filament network (Weiske et al., 2001). The cytosolic fragment has implications for the autoimmune disease, Pemphigus vulgaris (Tong et al. 2006).
FAK is a tyrosine kinase that localizes to focal adhesions and associates temporally and spatially with integrins (see references in Fischer et al., 2003 ). FAK is cleaved by caspases including caspase-7 (Wen et al., 1997). Caspases also cleave fodrin and components of the focal adhesion complex which links cortical actin filaments and membrane proteins to the extracellular matrix. Cleavage of these proteins is thought to promote cell shrinkage and cell detachment and disrupt antiapoptotic integrin signaling (see Fischer et al., 2003).
Cleavage of desmosomal proteins including desmoplakin contributes to cell rounding and disintegration of the intermediate filament system (Weiske et al., 2001). Caspase-3 inhibition prevents desmoplakin cleavage, implicating caspase-3 as the responsible endopeptidase (Weiske et al. 2001).
Plectin is a major cross-linking protein of the three main cytoplasmic filament systems. Caspase-8 mediated cleavage of plectin 1 appears to contribute to disruption of the microfilament system during the early stages of apoptosis (Stegh et al., 2000).
Cleavage of Gas2 during apoptosis is associated with changes of the microfilament system but does not interfere with its ability to bind F-actin (Brancolini et al., 1995).
Farnesyltransferase/geranyl-geranyltransferase catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. This enzyme complex consists of a heterodimer of an alpha and a beta subunit. The alpha subunit is thought to function in the formation of a stable complex with the substrate. This alpha subnit is cleaved by caspase 3. Expression of the cleavage product (60-379) induces cell death (Kim et al., 2001).
Caspase mediated cleavage of desmoglein 1 leads to decreased expression at the cell surface and re-localization of its C terminus diffusely throughout the cytoplasm. Cleavage is thought to contribute to the dismantling of desmosomes during keratinocyte apoptosis (Dusek et al., 2006).
The cleavage of E-cadherin at both the intracellular and extracellular domains likely contributes to the disruption of cadherin-mediated cell-cell contacts in apoptotic cells. Loss of cell contact is necessary for cell rounding and exit from the epithelium (Steinhusen et al., 2001).
Cleavage of APC by caspase 3 and release of the amino-terminal fragment (1-760) are required for the APC mediated acceleration of apoptosis-associated caspase activity (Qian et al., 2007).
HIP-55 is an actin binding SH3 domain protein that is cleaved by caspase-3. Cleavage results in dissociation of the actin-binding domain from the SH3 domain and may alter cell signaling to and from the actin cytoskeleton. In addition, this cleavage may be involved in the the alteration in cell morphology that occur during apoptosis (Chen et al., 2001).
Apoptosis induced caspases cleave cortical actin network components including fodrin and components of the focal adhesion complex components which links membrane proteins and cortical actin filaments to the extracellular matrix (Janicke et al.,1998). Cleavage of these proteins results in disruption of the cortical cytoskeleton and may contribute to membrane blebbing (see Fischer et al., 2003). The full length 240 kDa alpha-fodrin protein can be cleaved at several sites within its sequence by activated caspases to yield amino-terminal 150 kDa, carboxy-terminal 120 kDa and 35 kDa major products. Cleavage of alpha-II fodrin leads to membrane malfunction and cell shrinkage (Janicke et al., 1998).
Apoptosis-induced cleavage of beta-catenin by caspase 3 results in reduced alpha catenin binding, relocalization to the cytoplasm and a reduction in cell-cell contact. In addition, the resulting proteolytic fragments have reduced transcription factor activity (Steinhusen et al., 2000 ).
Caspase-3 cleaves the DFF45 subunit of the DFF45:DFF40 complex at two sites to generate an active DNA fragmentation factor. One site of cleavage is between residues 117,118 (Liu et al., 1997).
The translocation of the DFF complex from the cytoplasm to the nucleus is mediated by the importin alfa/beta heterodimer. Both DFF40 and DFF45 possess NLS at their C-termini that interact directly with the importin alfa/beta heterodimer. However, DFF complex binds more tightly compared with the individual subunits and C-termini of both subunits are required for DFF nuclear import (Neimanis et al., 2007).
Following its release from DFF45, DFF40 forms homodimers, which are the basic structures of the enzymatically active nuclease (Woo et al., 2004). Following dimerization, DFF40 can further oligomerize forming units containing at least 4 monomers (Liu et al., 1999; Widlak et al., 2003).
DNA Fragmentation Factor (DFF), is a heterodimer of 40 kDa (DFF40) and 45 kDa (DFF45) subunits (Liu et al., 1997). DFF45 (ICAD) appears to act as a chaperone for DFF40 (CAD) during its synthesis, remaining complexed with it to inhibit its DNase activity (Enari et al., 1998). The complex could exist as: a DFF40:DFF45 heterodimer, a (DFF40:DFF45)2 heterotetramer or a (DFF40:DFF40:DFF45:DFF45) heterotetramer (Lechardeur et al., 2005).
Direct interactions between the histone H1 C-terminal domain and DFF40/CAD possibly target the nuclease to chromatin linker DNA promoting the linker DNA cleavage during the terminal stages of apoptosis (Widlak et al., 2005). Noteworthy, it has been reported that DFF40/DFF45 complexes could also associate with chromatin and be activated with caspase-3 in DNA-bound state (Korn et al., 2005).
The DFF40 cleaves DNA substrates to generate fragments possessing ends with 5’-phosphate and 3’-hydroxyl groups, and generates exclusively double strand breaks (primarily blunt ends). It has some sequence preferences on naked DNA substrates and prefers purine/pyrimidine blocks with rotational symmetry (Widlak et al., 2000). DFF is both a deoxyribonucleotide-specific and a double-strand-specific endonuclease (Hanus et al., 2008).
p21-activated protein kinase (PAK-2), also known as gamma-PAK, is cleaved by caspase-3 during apoptosis and plays a role in regulating cell death. Cleavage produces two peptides; 1-212 containing most of the regulatory domain and 213-524 containing 34 amino acids of the regulatory domain as well as the catalytic domain (Walter et al., 1998). Proteolytic cleavage of PAK by caspase-3 creates the constitutively active PAK-2p34 fragment (Jakobi et al., 2003). Evidence for this reaction comes from experiments using both human and rabbit proteins.
The subcellular localization of PAK-2 is controlled by nuclear localization and nuclear export signal motifs (Jakobi et al.,2003). The regulatory domain contains a nuclear export signal motif that prevents the nuclear accumulation of full-length PAK-2. The activating proteolytic cleavage disrupts the nuclear export signal in PAK-2 and removes most its regulatory domain. The resulting activated PAK-2p34 fragment contains a nuclear localization signal and translocates to and is retained in the nucleus (Jakobi et al.,2003).
Caspases initiate the destruction of the nucleus cleavage of lamins leads to disassembly of the nuclear lamina. Lamin A is cleaved by active caspase 6 (Orth et al., 1996).
Caspases initiate the destruction of the nucleus cleavage of lamins leads to disassembly of the nuclear lamina. Lamin B is cleaved by active caspase 6 (Orth et al., 1996) (Rao et al., 1996).
The major HMG-box-containing chromatin proteins HMGB1 and HMGB2 stimulate DNA cleavage by DFF40/CAD (Liu et al., 1998; Toh et al., 1998; Widlak et al., 2000). Changes in DNA conformation following HMG-box binding makes the substrate more accessible to cleavage by DFF40/CAD nuclease and thus may contribute to preferential linker DNA cleavage during apoptosis (Kalinowska-Herok and Widlak., 2008).
Vimentin is cleaved by several caspases during apoptosis (Morishima et al., 1999, Byun et al., 2001). This clevage disrupts the cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Caspase-6 recognizes and cleaves C terminal side of Asp-429.
Vimentin is cleaved by several caspases during apoptosis (Morishima et al., 1999, Byun et al., 2001). This clevage disrupts the cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Asp259 is recognized and cleaved by caspase-6 (Byun et al., 2001).
MASK is cleaved in vitro by caspase 3 . C-terminally truncated forms of MASK can both induce apoptosis upon overexpression in mammalian cells (Dan et al., 2002).
Active caspase 8 associates with the membranes during apoptosis caused by multiple stimuli (Chandra et al., 2004). OMM-localized active caspase 8 can activate cytosolic caspase 3 and ER-localized BAP31 (Chandra et al., 2004) .
Cleavage of the C-terminal cytoplasmic domain of occludin during apoptosis generates a fragment that can no longer associate with the cytoplasmic adapter proteins ZO-1, -2 and -3 and, as a consequence, with the actin cytoskeleton (Bojarski et al., 2003). Cleavage of ZO-1 and ZO-2 further disrupts tight junction structure and function. Notably, claudins, which are associated with ZO-1, ZO-2 and ZO-3, completely lose their linkage to the actin cytoskeleton and other ZO-1-, ZO-2-, ZO-3-interacting proteins (Bojarski et al., 2003). Inhibition of caspase-3 prevents cleavage of ZO-2, implicating caspase-3 as the responsible endopeptidase (Bojarski et al. 2004).
Following iinduction of apoptosis in epithelial cells, tight junction are disrupted. Tight junction proteins, including the the transmembrane protein occludin and the cytoplasmic adaptor proteins ZO-1 and ZO-2 are fragmented by caspase cleavage (Bojarski et al., 2004). Inhibition of caspase-3 prevents cleavage of occludin, implicating caspase-3 as the responsible endopeptidase (Bojarski et al. 2004).
In apoptotic cells, intercellular contacts are disrupted through the activity of caspases. Apoptotic cleavage of Dsg2,the most widespread desmosomal cadherin, is mediated by caspase 3 in epithelial cells (Cirillo et al., 2008).
Caspase-8 mediated cleavage of BAP31 at the ER produces a pro-apoptotic p20 fragment that remains at the ER (Breckenridgeet al., 2003). Cleavage stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cytochrome C (Breckenridgeet al., 2003).
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).
Cleavage of the C-terminal cytoplasmic domain of occludin during apoptosis generates a fragment that can no longer associate with the cytoplasmic adapter proteins ZO-1, -2 and -3 and, as a consequence, with the actin cytoskeleton (Bojarski et al., 2003). Cleavage of ZO-1 and ZO-2 further disrupts tight junction structure and function. Notably, claudins, which are associated with ZO-1, ZO-2 and ZO-3, completely lose their linkage to the actin cytoskeleton and other ZO-1-, ZO-2-, ZO-3-interacting proteins (Bojarski et al., 2003). Caspase-3 was found to be responsible for TJP1 (ZO-1) cleavage in both dog and mouse cells (Chin et al. 2006, Zehendner et al. 2011).
Claspin is cleaved by caspase-7 during the initiation of apoptosis following DNA damage (Clarke et al., 2005). Claspin is cleaved at a single aspartate residue into a large N-terminal fragment and a smaller C-terminal fragment that contain different functional domains. Only the large N-terminal fragment retains Chk1 binding activity. The smaller C-terminal fragment associates with DNA and inhibits the DNA-dependent phosphorylation of Chk1 associated with its activation indicating that cleavage of Claspin by caspase-7 inactivates the Chk1 signaling pathway (Clarke et al., 2005).
Adenoviral expression of the BAP31 cleavage product, p20 causes early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and recruitment of Drp1 to the mitochondria (Breckenridge et al., 2003). Drp1 mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network.
Based on known mechanism of importin-alpha:importin-beta mode of action, cargo imported to the nucleus dissociates from the importin alpha/beta complex in a Ran:GTP-dependent manner. Dissociation of the DFF complex from the importin alpha/beta complex is therefore assumed. Ran:GTP is not shown as its role has not been studied in the context of the DFF complex (Neimanis et al. 2007).
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with the
importin-alpha:importin-beta complexwith the
importin-alpha:importin-beta complexDFFA (117,224):DFFB
complexAnnotated Interactions
with the
importin-alpha:importin-beta complexwith the
importin-alpha:importin-beta complexwith the
importin-alpha:importin-beta complexwith the
importin-alpha:importin-beta complexactive fragment that can depolymerize F-actin contributing to actin cytoskeletal collapse (Kothakota et al., 1997)
disassembly of the nuclear lamina. Lamin A is cleaved by active caspase 6 (Orth et al., 1996).
DFFA (117,224):DFFB
complexDFFA (117,224):DFFB
complex