Life and death decisions: regulation of apoptosis by proteolysis of signaling molecules

Abstract

Caspases are the major executioners of cell death, serving as molecular guillotines to behead many proteins required for maintenance of cellular homeostasis. Identification of caspase substrates has taken on increasing importance as we attempt to better understand the molecular mechanisms involved in regulating the struggle between life and death. Many caspase substrates have been described and include RNA binding proteins such as La and U1-70 kD, structural proteins such as keratin and nuclear lamins, and transcription factors or their regulatory proteins that include IkB, SP1, and SREBP. Kinases and other signaling proteins are perfectly suited to regulate life and death decisions in response to cellular stressors and have only recently been identified as important caspase substrates. Here we review the current status of signaling pathways that are activated, inactivated or dysregulated by proteases such as caspases and calpain to control entry into apoptosis. The emerging concept that some caspase pathways may be inhibited by cellular and viral apoptosis inhibitory proteins while other caspase pathways are preserved suggests that a subset of these kinases may exist as cleaved`isoforms' in cells that are not destined to perish. By acting as executioners and as important`molecular sensors' of the degree of cellular injury, the signaling proteins described in this review are strong candidates to mediate downstream events, both in condemned and in viable cells.

Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K

“…9 In addition, many kinases and phosphatases are targeted for cleavage, which can lead either to their inactivation or activation. 10 Although several spliceosomal proteins, such as the U1-70K protein, 11 are targets for caspase-3, it is unclear how the breakdown of the splicing machinery is established. Some nuclear proteins as well as their derived peptides can be followed as they are delocalized during apoptosis 12 and at a higher structural level, components of interchromatin granules, perichromatin fibrils and the nucleolus, normally present in the interchromatin space, become clustered in so-called heterogeneous ectopic RNP-derived structures (HERDS).…”

Two or three (thousands) things to do before dying

“…Molecular sensors of cell injury recruit proteolytic activities, which are responsible for the arrest of protein synthesis in dying cells, 1 for the qualitative modifications of intracellular auto-antigens, including proteins 4 and nucleic acids 2 and for the fine regulation of signaling pathways that control cell morphology, cellular repair, cell cycle and RNA splicing. 3 Cells, and the way they behave in response to injury, dramatically change.…”

“…Caspases, besides initiator or executioner of the apoptotic program, should be regarded as main determinants of an integrated scenario, in which proteolytic activities regulate the entry into apoptosis as well as cell survival. 3 This regulation does not obey to a binary logic: the cleavage of signaling molecules results in the re-distribution of crucial components, in the irreversible disruption of their functional activity 1,3 as well as in the alteration of their substrate specificity. 1 Caspase-dependent cleavage of kinases may determine their constitutive activation, uncoupling enzymatic sites from regulatory domains.…”

“…1 Caspase-dependent cleavage of kinases may determine their constitutive activation, uncoupling enzymatic sites from regulatory domains. 1,3 The cleavage of factors involved in cell repair or in cell cycle control will contribute to make survival unlikely. 1,3 In parallel, caspase-dependent cleave liberates the full proapoptotic activity of other kinases, like MEKK-1, capable in turn to activate other caspases, leading to the amplification of the earliest death signal.…”

“…1,3 The cleavage of factors involved in cell repair or in cell cycle control will contribute to make survival unlikely. 1,3 In parallel, caspase-dependent cleave liberates the full proapoptotic activity of other kinases, like MEKK-1, capable in turn to activate other caspases, leading to the amplification of the earliest death signal. 3 Conversely, survival factors activate the phosphoinositide-3 kinase that via the phosphorylation of selected targets such as BAD and caspase-9 promotes cell survival.…”