scholarly journals Death Receptor-Induced Activation of Initiator Caspase 8 Is Antagonized by Serine/Threonine Kinase PAK4

2003 ◽  
Vol 23 (21) ◽  
pp. 7838-7848 ◽  
Author(s):  
Nerina Gnesutta ◽  
Audrey Minden
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Intracellular Signaling ◽  
Death Receptor ◽  
Caspase 8 ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Different Types ◽  
Promote Cell Survival

ABSTRACT Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling proteins regulate apoptosis, or programmed cell death, other proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic protein Bad. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK proteins and suggests a new mechanism by which these proteins promote cell survival.

scholarly journals Akt/Protein Kinase B Inhibits Cell Death by Preventing the Release of Cytochrome c from Mitochondria

1999 ◽  
Vol 19 (8) ◽  
pp. 5800-5810 ◽  
Author(s):  
Scott G. Kennedy ◽  
Eugene S. Kandel ◽  
Torry K. Cross ◽  
Nissim Hay
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Inner Mitochondrial Membrane ◽  
Serine Threonine Kinase ◽  
Independent Manner ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Promote Cell Survival ◽  
Steady State Levels ◽  
Phosphoinositide 3 Kinase

ABSTRACT Growth factors signaling through the phosphoinositide 3-kinase/Akt pathway promote cell survival. The mechanism by which the serine/threonine kinase Akt prevents cell death remains unclear. We have previously shown that Akt inhibits the activity of DEVD-targeted caspases without changing the steady-state levels of Bcl-2 and Bcl-xL. Here we show that Akt inhibits apoptosis and the processing of procaspases to their active forms by delaying mitochondrial changes in a caspase-independent manner. Akt activation is sufficient to inhibit the release of cytochrome c from mitochondria and the alterations in the inner mitochondrial membrane potential. However, Akt cannot inhibit apoptosis induced by microinjection of cytochrome c. We also demonstrated that Akt inhibits apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family members. Taken together, our results show that Akt promotes cell survival by intervening in the apoptosis cascade before cytochrome c release and caspase activation via a mechanism that is distinct from Bad phosphorylation.

scholarly journals Dual Roles of Serine-Threonine Kinase Receptor-Associated Protein (STRAP) in Redox-Sensitive Signaling Pathways Related to Cancer Development

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Ravi Manoharan ◽  
Hyun-A Seong ◽  
Hyunjung Ha
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Tumor Formation ◽  
Serine Threonine Kinase ◽  
Receptor Associated Protein ◽  
Threonine Kinase

Serine-threonine kinase receptor-associated protein (STRAP) is a transforming growth factor β (TGF-β) receptor-interacting protein that has been implicated in both cell proliferation and cell death in response to various stresses. However, the precise roles of STRAP in these cellular processes are still unclear. The mechanisms by which STRAP controls both cell proliferation and cell death are now beginning to be unraveled. In addition to its biological roles, this review also focuses on the dual functions of STRAP in cancers displaying redox dysregulation, where it can behave as a tumor suppressor or an oncogene (i.e., it can either inhibit or promote tumor formation), depending on the cellular context. Further studies are needed to define the functions of STRAP and the redox-sensitive intracellular signaling pathways that enhance either cell proliferation or cell death in human cancer tissues, which may help in the development of effective treatments for cancer.

scholarly journals Evidence of necroptosis in hearts subjected to various forms of ischemic insults

2017 ◽  
Vol 95 (10) ◽  
pp. 1163-1169 ◽  
Author(s):  
Adriana Adameova ◽  
Jaroslav Hrdlicka ◽  
Adrian Szobi ◽  
Veronika Farkasova ◽  
Katarina Kopaskova ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cell Loss ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Ischemic Insult ◽  
The Past ◽  
Tnf Α ◽  
Different Types ◽  
Promote Cell Survival

Long-lasting ischemia can result in cell loss; however, repeated episodes of brief ischemia increase the resistance of the heart against deleterious effects of subsequent prolonged ischemic insult and promote cell survival. Traditionally, it is believed that the supply of blood to the ischemic heart is associated with release of cytokines, activation of inflammatory response, and induction of necrotic cell death. In the past few years, this paradigm of passive necrosis as an uncontrolled cell death has been re-examined and the existence of a strictly regulated form of necrotic cell death, necroptosis, has been documented. This controlled cell death modality, resembling all morphological features of necrosis, has been investigated in different types of ischemia-associated heart injuries. The process of necroptosis has been found to be dependent on the activation of RIP1–RIP3–MLKL axis, which induces changes leading to the rupture of cell membrane. This pathway is activated by TNF-α, which has also been implicated in the cardioprotective signaling pathway of ischemic preconditioning. Thus, this review is intended to describe the TNF-α-mediated signaling leading to either cell survival or necroptotic cell death. In addition, some experimental data suggesting a link between heart dysfunction and the cellular loss due to necroptosis are discussed in various conditions of myocardial ischemia.

scholarly journals Dap-Kinase Participates in TNF-α–And FAS-Induced Apoptosis and Its Function Requires the Death Domain

1999 ◽  
Vol 146 (1) ◽  
pp. 141-148 ◽  
Author(s):  
Ofer Cohen ◽  
Boaz Inbal ◽  
Joseph L. Kissil ◽  
Tal Raveh ◽  
Hanna Berissi ◽  
...  
Keyword(s):  
Cell Death ◽  
Dominant Negative ◽  
Protein Domain ◽  
Dominant Negative Mutant ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Dap Kinase ◽  
Tnf Α ◽  
Induced Apoptosis

Death-associated protein (DAP)–kinase is a calcium/calmodulin regulated serine/threonine kinase that carries ankyrin repeats, a death domain, and is localized to the cytoskeleton. Here, we report that this kinase is involved in tumor necrosis factor (TNF)-α and Fas-induced apoptosis. Expression of DAP-kinase antisense RNA protected cells from killing by anti–Fas/APO-1 agonistic antibodies. Deletion of the death domain abrogated the apoptotic functions of the kinase, thus, documenting for the first time the importance of this protein domain. Overexpression of a fragment encompassing the death domain of DAP-kinase acted as a specific dominant negative mutant that protected cells from TNF-α, Fas, and FADD/MORT1–induced cell death. DAP-kinase apoptotic function was blocked by bcl-2 as well as by crmA and p35 inhibitors of caspases, but not by the dominant negative mutants of FADD/MORT1 or of caspase 8. Thus, it functions downstream to the receptor complex and upstream to other caspases. The multidomain structure of this serine/threonine kinase, combined with its involvement in cell death induced by several different triggers, place DAP-kinase at one of the central molecular pathways leading to apoptosis.

scholarly journals Fist/Hipk3

2000 ◽  
Vol 192 (8) ◽  
pp. 1165-1174 ◽  
Author(s):  
Véronique Rochat-Steiner ◽  
Karin Becker ◽  
Olivier Micheau ◽  
Pascal Schneider ◽  
Kim Burns ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Death Receptor ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Interacting Protein ◽  
Threonine Kinase ◽  
Conserved Sequence ◽  
Mammalian Tissues ◽  
A Cell ◽  
Kinase Pathway

Fas is a cell surface death receptor that signals apoptosis. Several proteins have been identified that bind to the cytoplasmic death domain of Fas. Fas-associated death domain (FADD), which couples Fas to procaspase-8, and Daxx, which couples Fas to the Jun NH2-terminal kinase pathway, bind independently to the Fas death domain. We have identified a 130-kD kinase designated Fas-interacting serine/threonine kinase/homeodomain-interacting protein kinase (FIST/HIPK3) as a novel Fas-interacting protein. Binding to Fas is mediated by a conserved sequence in the COOH terminus of the protein. FIST/HIPK3 is widely expressed in mammalian tissues and is localized both in the nucleus and in the cytoplasm. In transfected cell lines, FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3–FADD–Fas interaction. Although Fas ligand–induced activation of Jun NH2-terminal kinase is impaired by overexpressed active FIST/HIPK3, cell death is not affected. These results suggest that Fas-associated FIST/HIPK3 modulates one of the two major signaling pathways of Fas.

scholarly journals Mechanisms of necroptosis in T cells

2011 ◽  
Vol 208 (4) ◽  
pp. 633-641 ◽  
Author(s):  
Irene L. Ch’en ◽  
Jennifer S. Tsau ◽  
Jeffery D. Molkentin ◽  
Masaaki Komatsu ◽  
Stephen M. Hedrick
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Lymphoproliferative Disease ◽  
Cell Populations ◽  
Caspase 8 ◽  
Related Protein ◽  
Cyclophilin D ◽  
Serine Threonine Kinase ◽  
Programmed Necrosis ◽  
Threonine Kinase

Cell populations are regulated in size by at least two forms of apoptosis. More recently, necroptosis, a parallel, nonapoptotic pathway of cell death, has been described, and this pathway is invoked in the absence of caspase 8. In caspase 8–deficient T cells, necroptosis occurs as the result of antigen receptor–mediated activation. Here, through a genetic analysis, we show that necroptosis in caspase 8–deficient T cells is related neither to the programmed necrosis as defined by the requirement for mitochondrial cyclophilin D nor to autophagy as defined by the requirement for autophagy-related protein 7. Rather, survival of caspase 8–defective T cells can be completely rescued by loss of receptor-interacting serine-threonine kinase (Ripk) 3. Additionally, complementation of a T cell–specific caspase 8 deficiency with a loss of Ripk3 gives rise to lymphoproliferative disease reminiscent of lpr or gld mice. In conjunction with previous work, we conclude that necroptosis in antigen-stimulated caspase 8–deficient T cells is the result of a novel Ripk1- and Ripk3-mediated pathway of cell death.

scholarly journals Caspase-8 deficiency induces a switch from TLR3 induced apoptosis to lysosomal cell death in neuroblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Anaïs Locquet ◽  
Gabriel Ichim ◽  
Joseph Bisaccia ◽  
Aurelie Dutour ◽  
Serge Lebecque ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Neuroblastoma Cell ◽  
Death Receptor ◽  
Neuroblastoma Cell Line ◽  
Caspase 8 ◽  
Caspase Activation ◽  
Extrinsic Pathway ◽  
Lysosomal Membrane Permeabilization ◽  
Induced Apoptosis

AbstractIn cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical apoptosis. When TLR3 was activated in the Caspase-8 negative neuroblastoma cell line SH-SY5Y, cell death was accompanied by lysosomal permeabilization. Despite caspases being activated, lysosomal permeabilization as well as cell death were not affected by blocking caspase-activity, positioning lysosomal membrane permeabilization (LMP) upstream of caspase activation. Taken together, our data suggest that LMP with its deadly consequences represents a “default” death mechanism in cancer cells, when Caspase-8 is absent and apoptosis cannot be induced.

Kinase cascades regulating entry into apoptosis

1997 ◽  
Vol 61 (1) ◽  
pp. 33-46
Author(s):  
P Anderson
Keyword(s):  
Cell Death ◽  
Cell Surface ◽  
Cell Survival ◽  
Tyrosine Kinases ◽  
Uv Light ◽  
Apoptotic Cell ◽  
Paracrine Factors ◽  
Surface Receptors ◽  
Promote Cell Survival ◽  
Necrosis Factor

All cells are constantly exposed to conflicting environment cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. In addition to survival factor withdrawal, cell death can be triggered by environmental stresses such as heat, UV light, and hyperosmolarity or by dedicated death receptors (e.g., FAS/APO-1 and tumor necrosis factor [TNF] receptors) that are counterparts of growth factor or survival receptors at the cell surface. One of the ways that cells integrate conflicting exogenous stimuli is by phosphorylation (or dephosphorylation) of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases (and phosphatases). Survival factors (e.g., growth factors and mitogens) activate receptor tyrosine kinases and selected mitogen-activated, cyclin-dependent, lipid-activated, nucleic acid-dependent, and cyclic AMP-dependent kinases to promote cell survival and proliferation, whereas environmental stress (or death factors such as FAS/APO-1 ligand and TNF-alpha) activates different members of these kinase families to inhibit cell growth and, under some circumstances, promote apoptotic cell death. Because individual kinase cascades can interact with one another, they are able to integrate conflicting exogenous stimuli and provide a link between cell surface receptors and the biochemical pathways leading to cell proliferation or cell death.

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