scholarly journals PAK2 links cell survival to mechanotransduction and metabolism

2019 ◽  
Vol 218 (6) ◽  
pp. 1958-1971 ◽  
Author(s):  
Hannah K. Campbell ◽  
Alicia M. Salvi ◽  
Timothy O’Brien ◽  
Richard Superfine ◽  
Kris A. DeMali
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
Apoptotic Response ◽  
Direct Binding ◽  
Trigger Cell Death ◽  
Pak2 Activation ◽  
E Cadherin

Too little or too much force can trigger cell death, yet factors that ensure the survival of cells remain largely unknown. Here, we demonstrate that E-cadherin responds to force by recruiting and activating p21-activated protein kinase 2 (PAK2) to allow cells to stiffen, metabolize, and survive. Interestingly, PAK2 activation and its control of the apoptotic response are specific for the amplitude of force applied. Specifically, under low amplitudes of physiological force, PAK2 is protected from proteolysis, thereby ensuring cell survival. In contrast, under higher amplitudes of physiological force, PAK2 is left unprotected and stimulates apoptosis, an effect that is prevented by cleavage-resistant forms of the protein. Finally, we demonstrate that PAK2 protection is conferred by direct binding of AMPK. Thus, PAK2 mediates the survival of cells under force. These findings reveal an unexpected paradigm for how mechanotransduction, metabolism, and cell survival are linked.

scholarly journals Two Faces of Protein Kinase Cδ: The Contrasting Roles of PKCδ in Cell Survival and Cell Death

2010 ◽  
Vol 10 ◽  
pp. 2272-2284 ◽  
Author(s):  
Alakananda Basu ◽  
Deepanwita Pal
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
Caspase 3 ◽  
Critical Role ◽  
Tumor Promotion ◽  
Cellular Processes ◽  
Proapoptotic Protein ◽  
Induced Apoptosis ◽  
Protein Kinase Cδ

Protein kinase Cδ (PKCδ) is a member of the PKC family that plays a critical role in the regulation of various cellular processes, including cell proliferation, cell death, and tumor promotion. Since the identification that PKCδ is a substrate for caspase-3, there has been overwhelming literature that linked PKCδ with proapoptotic signaling. While PKCδ generally functions as a proapoptotic protein during DNA damage-induced apoptosis, it can act as an antiapoptotic protein during receptor-initiated cell death. PKCδ has also been implicated in tumor suppression as well as survival of several cancers. The function of PKCδ depends on various factors, including its localization, tyrosine phosphorylation, and the presence of other pro- and antiapoptoic signaling molecules. This review discusses the current literature on the contrasting roles of PKCδ in cell survival and cell death.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest

2003 ◽  
Vol 14 (5) ◽  
pp. 2071-2087 ◽  
Author(s):  
Karl Deacon ◽  
Pratibha Mistry ◽  
Jonathan Chernoff ◽  
Jonathan L. Blank ◽  
Rajnikant Patel
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Chemotherapeutic Drugs ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase

Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death.

scholarly journals Rab7 Activation by Growth Factor Withdrawal Contributes to the Induction of Apoptosis

2009 ◽  
Vol 20 (12) ◽  
pp. 2831-2840 ◽  
Author(s):  
Kimberly Romero Rosales ◽  
Eigen R. Peralta ◽  
Garret G. Guenther ◽  
Susan Y. Wong ◽  
Aimee L. Edinger
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Cell Survival ◽  
Fusion Reactions ◽  
Kinase C ◽  
Late Endosomes ◽  
Growth Factor Deprivation ◽  
Induction Of Apoptosis ◽  
Trigger Cell Death ◽  
Induced Proteins

The Rab7 GTPase promotes membrane fusion reactions between late endosomes and lysosomes. In previous studies, we demonstrated that Rab7 inactivation blocks growth factor withdrawal-induced cell death. These results led us to hypothesize that growth factor withdrawal activates Rab7. Here, we show that growth factor deprivation increased both the fraction of Rab7 that was associated with cellular membranes and the percentage of Rab7 bound to guanosine triphosphate (GTP). Moreover, expressing a constitutively GTP-bound mutant of Rab7, Rab7-Q67L, was sufficient to trigger cell death even in the presence of growth factors. This activated Rab7 mutant was also able to reverse the growth factor-independent cell survival conferred by protein kinase C (PKC) δ inhibition. PKCδ is one of the most highly induced proteins after growth factor withdrawal and contributes to the induction of apoptosis. To evaluate whether PKCδ regulates Rab7, we first examined lysosomal morphology in cells with reduced PKCδ activity. Consistent with a potential role as a Rab7 activator, blocking PKCδ function caused profound lysosomal fragmentation comparable to that observed when Rab7 was directly inhibited. Interestingly, PKCδ inhibition fragmented the lysosome without decreasing Rab7-GTP levels. Taken together, these results suggest that Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis and that Rab7-dependent fusion reactions may be targeted by signaling pathways that limit growth factor-independent cell survival.

scholarly journals Relaxin confers cytotrophoblast protection from hypoxia-reoxygenation injury through the phosphatidylinositol 3-kinase-Akt/protein kinase B cell survival pathway

2017 ◽  
Vol 312 (4) ◽  
pp. R559-R568 ◽  
Author(s):  
Oluseyi Ogunleye ◽  
Bertha Campo ◽  
Diana Herrera ◽  
Emiel D. Post Uiterweer ◽  
Kirk P. Conrad
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
Protein Kinase B ◽  
Serum Deprivation ◽  
Phosphatidylinositol 3 Kinase ◽  
Concurrent Treatment ◽  
B Cell Survival ◽  
Survival Pathway ◽  
Hypoxia Reoxygenation

Preeclampsia is a hypertensive syndrome that manifests after 20 wk of gestation. Contemporary understanding of the maternal-fetal interface in preeclampsia suggests a major role for placental oxidative stress resulting from ischemia-reperfusion injury. We hypothesized that the pregnancy hormone relaxin would reduce cytotrophoblast apoptosis and necrosis (aponecrosis) and, hence, the export of placental debris into the maternal circulation. If so, then relaxin might be employed as a therapeutic intervention to diminish the activation of the maternal systemic inflammatory response central to the development of clinical disease. HTR-8/SVneo cells, a model for first trimester extravillous trophoblast, were subjected to serum deprivation and hypoxia or hypoxia-reoxygenation. The cells were treated with recombinant human relaxin or vehicle and apoptosis and/or necrosis evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), CellEvent Caspase-3/7 and SYTOX AADvanced kit, and propidium iodide staining as determined by fluorescence microscopy or flow cytometry. To interrogate mechanisms of relaxin cytoprotection, HTR-8/SVneo cells were pretreated with pharmacological inhibitors of PI3-kinase LY294004, Akt/PKB MK-2206, or DMSO vehicle. HTR-8/SVneo cell identity was first confirmed by RT-PCR. The cells expressed placental alkaline phosphatase, aromatase, and human leukocyte antigen G. In addition, the cells expressed the relaxin receptor RXFP1 as well as H1 and H2 relaxins. Serum deprivation and hypoxia increased apoptotic cell death in HTR-8/SVneo cells, which was significantly ameliorated by concurrent treatment with relaxin. Serum deprivation and hypoxia-reoxygenation increased necrotic cell death in HTR-8/SVneo cells, which was also significantly rescued by concurrent treatment with relaxin. Pretreatment with LY294002 or MK-2206, to inhibit the phosphatidylinositol 3-kinase-Akt/protein kinase B cell survival pathway, significantly blunted the cytoprotective effect of relaxin. We demonstrated trophoblast cytoprotection by intervention with supraphysiological concentrations of relaxin, a process in part mediated through the PI3-kinase-Akt/PKB cell survival pathway. These results provide further rationale for clinical investigation of relaxin as a potential therapeutic in preeclampsia.

Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

2019 ◽  
Vol 16 (1) ◽  
pp. 3-11
Author(s):  
Luisa Halbe ◽  
Abdelhaq Rami
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cell Damage ◽  
Protective Mechanism ◽  
Unfolded Proteins ◽  
Neuronal Viability ◽  
Hippocampal Cell ◽  
Trigger Cell Death ◽  
Autophagy Inhibition

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

Neuroglobin and Estrogen Receptors: A New Pathway of Cell Survival and Cell Death Balance

2015 ◽  
Vol 14 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Maria T. Nuzzo ◽  
Marco Fiocchetti ◽  
Paolo Ascenzi ◽  
Maria Marino
Keyword(s):  
Cell Death ◽  
Estrogen Receptors ◽  
Cell Survival
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