ASK1 and Its Role in Neurodegenerative Diseases

Sturchler, Emmanuel; Feurstein, Daniel; McDonald, Patricia; Duckett, Derek R.

doi:10.5772/28950

Cited by 3 publications

(4 citation statements)

References 99 publications

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“… 6 Thus, the inhibition of ASK1 has been reported to decrease the progression and severity of several diseases, including cardiovascular and neurodegenerative diseases. 7 , 8 …”

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confidence: 99%

Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival

Eaton

Diallo

et al. 2014

Cell Death Dis

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Endochondral ossification is the result of chondrocyte differentiation, hypertrophy, death and replacement by bone. The careful timing and progression of this process is important for normal skeletal bone growth and development, as well as fracture repair. Apoptosis Signal-Regulating Kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK), which is activated by reactive oxygen species and other cellular stress events. Activation of ASK1 initiates a signaling cascade known to regulate diverse cellular events including cytokine and growth factor signaling, cell cycle regulation, cellular differentiation, hypertrophy, survival and apoptosis. ASK1 is highly expressed in hypertrophic chondrocytes, but the role of ASK1 in skeletal tissues has not been investigated. Herein, we report that ASK1 knockout (KO) mice display alterations in normal growth plate morphology, which include a shorter proliferative zone and a lengthened hypertrophic zone. These changes in growth plate dynamics result in accelerated long bone mineralization and an increased formation of trabecular bone, which can be attributed to an increased resistance of terminally differentiated chondrocytes to undergo cell death. Interestingly, under normal cell culture conditions, mouse embryonic fibroblasts (MEFs) derived from ASK1 KO mice show no differences in either MAPK signaling or osteogenic or chondrogenic differentiation when compared with wild-type (WT) MEFs. However, when cultured with stress activators, H2O2 or staurosporine, the KO cells show enhanced survival, an associated decrease in the activation of proteins involved in death signaling pathways and a reduction in markers of terminal differentiation. Furthermore, in both WT mice treated with the ASK1 inhibitor, NQDI-1, and ASK1 KO mice endochondral bone formation was increased in an ectopic ossification model. These findings highlight a previously unrealized role for ASK1 in regulating endochondral bone formation. Inhibition of ASK1 has clinical potential to treat fractures or to slow osteoarthritic progression by enhancing chondrocyte survival and slowing hypertrophy.

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“… 6 Thus, the inhibition of ASK1 has been reported to decrease the progression and severity of several diseases, including cardiovascular and neurodegenerative diseases. 7 , 8 …”

mentioning

confidence: 99%

Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival

Eaton

Diallo

et al. 2014

Cell Death Dis

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“…22 Thus, ASK1 is well validated as a drug target for a variety of human diseases. To date, a few ASK1 selective inhibitors have been described in the literature.…”

Section: Discussionmentioning

confidence: 99%

Development of an HTS-Compatible Assay for the Discovery of ASK1 Signalosome Inhibitors Using AlphaScreen Technology

Sturchler

Chen

Spicer

et al. 2014

ASSAY and Drug Development Technologies

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Genetic target validation studies have demonstrated that the apoptosis signal-regulating kinase 1 (ASK1) represents an important target for the treatment of rheumatoid arthritis, cardiac diseases, and several neurodegenerative disorders. To identify small-molecule inhibitors of ASK1, we have developed a high-throughput screening-compatible, homogenous, biochemical assay using AlphaScreen technology. This novel assay design utilizes purified stress-activated ASK1 signalosome complex, and it monitors phosphorylation of its full-length native substrate, MKK6. The assay has been optimized in a 384-well format and validated by screening the Sigma LOPAC library. The results presented here demonstrate that the assay is sensitive and robust with a Z 0 factor value of 0.88 -0.04 and a signal-to-background ratio of 11, indicating that this assay can be used to screen large chemical libraries to discover novel inhibitors of ASK1.

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“…As a mediator of the stress response and pro-apoptotic signaling, ASK1 activity is tightly regulated through multiple mechanisms, such as engaging in protein-protein interactions (PPIs) and through post-translational modifications (PTMs) (Tobiume et al, 2002;Sturchler et al, 2011). Many proteins have been identified that play critical roles in the regulation of ASK1, which can have positive or negative effects on its activity.…”

Section: Introductionmentioning

confidence: 99%

“…The importance of maintaining proper regulation of ASK1 activity can be seen in human diseases, where perturbation of ASK1 signaling can impact disease progression and treatment. ASK1 is pathogenic in many neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, where it promotes cell death (Nishitoh et al, 2002;Sturchler et al, 2011). In cancer, ASK1 can mediate apoptosis caused by common chemotherapeutic agents such as platinum-based drugs and microtubule disruptors (Chen et al, 1999;Yuan et al, 2003;Brozovic and Osmak, 2007).…”

Section: Introductionmentioning

confidence: 99%

Large tumor suppressor 2, LATS2, activates JNK in a kinase-independent mechanism through ASK1

Rusnak

Tang

et al. 2018

Journal of Molecular Cell Biology

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Apoptosis signal-regulating kinase 1 (ASK1) is an important mediator of the cell stress response pathways. Because of its central role in regulating cell death, the activity of ASK1 is tightly regulated by protein–protein interactions and post-translational modifications. Deregulation of ASK1 activity has been linked to human diseases, such as neurological disorders and cancer. Here we describe the identification and characterization of large tumor suppressor 2 (LATS2) as a novel binding partner for ASK1. LATS2 is a core kinase in the Hippo signaling pathway and is commonly downregulated in cancer. We found that LATS2 interacts with ASK1 and increases ASK1-mediated signaling to promote apoptosis and activate the JNK mitogen-activated protein kinase (MAPK). This change in MAPK signaling is dependent on the catalytic activity of ASK1 but does not require LATS2 kinase activity. This work identifies a novel role for LATS2 as a positive regulator of the ASK1–MKK–JNK signaling pathway and establishes a kinase-independent function of LATS2 that may be part of the intricate regulatory system for cellular response to diverse stress signals.

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ASK1 and Its Role in Neurodegenerative Diseases

Cited by 3 publications

References 99 publications

Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival

Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival

Development of an HTS-Compatible Assay for the Discovery of ASK1 Signalosome Inhibitors Using AlphaScreen Technology

Large tumor suppressor 2, LATS2, activates JNK in a kinase-independent mechanism through ASK1

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