scholarly journals Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant

2021 ◽  
Author(s):  
Ann-Kathrin Reuschl ◽  
Lucy G. Thorne ◽  
Lorena Zuliani-Alvarez ◽  
Mehdi Bouhaddou ◽  
Kirsten Obernier ◽  
...  
Keyword(s):  
Elongation Factor ◽  
Therapy Resistance ◽  
P38 Map Kinase ◽  
Therapeutic Interventions ◽  
Health Concern ◽  
The United Kingdom ◽  
Map Kinase Cascade ◽  
New Variant ◽  
Order Of Magnitude ◽  
Kinase Cascade

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal and economic burden. Recently, a new variant of SARS-CoV-2, known as B.1.1.7, was first detected in the United Kingdom and is spreading in several other countries, heightening public health concern and raising questions as to the resulting effectiveness of vaccines and therapeutic interventions. We and others previously identified host-directed therapies with antiviral efficacy against SARS-CoV-2 infection. Less prone to the development of therapy resistance, host-directed drugs represent promising therapeutic options to combat emerging viral variants as host genes possess a lower propensity to mutate compared to viral genes. Here, in the first study of the full-length B.1.1.7 variant virus, we find two host-directed drugs, plitidepsin (aplidin; inhibits translation elongation factor eEF1A) and ralimetinib (inhibits p38 MAP kinase cascade), as well as remdesivir, to possess similar antiviral activity against both the early-lineage SARS-CoV-2 and the B.1.1.7 variant, evaluated in both human gastrointestinal and lung epithelial cell lines. We find that plitidepsin is over an order of magnitude more potent than remdesivir against both viruses. These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks.

Identification of Op18/stathmin as a potential target of ASK1-p38 MAP kinase cascade

2005 ◽  
Vol 206 (2) ◽  
pp. 363-370 ◽  
Author(s):  
Kenji Mizumura ◽  
Kohsuke Takeda ◽  
Shu Hashimoto ◽  
Takashi Horie ◽  
Hidenori Ichijo
Keyword(s):  
Map Kinase ◽  
P38 Map Kinase ◽  
Potential Target ◽  
Map Kinase Cascade ◽  
Kinase Cascade

scholarly journals Ral Signals through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning

Cell Reports ◽  
2018 ◽  
Vol 24 (10) ◽  
pp. 2669-2681.e5 ◽  
Author(s):  
Hanna Shin ◽  
Rebecca E.W. Kaplan ◽  
Tam Duong ◽  
Razan Fakieh ◽  
David J. Reiner
Keyword(s):  
Map Kinase ◽  
Cell Fate ◽  
P38 Map Kinase ◽  
C Elegans ◽  
Map Kinase Cascade ◽  
Kinase Cascade

scholarly journals Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade

2002 ◽  
Vol 22 (12) ◽  
pp. 4073-4085 ◽  
Author(s):  
Rachel J. Buchsbaum ◽  
Beth A. Connolly ◽  
Larry A. Feig
Keyword(s):  
Map Kinase ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Nucleotide Exchange ◽  
Rac Gtpase ◽  
Signaling Specificity ◽  
Map Kinase Cascade ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
In Cells

ABSTRACT Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.

scholarly journals Legionella pneumophila Suppresses Macrophage Interleukin-12 Production by Activating the p42/44 Mitogen-Activated Protein Kinase Cascade

2003 ◽  
Vol 71 (11) ◽  
pp. 6672-6675 ◽  
Author(s):  
Kazuto Matsunaga ◽  
Hiroyuki Yamaguchi ◽  
Thomas W. Klein ◽  
Herman Friedman ◽  
Yoshimasa Yamamoto
Keyword(s):  
Map Kinase ◽  
Legionella Pneumophila ◽  
Kinase Inhibitors ◽  
Selective Inhibition ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Map Kinase Cascade ◽  
Mitogen Activated Protein ◽  
Kinase Cascade

ABSTRACT A possible involvement of the mitogen-activated protein (MAP) kinase cascade in the inhibition of macrophage interleukin-12 (IL-12) production by Legionella pneumophila infection was examined. The results of MAP kinase inhibition by p42/44 and p38 MAP kinase inhibitors and of p42/44 MAP kinase activity assays indicate that L. pneumophila infection of macrophages causes a selective inhibition of lipopolysaccharide-induced IL-12 production by activating the p42/44 MAP kinase cascade. In addition, it was also revealed that the p38 MAP kinase may be important for the production of IL-12 but not for the inhibition caused by L. pneumophila infection.

Novel Kinase Signaling Cascades in Pancreatic Acinar Cells

Physiology ◽  
1997 ◽  
Vol 12 (3) ◽  
pp. 117-121
Author(s):  
JA Williams ◽  
A Dabrowski ◽  
CD Logsdon
Keyword(s):  
Map Kinase ◽  
Digestive Enzyme ◽  
P38 Map Kinase ◽  
Signaling Cascades ◽  
Pancreatic Acinar Cells ◽  
Jun Kinase ◽  
Map Kinase Cascade ◽  
Kinase Cascade ◽  
Intracellular Mediators ◽  
Digestive Enzyme Secretion

Pancreatic secretagogues that activate digestive enzyme secretion through classic intracellular mediators such as Ca2+ also activate novel signaling kinase cascades. The best defined of these is the MAP kinase cascade, but cholecystokinin also activates jun kinase, p38 MAP kinase, and S6 kinase. These novel pathways are likely involved with pancreatic growth and gene expression.

scholarly journals Ral signals through a MAP4 Kinase-p38 MAP kinase cascade in C. elegans cell fate patterning

2018 ◽  
Author(s):  
Hanna Shin ◽  
Rebecca E.W. Kaplan ◽  
Tam Duong ◽  
Razan Fakieh ◽  
David J. Reiner
Keyword(s):  
Map Kinase ◽  
Cell Fate ◽  
P38 Map Kinase ◽  
High Dose ◽  
C Elegans ◽  
Oncogenic Ras ◽  
Map Kinase Cascade ◽  
Kinase Cascade ◽  
Vulval Precursor Cell

SummaryC. elegans vulval precursor cell (VPC) fates are patterned by an EGF gradient. High dose EGF induces 1° VPC fate, while lower dose EGF contributes to 2° fate in support of LIN-12/Notch. We previously showed that the EGF 2°-promoting signal is mediated by LET-60/Ras switching effectors, from the canonical Raf-MEK-ERK MAP kinase cascade that promotes 1° fate to the non-canonical RalGEF-Ral that promotes 2° fate. Of oncogenic Ras effectors, RalGEF-Ral is by far the least well-understood. We use genetic analysis to identify an effector cascade downstream of C. elegans RAL-1/Ral, starting with an established Ral binding partner, Exo84 of the exocyst complex. Additionally, RAL-1 signals through GCK-2, a CNH domain-containing MAP4 kinase, and PMK-1/p38 MAP kinase cascade to promote 2° fate. Our study delineates a Ral-dependent developmental signaling cascade in vivo, thus providing the mechanism by which lower EGF dose is transduced.

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