scholarly journals Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Blood ◽  
2021 ◽  
Author(s):  
Margaux Sevin ◽  
Franck Debeurme ◽  
Lucie Laplane ◽  
Severine Badel ◽  
Margot Morabito ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Methylation Pattern ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Molecule Inhibitor ◽  
Mitogen Activated Protein ◽  
Monocyte Apoptosis ◽  
Combined Strategy

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

scholarly journals TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii

2004 ◽  
Vol 72 (10) ◽  
pp. 5662-5667 ◽  
Author(s):  
Nicola J. Mason ◽  
Jim Fiore ◽  
Takashi Kobayashi ◽  
Katherine S. Masek ◽  
Yongwon Choi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Wild Type ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-κB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-κB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-κB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6−/− mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6−/− mice failed to produce IL-12(p40) in response to STAg, and TRAF6−/− macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6−/− macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.

scholarly journals Zinc is a novel intracellular second messenger

2007 ◽  
Vol 177 (4) ◽  
pp. 637-645 ◽  
Author(s):  
Satoru Yamasaki ◽  
Kumiko Sakata-Sogawa ◽  
Aiko Hasegawa ◽  
Tomoyuki Suzuki ◽  
Koki Kabu ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Calcium Influx ◽  
Second Messenger ◽  
Zinc Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Signaling Events ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli

Zinc is an essential trace element required for enzymatic activity and for maintaining the conformation of many transcription factors; thus, zinc homeostasis is tightly regulated. Although zinc affects several signaling molecules and may act as a neurotransmitter, it remains unknown whether zinc acts as an intracellular second messenger capable of transducing extracellular stimuli into intracellular signaling events. In this study, we report that the cross-linking of the high affinity immunoglobin E receptor (Fcε receptor I [FcεRI]) induced a release of free zinc from the perinuclear area, including the endoplasmic reticulum in mast cells, a phenomenon we call the zinc wave. The zinc wave was dependent on calcium influx and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation. The results suggest that the zinc wave is involved in intracellular signaling events, at least in part by modulating the duration and strength of FcεRI-mediated signaling. Collectively, our findings indicate that zinc is a novel intracellular second messenger.

scholarly journals Noncanonical Function of MEKK2 and MEK5 PB1 Domains for Coordinated Extracellular Signal-Regulated Kinase 5 and c-Jun N-Terminal Kinase Signaling

2007 ◽  
Vol 27 (12) ◽  
pp. 4566-4577 ◽  
Author(s):  
Kazuhiro Nakamura ◽  
Gary L. Johnson
Keyword(s):  
Ternary Complex ◽  
Mitogen Activated Protein Kinase ◽  
Docking Site ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Differential Binding ◽  
Pb1 Domain ◽  
Jnk Activation

ABSTRACT MEKK2 and MEK5 encode Phox/Bem1p (PB1) domains that heterodimerize with one another. MEKK2, MEK5, and extracellular signal-related kinase 5 (ERK5) form a ternary complex through interactions involving the MEKK2 and MEK5 PB1 domains and a 34-amino-acid C-terminal extension of the MEK5 PB1 domain. This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5. The PB1 domains bind in a front-to-back arrangement, with a cluster of basic amino acids in the front of the MEKK2 PB1 domain binding to the back-end acidic clusters of the MEK5 PB1 domain. The C-terminal moiety, including the acidic cluster of the MEKK2 PB1 domain, is not required for MEK5 binding and binds MKK7. Quiescent MEKK2 preferentially binds MEK5, and MEKK2 activation results in ERK5 activation. Activated MEKK2 binds and activates MKK7, leading to JNK activation. The findings define how the MEKK2 and MEK5 PB1 domains are uniquely used for differential binding of two mitogen-activated protein kinase kinases, MEK5 and MKK7, for the coordinated control of ERK5 and c-Jun N-terminal kinase activation.

scholarly journals Novel Molecular Basis for Synapse Formation: Small Non-coding Vault RNA Functions as a Riboregulator of MEK1 to Modulate Synaptogenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Shuji Wakatsuki ◽  
Toshiyuki Araki
Keyword(s):  
Protein Kinase ◽  
Molecular Basis ◽  
Synapse Formation ◽  
Regulatory Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Small non-coding vault RNAs (vtRNAs) have been described as a component of the vault complex, a hollow-and-barrel-shaped ribonucleoprotein complex found in most eukaryotes. It has been suggested that the function of vtRNAs might not be limited to simply maintaining the structure of the vault complex. Despite the increasing research on vtRNAs, little is known about their physiological functions. Recently, we have shown that murine vtRNA (mvtRNA) up-regulates synaptogenesis by activating the mitogen activated protein kinase (MAPK) signaling pathway. mvtRNA binds to and activates mitogen activated protein kinase 1 (MEK1), and thereby enhances MEK1-mediated extracellular signal-regulated kinase activation. Here, we introduce the regulatory mechanism of MAPK signaling in synaptogenesis by vtRNAs and discuss the possibility as a novel molecular basis for synapse formation.

scholarly journals Selective deficiency in protein kinase C isoenzyme expression and inadequacy in mitogen-activated protein kinase activation in cord blood T cells

2003 ◽  
Vol 370 (2) ◽  
pp. 497-503 ◽  
Author(s):  
Charles S.T. HII ◽  
Maurizio COSTABILE ◽  
George C. MAYNE ◽  
Channing J. DER ◽  
Andrew W. MURRAY ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
Cord Blood ◽  
Map Kinase ◽  
Map Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Biochemical Basis ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

The biochemical basis for the reduced lymphokine production by neonatal T cells compared with adult T cells remains poorly defined. Previous studies have raised the possibility that neonatal T cells could be deficient in their ability to transmit signals via protein kinase (PK) C. We now report that while PKC-dependent activation of the mitogen-activated protein (MAP) kinases, c-Jun N-terminal protein kinase and the extracellular signal-regulated protein kinase (ERK)1/ERK2, was deficient in cord blood T cells compared with adult blood T cells, marked activation of the MAP kinases in cord blood T cells was achieved via PKC-independent means. Consistent with a deficiency in the signalling capability of PKC, cord blood T cells were selectively deficient in the expression of PKCβI, ∊, θ and ζ. Stimulation of cord blood T cells resulted in a time-dependent increase in PKC expression, with increases detectable by 4h. This was accompanied by an enhancement in MAP kinase activation via PKC-dependent means. These novel data suggest that an inadequacy in PKC-MAP kinase signalling may be responsible, at least in part, for the phenotype of cord blood T cells.

scholarly journals Optimizing photoswitchable MEK

2019 ◽  
Vol 116 (51) ◽  
pp. 25756-25763 ◽  
Author(s):  
Aleena L. Patel ◽  
Eyan Yeung ◽  
Sarah E. McGuire ◽  
Andrew Y. Wu ◽  
Jared E. Toettcher ◽  
...  
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Erk Activation ◽  
Signaling Systems ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Morphogenetic Event ◽  
Zebrafish Embryogenesis

Optogenetic approaches are transforming quantitative studies of cell-signaling systems. A recently developed photoswitchable mitogen-activated protein kinase kinase 1 (MEK1) enzyme (psMEK) short-circuits the highly conserved Extracellular Signal-Regulated Kinase (ERK)-signaling cascade at the most proximal step of effector kinase activation. However, since this optogenetic tool relies on phosphorylation-mimicking substitutions in the activation loop of MEK, its catalytic activity is predicted to be substantially lower than that of wild-type MEK that has been phosphorylated at these residues. Here, we present evidence that psMEK indeed has suboptimal functionality in vivo and propose a strategy to circumvent this limitation by harnessing gain-of-function, destabilizing mutations in MEK. Specifically, we demonstrate that combining phosphomimetic mutations with additional mutations in MEK, chosen for their activating potential, restores maximal kinase activity in vitro. We establish that this modification can be tuned by the choice of the destabilizing mutation and does not interfere with reversible activation of psMEK in vivo in bothDrosophilaand zebrafish. To illustrate the types of perturbations enabled by optimized psMEK, we use it to deliver pulses of ERK activation during zebrafish embryogenesis, revealing rheostat-like responses of an ERK-dependent morphogenetic event.

scholarly journals Control of Mycobacterial Replication in Human Macrophages: Roles of Extracellular Signal-Regulated Kinases 1 and 2 and p38 Mitogen-Activated Protein Kinase Pathways

2002 ◽  
Vol 70 (9) ◽  
pp. 4961-4967 ◽  
Author(s):  
Antje Blumenthal ◽  
Stefan Ehlers ◽  
Martin Ernst ◽  
Hans-Dieter Flad ◽  
Norbert Reiling
Keyword(s):  
Protein Kinase ◽  
Growth Control ◽  
Human Monocyte ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Bacterial Replication

ABSTRACT Intracellular persistence of mycobacteria may result from an intricate balance between bacterial replication and signaling events leading to antimicrobial macrophage activities. Using human monocyte-derived macrophages, we investigated the relevance of mitogen-activated protein kinase activation for the growth control of Mycobacterium avium isolates differing in their abilities to multiply intracellularly. The highly replicative smooth transparent morphotype of M. avium strain 2151 induced significantly less p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation than the smooth opaque morphotype of the same strain, which was gradually eliminated from macrophage cultures. Inhibition of the p38 pathway by highly specific inhibitors did not significantly affect mycobacterial replication within macrophages, regardless of the in vitro virulence of the M. avium strain. However, repression of the ERK1/2 pathway further enhanced intracellular growth of highly replicative M. avium strains, although it did not increase survival of the poorly replicating M. avium isolate. Inhibition of the ERK1/2 pathway resulted in decreased tumor necrosis alpha (TNF-α) secretion irrespective of the virulence of the M. avium isolate used for infection, revealing that TNF-α could have been only partially responsible for the control of intracellular M. avium growth. In conclusion, ERK1/2- and TNF-α-independent pathways are sufficient to limit intramacrophage growth of less-virulent M. avium strains, but early ERK1/2 activation in infected macrophages is critically involved in controlling the growth of highly replicative M. avium strains.

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