Downstream Signaling Mechanism Underlying MAPK-Induced Generation of the ER-Negative Phenotype

2003 ◽  
Author(s):  
Jamie N. Holloway
Keyword(s):  
Signaling Mechanism ◽  
Downstream Signaling ◽  
Negative Phenotype

scholarly journals Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

2013 ◽  
Vol 16 (2) ◽  
pp. 177 ◽  
Author(s):  
Antonio Villalobo ◽  
Irene García-Palmero ◽  
Silviya R. Stateva ◽  
Karim Jellali
Keyword(s):  
Cancer Therapy ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Short Review ◽  
Receptor Protein ◽  
Pharmacological Intervention ◽  
Erbb Receptors ◽  
Aberrant Expression ◽  
Signaling Mechanism ◽  
Downstream Signaling

Signal transduction pathways essential for the survival and viability of the cell and that frequently present aberrant expression or function in tumors are attractive targets for pharmacological intervention in human cancers. In this short review we will describe the regulation exerted by the calcium-receptor protein calmodulin (CaM) on signaling routes involving the family of ErbB receptors - highlighting the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 - and the adaptor protein Grb7, a downstream signaling component of these receptors. The signaling mechanism of the ErbB/Grb7 axis and the regulation exerted by CaM on this pathway will be described. We will present a brief overview of the current efforts to inhibit the hyperactivity of ErbB receptors and Grb7 in tumors. The currently available information on targeting the CaM-binding site of these signaling proteins will be analyzed, and the pros and cons of directly targeting CaM versus the CaM-binding domain of the ErbB receptors and Grb7 as potential anti-cancer therapy will be discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Mevalonate metabolism–dependent protein geranylgeranylation regulates thymocyte egress

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Xingrong Du ◽  
Hu Zeng ◽  
Shaofeng Liu ◽  
Cliff Guy ◽  
Yogesh Dhungana ◽  
...  
Keyword(s):  
T Cell ◽  
Similar Process ◽  
Immune Homeostasis ◽  
T Cell Homeostasis ◽  
Protein Prenylation ◽  
Critical Determinant ◽  
Cell Homeostasis ◽  
Signaling Mechanism ◽  
Downstream Signaling

Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein–coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism–fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.

scholarly journals ß2-Arrestin germline knockout does not attenuate opioid respiratory depression

2020 ◽  
Author(s):  
Iris Bachmutsky ◽  
Adelae Durand ◽  
Kevin Yackle
Keyword(s):  
United States ◽  
Respiratory Depression ◽  
Side Effect ◽  
Opioid Analgesics ◽  
The United States ◽  
Common Side Effect ◽  
Signaling Mechanism ◽  
Downstream Signaling ◽  
Respiratory Behavior ◽  
Downstream Signaling Pathway

AbstractOpioids are perhaps the most effective analgesics in medicine. However, from 1999 to 2018, they also killed more than 400,000 people in the United States by suppressing breathing, a common side-effect known as opioid induced respiratory depression. This doubled-edged sword has inspired the dream of developing novel therapeutics that provide opioid-like analgesia without respiratory depression. One such approach has been to develop so-called ‘biased agonists’ that activate some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This hypothesis stems from a study suggesting that MOR-mediated activation of ß2-Arrestin is the downstream signaling pathway responsible for respiratory depression, whereas inhibition of adenylyl cyclase produces analgesia. To further verify this model, which represents the motivation for the biased agonist approach, we examined respiratory behavior in mice lacking the gene for ß2-Arrestin. Contrary to previous findings, we find no correlation between ß2-Arrestin function and opioid-induced respiratory depression, suggesting that any effect of biased agonists must be mediated through an as-yet to be identified signaling mechanism.

scholarly journals Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling

2015 ◽  
Vol 112 (38) ◽  
pp. 11876-11880 ◽  
Author(s):  
Askar M. Akimzhanov ◽  
Darren Boehning
Keyword(s):  
Tyrosine Kinase ◽  
Protein Function ◽  
Intracellular Signaling ◽  
Signaling Mechanism ◽  
Fas Receptor ◽  
Downstream Signaling ◽  
Fatty Acid Chain ◽  
Protein Palmitoylation ◽  
Thioester Bond ◽  
Fas Signaling

Palmitoylation is the posttranslational modification of proteins with a 16-carbon fatty acid chain through a labile thioester bond. The reversibility of protein palmitoylation and its profound effect on protein function suggest that this modification could play an important role as an intracellular signaling mechanism. Evidence that palmitoylation of proteins occurs with the kinetics required for signal transduction is not clear, however. Here we show that engagement of the Fas receptor by its ligand leads to an extremely rapid and transient increase in palmitoylation levels of the tyrosine kinase Lck. Lck palmitoylation kinetics are consistent with the activation of downstream signaling proteins, such as Zap70 and PLC-γ1. Inhibiting Lck palmitoylation not only disrupts proximal Fas signaling events, but also renders cells resistant to Fas-mediated apoptosis. Knockdown of the palmitoyl acyl transferase DHHC21 eliminates activation of Lck and downstream signaling after Fas receptor stimulation. Our findings demonstrate highly dynamic Lck palmitoylation kinetics that are essential for signaling downstream of the Fas receptor.

scholarly journals Effects of Estradiol on Immunoglobulin G Glycosylation: Mapping of the Downstream Signaling Mechanism

2021 ◽  
Vol 12 ◽  
Author(s):  
Anika Mijakovac ◽  
Julija Jurić ◽  
Wendy M. Kohrt ◽  
Jasminka Krištić ◽  
Domagoj Kifer ◽  
...  
Keyword(s):  
Immunoglobulin G ◽  
Controlled Trial ◽  
Premenopausal Women ◽  
Gonadal Hormones ◽  
Total Serum ◽  
Signaling Mechanism ◽  
Effector Functions ◽  
Downstream Signaling ◽  
Transient System ◽  
Igg Glycosylation

Glycans attached to immunoglobulin G (IgG) directly affect this antibody effector functions and regulate inflammation at several levels. The composition of IgG glycome changes significantly with age. In women, the most notable change coincides with the perimenopausal period. Aiming to investigate the effect of estrogen on IgG glycosylation, we analysed IgG and total serum glycomes in 36 healthy premenopausal women enrolled in a randomized controlled trial of the gonadotropin-releasing hormone analogue (GnRHAG) leuprolide acetate to lower gonadal steroids to postmenopausal levels and then randomized to transdermal placebo or estradiol (E2) patch. The suppression of gonadal hormones induced significant changes in the IgG glycome, while E2 supplementation was sufficient to prevent changes. The observed glycan changes suggest that depletion of E2 primarily affects B cell glycosylation, while liver glycosylation stays mostly unchanged. To determine whether previously identified IgG GWAS hits RUNX1, RUNX3, SPINK4, and ELL2 are involved in downstream signaling mechanisms, linking E2 with IgG glycosylation, we used the FreeStyle 293-F transient system expressing IgG antibodies with stably integrated CRISPR/dCas9 expression cassettes for gene up- and downregulation. RUNX3 and SPINK4 upregulation using dCas9-VPR resulted in a decreased IgG galactosylation and, in the case of RUNX3, a concomitant increase in IgG agalactosylation.

scholarly journals TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Tunyu Jian ◽  
Niuniu Yang ◽  
Yan Yang ◽  
Chan Zhu ◽  
Xiaolin Yuan ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Underlying Mechanism ◽  
Receptor Activation ◽  
Ruthenium Red ◽  
Drg Neurons ◽  
Histamine H4 Receptor ◽  
Signaling Mechanism ◽  
Downstream Signaling ◽  
Intracellular Ca ◽  
H4 Receptor

Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG) neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip)—a histamine H4 receptor special agonist under cutaneous injection—obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3–50 μM) could also induce a dose-dependent increase in intracellular Ca2+(Ca2+i) of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca2+responses. In addition, immepip-inducedCa2+iincrease could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons’ responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.

scholarly journals Inferring the structures of signaling motifs from paired dynamic traces of single cells

2021 ◽  
Vol 17 (2) ◽  
pp. e1008657
Author(s):  
Raymond A. Haggerty ◽  
Jeremy E. Purvis
Keyword(s):  
Time Series ◽  
Single Cells ◽  
Underlying Mechanism ◽  
Repeated Measurements ◽  
Signaling Mechanism ◽  
Downstream Signaling ◽  
Signaling Dynamics ◽  
Functional Consequences ◽  
Averaging Time ◽  
Cell To Cell Variability

Individual cells show variability in their signaling dynamics that often correlates with phenotypic responses, indicating that cell-to-cell variability is not merely noise but can have functional consequences. Based on this observation, we reasoned that cell-to-cell variability under the same treatment condition could be explained in part by a single signaling motif that maps different upstream signals into a corresponding set of downstream responses. If this assumption holds, then repeated measurements of upstream and downstream signaling dynamics in a population of cells could provide information about the underlying signaling motif for a given pathway, even when no prior knowledge of that motif exists. To test these two hypotheses, we developed a computer algorithm called MISC (Motif Inference from Single Cells) that infers the underlying signaling motif from paired time-series measurements from individual cells. When applied to measurements of transcription factor and reporter gene expression in the yeast stress response, MISC predicted signaling motifs that were consistent with previous mechanistic models of transcription. The ability to detect the underlying mechanism became less certain when a cell’s upstream signal was randomly paired with another cell’s downstream response, demonstrating how averaging time-series measurements across a population obscures information about the underlying signaling mechanism. In some cases, motif predictions improved as more cells were added to the analysis. These results provide evidence that mechanistic information about cellular signaling networks can be systematically extracted from the dynamical patterns of single cells.

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