scholarly journals TRAF2 Ser-11 Phosphorylation Promotes Cytosolic Translocation of the CD40 Complex To Regulate Downstream Signaling Pathways

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Lauren M. Workman ◽  
Laiqun Zhang ◽  
Yumei Fan ◽  
Weizhou Zhang ◽  
Hasem Habelhah
Keyword(s):  
Signaling Pathways ◽  
Secondary Phase ◽  
Ring Domain ◽  
Membrane Phospholipids ◽  
Cd40 Ligation ◽  
Jnk Pathway ◽  
Downstream Signaling ◽  
Signaling Mechanisms ◽  
Mutant Forms ◽  
Full Activation

ABSTRACT CD40 plays an important role in immune responses by activating the c-Jun N-terminal protein kinase (JNK) and NF-κB pathways; however, the precise mechanisms governing the spatiotemporal activation of these two signaling pathways are not fully understood. Here, using four different TRAF2-deficient cell lines (A20.2J, CH12.LX, HAP1, and mouse embryonic fibroblasts [MEFs]) reconstituted with wild-type or phosphorylation mutant forms of TRAF2, along with immunoprecipitation, immunoblotting, gene expression, and immunofluorescence analyses, we report that CD40 ligation elicits TANK-binding kinase 1 (TBK1)-mediated phosphorylation of TRAF2 at Ser-11. This phosphorylation interfered with the interaction between TRAF2’s RING domain and membrane phospholipids and enabled translocation of the TRAF2 complex from CD40 to the cytoplasm. We also observed that this cytoplasmic translocation is required for full activation of the JNK pathway and the secondary phase of the NF-κB pathway. Moreover, we found that in the absence of Ser-11 phosphorylation, the TRAF2 RING domain interacts with phospholipids, leading to the translocation of the TRAF2 complex to lipid rafts, resulting in its degradation and activation of the noncanonical NF-κB pathway. Thus, our results provide new insights into the CD40 signaling mechanisms whereby Ser-11 phosphorylation controls RING domain-dependent subcellular localization of TRAF2 to modulate the spatiotemporal activation of the JNK and NF-κB pathways.

scholarly journals Structural basis of O-GlcNAc recognition by mammalian 14-3-3 proteins

2018 ◽  
Vol 115 (23) ◽  
pp. 5956-5961 ◽  
Author(s):  
Clifford A. Toleman ◽  
Maria A. Schumacher ◽  
Seok-Ho Yu ◽  
Wenjie Zeng ◽  
Nathan J. Cox ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Protein Interactions ◽  
Posttranslational Modification ◽  
Structural Basis ◽  
Biological Processes ◽  
Protein Protein Interactions ◽  
Downstream Signaling ◽  
Biochemical Effects ◽  
Signaling Mechanisms ◽  
Human Proteins

O-GlcNAc is an intracellular posttranslational modification that governs myriad cell biological processes and is dysregulated in human diseases. Despite this broad pathophysiological significance, the biochemical effects of most O-GlcNAcylation events remain uncharacterized. One prevalent hypothesis is that O-GlcNAc moieties may be recognized by “reader” proteins to effect downstream signaling. However, no general O-GlcNAc readers have been identified, leaving a considerable gap in the field. To elucidate O-GlcNAc signaling mechanisms, we devised a biochemical screen for candidate O-GlcNAc reader proteins. We identified several human proteins, including 14-3-3 isoforms, that bind O-GlcNAc directly and selectively. We demonstrate that 14-3-3 proteins bind O-GlcNAc moieties in human cells, and we present the structures of 14-3-3β/α and γ bound to glycopeptides, providing biophysical insights into O-GlcNAc-mediated protein–protein interactions. Because 14-3-3 proteins also bind to phospho-serine and phospho-threonine, they may integrate information from O-GlcNAc and O-phosphate signaling pathways to regulate numerous physiological functions.

scholarly journals Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases

2020 ◽  
Vol 21 (10) ◽  
pp. 3665
Author(s):  
Wiwin Is Effendi ◽  
Tatsuya Nagano ◽  
Helmia Hasan ◽  
Resti Yudhawati
Keyword(s):  
Immune System ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Lung Diseases ◽  
Wound Repair ◽  
Tissue Injury ◽  
Interstitial Lung Diseases ◽  
Downstream Signaling ◽  
Cytokine Activation ◽  
Immune Impairment

The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.

Candida tropicalis induces pro-inflammatory cytokine production, NF-κB and MAPKs pathways regulation, and dectin-1 activation

2018 ◽  
Vol 64 (12) ◽  
pp. 937-944 ◽  
Author(s):  
Zhimin Duan ◽  
Qing Chen ◽  
Rong Zeng ◽  
Leilei Du ◽  
Caixia Liu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Cytokine ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Downstream Signaling ◽  
Tnf Α ◽  
Mitogen Activated Protein

The prevalence of Candida infection induced by non-albicans Candida (NAC) species is increasing. However, as a common NAC species, C. tropicalis has received much less study in terms of host immunity than C. albicans has. In this study, we evaluated the pro-inflammatory cytokine responses evoked by C. tropicalis and determined whether dectin-1 and downstream NF-κB and mitogen-activated protein kinases (MAPKs) signaling pathways played roles in inflammation in human peripheral blood mononuclear cells (PBMCs) and THP-1 macrophage-like cells. Exposure of PBMCs and THP-1 macrophage-like cells to C. tropicalis led to the enhanced gene expression and secretion of TNF-α and IL-6 in a time- and dose-dependent manner. THP-1 macrophage-like cells being challenged by C. tropicalis resulted in the activation of the NF-κB, p38, and ERK1/2 MAPK signaling pathways. We also found that the expression of dectin-1 was increased with C. tropicalis treatment. These data reveal that dectin-1 may play a role in sensing the inflammation response induced by C. tropicalis and that NF-κB and MAPK are involved in the downstream signaling pathways in macrophages.

scholarly journals Novel CD44-downstream signaling pathways mediating breast tumor invasion

2018 ◽  
Vol 14 (13) ◽  
pp. 1782-1790 ◽  
Author(s):  
Allal Ouhtit ◽  
Balsam Rizeq ◽  
Haissam Abou Saleh ◽  
MD Mizanur Rahman ◽  
Hatem Zayed
Keyword(s):  
Signaling Pathways ◽  
Breast Tumor ◽  
Tumor Invasion ◽  
Downstream Signaling

Effects of Ethanol on Pathways of Platelet Aggregation In Vitro

1988 ◽  
Vol 59 (03) ◽  
pp. 383-387 ◽  
Author(s):  
Margaret L Rand ◽  
Marian A Packham ◽  
Raelene L Kinlough-Rathbone ◽  
J Fraser Mustard
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Secondary Phase ◽  
Primary Phase ◽  
Rabbit Platelet ◽  
Membrane Phospholipids ◽  
Rabbit Platelets ◽  
Induced Aggregation

SummaryEthanol, at physiologically tolerable concentrations, did not affect the primary phase of ADP-induced aggregation of human or rabbit platelets, which is not associated with the secretion of granule contents. Potentiation by epinephrine of the primary phase of ADP-induced aggregation of rabbit platelets was also not inhibited by ethanol. However, ethanol did inhibit the secondary phase of ADP-induced aggregation which occurs with human platelets in citrated platelet-rich plasma and is dependent on the formation of thromboxane A2. Inhibition by ethanol of thromboxane production by stimulated platelets is likely due to inhibition of the mobilization of arachidonic acid from membrane phospholipids, as ethanol had little or no effect on aggregation and secretion induced by arachidonic acid or the thromboxane mimetic U46619. Rabbit platelet aggregation and secretion in response to low concentrations of collagen, thrombin, or PAF were inhibited by ethanol. Inhibition of the effects of thrombin and PAF was also observed with aspirin-treated platelets. Thus, in addition to inhibiting the mobilization of arachidonate for thromboxane formation that occurs with most agonists, ethanol can also inhibit aggregation and secretion through other effects on platelet responses.

scholarly journals TIMP-2 disrupts FGF-2-induced downstream signaling pathways

2008 ◽  
Vol 76 (3) ◽  
pp. 145-151 ◽  
Author(s):  
Dong-Wan Seo ◽  
Soo Hyeon Kim ◽  
Seok-Hyun Eom ◽  
Hyun Jae Yoon ◽  
Young-Rak Cho ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Downstream Signaling

scholarly journals The Emerging Mechanisms of Wnt Secretion and Signaling in Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Shefali Mehta ◽  
Swapnil Hingole ◽  
Varun Chaudhary
Keyword(s):  
Signaling Pathways ◽  
Protein Secretion ◽  
Extracellular Space ◽  
Tissue Homeostasis ◽  
Secreted Proteins ◽  
Complex Interplay ◽  
The Past ◽  
Signaling Mechanisms ◽  
Protein Gradients ◽  
Multiple Signaling

Wnts are highly-conserved lipid-modified secreted proteins that activate multiple signaling pathways. These pathways regulate crucial processes during various stages of development and maintain tissue homeostasis in adults. One of the most fascinating aspects of Wnt protein is that despite being hydrophobic, they are known to travel several cell distances in the extracellular space. Research on Wnts in the past four decades has identified several factors and uncovered mechanisms regulating their expression, secretion, and mode of extracellular travel. More recently, analyses on the importance of Wnt protein gradients in the growth and patterning of developing tissues have recognized the complex interplay of signaling mechanisms that help in maintaining tissue homeostasis. This review aims to present an overview of the evidence for the various modes of Wnt protein secretion and signaling and discuss mechanisms providing precision and robustness to the developing tissues.

scholarly journals Registered report: Widespread potential for growth factor-driven resistance to anticancer kinase inhibitors

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Edward Greenfield ◽  
Erin Griner ◽  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Open Science ◽  
Downstream Signaling ◽  
Rtk Inhibitors ◽  
Block Sensitivity

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered Report describes the proposed replication plan of key experiments from ‘Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors’ by Wilson and colleagues, published in Nature in 2012 (<xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The experiments that will be replicated are those reported in Figure 2B and C. In these experiments, Wilson and colleagues show that sensitivity to receptor tyrosine kinase (RTK) inhibitors can be bypassed by various ligands through reactivation of downstream signaling pathways (Figure 2A; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>), and that blocking the receptors for these bypassing ligands abrogates their ability to block sensitivity to the original RTK inhibitor (Figure 2C; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

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