Engineering of Biological Pathways: Complex Formation and Signal Transduction

2021 ◽  
pp. 59-70
Author(s):  
Philipp Junk ◽  
Christina Kiel
Keyword(s):  
Signal Transduction ◽  
Complex Formation ◽  
Biological Pathways

scholarly journals The MC160 Protein Expressed by the Dermatotropic Poxvirus Molluscum Contagiosum Virus Prevents Tumor Necrosis Factor Alpha-Induced NF-κB Activation via Inhibition of I Kappa Kinase Complex Formation

2006 ◽  
Vol 80 (2) ◽  
pp. 578-586 ◽  
Author(s):  
Daniel Brian Nichols ◽  
Joanna L. Shisler
Keyword(s):  
Signal Transduction ◽  
Complex Formation ◽  
Tumor Necrosis ◽  
Molluscum Contagiosum ◽  
Tnf Receptor ◽  
Molluscum Contagiosum Virus ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The pluripotent cytokine tumor necrosis factor alpha (TNF-α) binds to its cognate TNF receptor I (TNF-RI) to stimulate inflammation via activation of the NF-κB transcription factor. To prevent the detrimental effects of TNF-α in keratinocytes infected with the molluscum contagiosum virus (MCV), this poxvirus is expected to produce proteins that block at least one step of the TNF-RI signal transduction pathway. One such product, the MC160 protein, is predicted to interfere with this cellular response because of its homology to other proteins that regulate TNF-RI-mediated signaling. We report here that expression of MC160 molecules did significantly reduce TNF-α-mediated NF-κB activation in 293T cells, as measured by gene reporter and gel mobility shift assays. Since we observed that MC160 decreased other NF-κB activation pathways, namely those activated by receptor-interacting protein, TNF receptor-associated factor 2, NF-κB-inducing kinase, or MyD88, we hypothesized that the MC160 product interfered with I kappa kinase (IKK) activation, an event common to multiple signal transduction pathways. Indeed, MC160 protein expression was associated with a reduction in in vitro IKK kinase activity and IKK subunit phosphorylation. Further, IKK1-IKK2 interactions were not detected in MC160-expressing cells, under conditions demonstrated to induce IKK complex formation, but interactions between the MC160 protein and the major IKK subunits were undetectable. Surprisingly, MC160 expression correlated with a decrease in IKK1, but not IKK2 levels, suggesting a mechanism for MC160 disruption of IKK1-IKK2 interactions. MCV has probably retained its MC160 gene to inhibit NF-κB activation by interfering with signaling via multiple biological mediators. In the context of an MCV infection in vivo, MC160 protein expression may dampen the cellular production of proinflammatory molecules and enhance persistent infections in host keratinocytes.

Dimerization quality control ensures neuronal development and survival

Science ◽  
2018 ◽  
Vol 362 (6411) ◽  
pp. eaap8236 ◽  
Author(s):  
Elijah L. Mena ◽  
Rachel A. S. Kjolby ◽  
Robert A. Saxton ◽  
Achim Werner ◽  
Brandon G. Lew ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Quality Control ◽  
Complex Formation ◽  
Neural Crest ◽  
Neuronal Development ◽  
Coiled Coils ◽  
Leucine Zippers ◽  
E3 Ligases ◽  
Physiological Importance ◽  
Control Complex

Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains.

scholarly journals Cells must Accumulate Interleukin-4 Receptor Subunits within Cortical Signaling Endosomes to Drive Complex Formation and Signal Transduction

2013 ◽  
Vol 104 (2) ◽  
pp. 610a
Author(s):  
Kristina Kurgonaite ◽  
Hetvi Gandhi ◽  
Remigiusz Worch ◽  
Benjamin Obermann ◽  
Martin Hintersteiner ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Complex Formation ◽  
Interleukin 4 ◽  
Interleukin 4 Receptor

Requirement of Lipid Raft Integrity for Signaling by JAK2-V617F

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4191-4191
Author(s):  
Lori N. Griner ◽  
Kathy L. McGraw ◽  
Joseph O. Johnson ◽  
Alan F. List ◽  
Gary W. Reuther
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
Complex Formation ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Kinase Activity ◽  
Jak2 V617f ◽  
Cytokine Receptors ◽  
Downstream Signaling ◽  
Stat Signaling

Abstract Abstract 4191 JAK2 is a cytoplasmic tyrosine kinase that plays an important role in signaling following activation of various cytokine receptors. JAK2 activation promotes growth, survival, and differentiation of various cell types. Mutation of JAK2 is seen in numerous hematopoietic diseases, most notably in myeloproliferative neoplasms (MPNs). JAK2-V617F is a frequent mutation found in the classical MPNs: polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The single amino acid change of valine to phenylalanine occurs in the pseudokinase domain of JAK2, relieving auto-inhibition of the kinase domain and allowing constitutive kinase activity. Numerous mouse models have demonstrated that JAK2-V617F can induce MPN-like disorders in mice. Thus, this point mutation, as well as other less common JAK2 mutations, is believed to play an important etiologic role in the development of MPNs in humans. The development and use of JAK2 inhibitors in clinical trials has shown promising results, again demonstrating the important role JAK2 plays in MPNs. While the JAK2-V617F mutation, as well as other JAK2 mutations, decreases auto-inhibition of JAK2 kinase activity, it is clear that mutated JAK2 still requires the expression of cytokine receptors to induce activation of transforming signals in hematopoietic cells. Normally, JAK2 binds to homodimeric and heterodimeric cytokine receptors through specific receptor motifs and is activated by various structural changes induced by cytokine stimulation. Following activation it utilizes receptor tyrosines as substrates for phosphorylation, leading to recruitment of downstream signaling molecules, such as STAT5, among others. JAK2 then activates STAT5 via phosphorylation and STAT5 then translocates to the nucleus to regulate transcription of target genes. JAK2-V617F does not require ligand for activation, but still requires the scaffolding function of cytokine receptors to facilitate its full activation and activation of downstream signaling via phosphorylation. Lipid rafts are microdomains of the plasma membrane that are enriched in cholesterol and sphingolipids. They have gained appreciation in signal transduction as sites of localization of signaling mediators, including membrane-bound receptors. Congregation of signaling proteins in lipid rafts within the plasma membrane promotes complex formation and signaling cascade activation. We have recently demonstrated that JAK2 is present in lipid rafts during erythropoietin signaling and that lipid raft integrity is required for erythropoietin-mediated signal transduction (Blood 2009, 114: 292). In our current study, we demonstrate that constitutive JAK-STAT signaling driven by JAK2-V617F is sensitive to lipid raft disruption. Human erythroleukemia (HEL) cells express constitutive activation of JAK-STAT signaling due to the presence of JAK2-V617F. Treatment of these cells with methyl-beta-cyclodextrin to disrupt lipid rafts abolished JAK2, STAT5, and STAT3 activation. Similar results are obtained in other cell lines harboring JAK2-V617F and that exhibit JAK-STAT activation that is dependent on this activated form of JAK2. We also demonstrate that JAK2-V617F co-localizes with lipid rafts, as shown by immunofluorescence, and that this co-localization is abolished by lipid raft disruption. This suggests the loss of JAK2-V617F-mediated JAK-STAT activation we observe following lipid raft disruption may be due to an inhibition of properly localized protein complex formation in the plasma membrane that is necessary for JAK2-V617F signaling. Lipid rafts may provide a site for an accumulation of JAK2-V617F-containing signaling complexes and may be necessary for the cellular signals initiated by JAK2-V617F. Our data show JAK2-V617F-driven JAK-STAT pathway activation is vulnerable to lipid raft disrupting agents and suggest lipid raft integrity as a potential therapeutic target for JAK2-V617F positive neoplasms. Targeting lipid rafts in combination with JAK2 kinase inhibitors may allow for more effective kinase inhibition at lower doses, potentially decreasing undesirable side effects associated with kinase inhibitor treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Complex Formation with the Type B γ-Aminobutyric Acid Receptor Affects the Expression and Signal Transduction of the Extracellular Calcium-sensing Receptor

2007 ◽  
Vol 282 (34) ◽  
pp. 25030-25040 ◽  
Author(s):  
Wenhan Chang ◽  
Chialing Tu ◽  
Zhiqiang Cheng ◽  
Luis Rodriguez ◽  
Tsui-Hua Chen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Complex Formation ◽  
Extracellular Calcium ◽  
Aminobutyric Acid ◽  
Type B ◽  
Calcium Sensing Receptor ◽  
Acid Receptor ◽  
Calcium Sensing

scholarly journals Nutritional regulation of late meiotic events in Saccharomyces cerevisiae through a pathway distinct from initiation.

1996 ◽  
Vol 16 (6) ◽  
pp. 3222-3232 ◽  
Author(s):  
R H Lee ◽  
S M Honigberg
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Signal Transduction ◽  
Complex Formation ◽  
Stationary Phase ◽  
Chromosome Segregation ◽  
Sporulation Medium ◽  
Nutritional Regulation ◽  
Yeast Saccharomyces Cerevisiae ◽  
Synaptonemal Complex Formation ◽  
Late Stages

The IME1 gene is essential for initiation of meiosis in the yeast Saccharomyces cerevisiae, although it is not required for growth. Here we report that in stationary-phase cultures containing low concentration of glucose, cells overexpressing IME1 undergo the early meiotic events, including DNA replication, commitment to recombination, and synaptonemal complex formation and dissolution. In contrast, later meiotic events, such as chromosome segregation, commitment to meiosis, and spore formation, do not occur. Thus, nutrients can repress the late stages of meiosis independently of their block of initiation. Cells arrested at this midpoint in meiosis are relatively stable and can resume meiotic differentiation if transferred to sporulation conditions. Resumption of meiosis does not require repression of IME1 expression, since IME1 RNA levels stay high after transfer of the arrested cells to sporulation medium. These results suggest that meiosis in S. cerevisiae is a paradigm of a differentiation pathway regulated by signal transduction at both early and late stages.

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