Difference between revisions of "Part:BBa K4160002"

 
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<partinfo>BBa_K4160002 short</partinfo>
 
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IL-6RB is a trans-membrane protein that serves as the signal-transducing &#946;-subunit of the interleukin 6 receptor.
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<p>Interleukin-6 receptor subunit beta (IL-6RB) (Figure 1) is a single transmembrane glycoprotein that is defined as a type I cytokine receptor.<sup>1</sup> IL-6RB functions as a signaling transducer.<sup>2 </sup>
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===Usage and Biology===
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<figure><img src="https://static.igem.org/mediawiki/parts/1/15/BBa_K4160002_TU-Eindhoven_IL-6RB_structure.png" width="300px" heigth=220px">
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<p><b>Figure 1 | 3D structure of IL-6RB.</b> (PDB: 1BJ8)<sup>3</sup></p>
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</figure><br>
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<span class='h3bb'>Sequence and Features</span>
 
<span class='h3bb'>Sequence and Features</span>
 
<partinfo>BBa_K4160002 SequenceAndFeatures</partinfo>
 
<partinfo>BBa_K4160002 SequenceAndFeatures</partinfo>
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<body>
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<br>
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<h2>Usage and Biology</h2>
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<p>IL-6RB is part of the receptor system for IL-6 derived from <i>Homo sapiens (Human)</i>. The receptor system is a protein complex that consists of IL-6Ralfa, IL-6, and signal transducer IL-6RB (also called gp130 or IL-6ST).<sup>1</sup> Binding of IL-6 induces IL-6RB homodimerization, which induces activation of IL-6RB-associated Janus kinases (JAKs).<sup>1</sup> Consequently, IL-6Rb gets phosphorylated at its tyrosine sites, which results in the recruitment and activation of SHP2 (Src homology-2 containing protein tyrosine phosphatase-2) and STAT3 (Signal Transducer and Activator of Transcription 3) (Figure 1).<sup>1</sup> Tyrosine phosphorylation of STAT3 (<a href="https://parts.igem.org/Part:BBa_K4160005">BBa_K4160005</a>) leads to heterodimerization complex of STAT3 and STAT1. This complex enters the nucleus and regulates the expression of various genes.<sup>1</sup> STAT3 regulates the expression of suppressor of cytokine signaling (SOCS) 1 and SOCS3 in IL-6RB signaling. SOCS3 is a direct inhibitor of IL-6RB, whereas SOCS1 inhibits IL-6RB indirectly by interaction with JAKs.<sup>1</sup> Phosphorylated SHP2 at the tyrosine site forms a complex with Grb2, which is associated with Sos, a GFP-GTP exchanger for Ras. The complex activates the MAPK pathway and regulates associated genes.<sup>1</sup> Phosphorylated SHP2 can also bind to Gab proteins to mediate signals in the ERK MAP system and AKT signaling pathway.<sup>1</sup></p><br>
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<figure><img src="https://static.igem.org/mediawiki/parts/b/b4/BBa_K4160002_TU-Eindhoven_IL-6RB_signaling.png" width="640px" heigth=480px">
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<figcaption>
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<p><b>Figure 2 | signaling pathway of IL-6 receptor activation.</b> Adapted from Wang et al., 2012.<sup>4</sup> Figure created with Biorender.</p>
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<h3>Biological activity</h3>
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<p>In hematopoietic lineages, activation of IL-6RB induces the production of antibodies by B-cells. In addition, it leads to the proliferation of myeloma and plasmacytoma cells, hematopoietic progenitors expanding, megakaryocyte progenitors proliferating and differentiating, and  T-lymphocytes proliferating and differentiating into cytotoxic T-cells.<sup>5</sup> Furthermore, activation of IL-6RB induces hepatocyte stimulation, differentiation of neuronal cells in the nervous system, and stimulation of several anterior pituitary hormones such as growth hormones, luteinizing hormone, and prolactin.<sup>5</sup></p><br>
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<h3>GEMS receptor</h3>
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<p><a href="https://2022.igem.wiki/tu-eindhoven/">TU-Eindhoven 2022</a> used this part to transduce signals intracellularly with the Generalized Extracellular Molecule Sensor (GEMS) receptor (<a href="https://parts.igem.org/Part:BBa_K4160008">BBa_K4160008</a>). In this receptor, the IL-6RB is incorporated at the intracellular domain of the EpoR scaffold (<a href="https://parts.igem.org/Part:BBa_K4160001">BBa_K4160001</a>). Upon dimerization of the EpoR, IL-6RB activates downstream signaling of the JAK/STAT pathway.<sup>3</sup> The Generalized Extracellular Molecule Sensor (GEMS) platform allows for the binding of a variety of target molecules, due to the modularity of the GEMS receptor. Upon binding, IL-6RB induces the intracellular JAK/STAT pathway, which results in transgene expression.<sup>3</sup></p><br>
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<h2>Characterization</h2>
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<p>Characterization of the IL-6RB incorporated in the GEMS receptor can be found on the <a href="https://parts.igem.org/Part:BBa_K4160008">BBa_K4160008</a> page.</p><br><br>
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<h2>References</h2>
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<p><small>
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<ol>
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<li>Murakami M, Ohtani T, Hirano T. Interleukin-6. Ref Modul Biomed Sci. Published online January 1, 2014. doi:10.1016/B978-0-12-801238-3.04059-9</li>
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<li>IL6ST - Interleukin-6 receptor subunit beta - Homo sapiens (Human) | UniProtKB | UniProt. Accessed October 2, 2022. https://www.uniprot.org/uniprotkb/P40189/entry#names_and_taxonomy</li>
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<li>Scheller L, Strittmatter T, Fuchs D, Bojar D, Fussenegger M. Generalized extracellular molecule sensor platform for programming cellular behavior. Nat Chem Biol. Published online 2018. doi:10.1038/s41589-018-0046-z</li>
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<li>Wang Z, Kang Z, Zhang Y, Tse W, Bunting KD. Mutation of STAT1/3 binding sites in gp130FXXQ knock-inmice does not alter hematopoietic stem cell repopulation or self-renewal potential. Am J Stem Cells. 2012;1(2):146. Accessed October 2, 2022. /pmc/articles/PMC3385990/</li>
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<li>Taga T, Kishimoto T. gp130 AND THE INTERLEUKIN-6 FAMILY OF CYTOKINES. http://dx.doi.org/101146/annurev.immunol151797. 2003;15:797-819. doi:10.1146/ANNUREV.IMMUNOL.15.1.797</li>
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</ol>
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</small></p>
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Revision as of 13:02, 11 October 2022


IL-6RB

Interleukin-6 receptor subunit beta (IL-6RB) (Figure 1) is a single transmembrane glycoprotein that is defined as a type I cytokine receptor.1 IL-6RB functions as a signaling transducer.2

Figure 1 | 3D structure of IL-6RB. (PDB: 1BJ8)3


Sequence and Features


Assembly Compatibility:
  • 10
    INCOMPATIBLE WITH RFC[10]
    Illegal PstI site found at 531
    Illegal PstI site found at 692
  • 12
    INCOMPATIBLE WITH RFC[12]
    Illegal PstI site found at 531
    Illegal PstI site found at 692
  • 21
    INCOMPATIBLE WITH RFC[21]
    Illegal BglII site found at 9
    Illegal BglII site found at 195
    Illegal BglII site found at 459
  • 23
    INCOMPATIBLE WITH RFC[23]
    Illegal PstI site found at 531
    Illegal PstI site found at 692
  • 25
    INCOMPATIBLE WITH RFC[25]
    Illegal PstI site found at 531
    Illegal PstI site found at 692
  • 1000
    COMPATIBLE WITH RFC[1000]


Usage and Biology

IL-6RB is part of the receptor system for IL-6 derived from Homo sapiens (Human). The receptor system is a protein complex that consists of IL-6Ralfa, IL-6, and signal transducer IL-6RB (also called gp130 or IL-6ST).1 Binding of IL-6 induces IL-6RB homodimerization, which induces activation of IL-6RB-associated Janus kinases (JAKs).1 Consequently, IL-6Rb gets phosphorylated at its tyrosine sites, which results in the recruitment and activation of SHP2 (Src homology-2 containing protein tyrosine phosphatase-2) and STAT3 (Signal Transducer and Activator of Transcription 3) (Figure 1).1 Tyrosine phosphorylation of STAT3 (BBa_K4160005) leads to heterodimerization complex of STAT3 and STAT1. This complex enters the nucleus and regulates the expression of various genes.1 STAT3 regulates the expression of suppressor of cytokine signaling (SOCS) 1 and SOCS3 in IL-6RB signaling. SOCS3 is a direct inhibitor of IL-6RB, whereas SOCS1 inhibits IL-6RB indirectly by interaction with JAKs.1 Phosphorylated SHP2 at the tyrosine site forms a complex with Grb2, which is associated with Sos, a GFP-GTP exchanger for Ras. The complex activates the MAPK pathway and regulates associated genes.1 Phosphorylated SHP2 can also bind to Gab proteins to mediate signals in the ERK MAP system and AKT signaling pathway.1


Figure 2 | signaling pathway of IL-6 receptor activation. Adapted from Wang et al., 2012.4 Figure created with Biorender.


Biological activity

In hematopoietic lineages, activation of IL-6RB induces the production of antibodies by B-cells. In addition, it leads to the proliferation of myeloma and plasmacytoma cells, hematopoietic progenitors expanding, megakaryocyte progenitors proliferating and differentiating, and T-lymphocytes proliferating and differentiating into cytotoxic T-cells.5 Furthermore, activation of IL-6RB induces hepatocyte stimulation, differentiation of neuronal cells in the nervous system, and stimulation of several anterior pituitary hormones such as growth hormones, luteinizing hormone, and prolactin.5


GEMS receptor

TU-Eindhoven 2022 used this part to transduce signals intracellularly with the Generalized Extracellular Molecule Sensor (GEMS) receptor (BBa_K4160008). In this receptor, the IL-6RB is incorporated at the intracellular domain of the EpoR scaffold (BBa_K4160001). Upon dimerization of the EpoR, IL-6RB activates downstream signaling of the JAK/STAT pathway.3 The Generalized Extracellular Molecule Sensor (GEMS) platform allows for the binding of a variety of target molecules, due to the modularity of the GEMS receptor. Upon binding, IL-6RB induces the intracellular JAK/STAT pathway, which results in transgene expression.3


Characterization

Characterization of the IL-6RB incorporated in the GEMS receptor can be found on the BBa_K4160008 page.



References

  1. Murakami M, Ohtani T, Hirano T. Interleukin-6. Ref Modul Biomed Sci. Published online January 1, 2014. doi:10.1016/B978-0-12-801238-3.04059-9
  2. IL6ST - Interleukin-6 receptor subunit beta - Homo sapiens (Human) | UniProtKB | UniProt. Accessed October 2, 2022. https://www.uniprot.org/uniprotkb/P40189/entry#names_and_taxonomy
  3. Scheller L, Strittmatter T, Fuchs D, Bojar D, Fussenegger M. Generalized extracellular molecule sensor platform for programming cellular behavior. Nat Chem Biol. Published online 2018. doi:10.1038/s41589-018-0046-z
  4. Wang Z, Kang Z, Zhang Y, Tse W, Bunting KD. Mutation of STAT1/3 binding sites in gp130FXXQ knock-inmice does not alter hematopoietic stem cell repopulation or self-renewal potential. Am J Stem Cells. 2012;1(2):146. Accessed October 2, 2022. /pmc/articles/PMC3385990/
  5. Taga T, Kishimoto T. gp130 AND THE INTERLEUKIN-6 FAMILY OF CYTOKINES. http://dx.doi.org/101146/annurev.immunol151797. 2003;15:797-819. doi:10.1146/ANNUREV.IMMUNOL.15.1.797