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Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth
Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also het...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The American Society for Cell Biology
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912364/ https://www.ncbi.nlm.nih.gov/pubmed/20554759 http://dx.doi.org/10.1091/mbc.E10-03-0240 |
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author | Suthaus, Jan Tillmann, Anna Lorenzen, Inken Bulanova, Elena Rose-John, Stefan Scheller, Jürgen |
author_facet | Suthaus, Jan Tillmann, Anna Lorenzen, Inken Bulanova, Elena Rose-John, Stefan Scheller, Jürgen |
author_sort | Suthaus, Jan |
collection | PubMed |
description | Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also heterodimeric complexes within the gp130 family may have tumorigenic potential, we seek to generate ligand-independent constitutively active heterodimers for all known gp130-receptor complexes based on IL-15/IL-15Rα-sushi fusion proteins. Ligand-independent heterodimerization of gp130 with WSX-1, LIFR, and OSMR and of OSMR with GPL led to constitutive, ligand-independent STAT1 and/or STAT3 and ERK1/2 phosphorylation. Moreover, these receptor combinations induced transcription of the STAT3 target genes c-myc and Pim-1 and factor-independent growth of stably transduced Ba/F3-gp130 cells. Here, we establish the IL-15/IL-15Rα-sushi system as a new system to mimic constitutive and ligand-independent activation of homo- and heterodimeric receptor complexes, which might be applicable to other heterodimeric receptor families. A mutated IL-15 protein, which was still able to bind the IL-15Rα-sushi domain, but not to β- and γ-receptor chains, in combination with the 2A peptide technology may be used to translate our in vitro data into the in vivo situation to assess the tumorigenic potential of gp130-heterodimeric receptor complexes. |
format | Text |
id | pubmed-2912364 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-29123642010-10-16 Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth Suthaus, Jan Tillmann, Anna Lorenzen, Inken Bulanova, Elena Rose-John, Stefan Scheller, Jürgen Mol Biol Cell Articles Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also heterodimeric complexes within the gp130 family may have tumorigenic potential, we seek to generate ligand-independent constitutively active heterodimers for all known gp130-receptor complexes based on IL-15/IL-15Rα-sushi fusion proteins. Ligand-independent heterodimerization of gp130 with WSX-1, LIFR, and OSMR and of OSMR with GPL led to constitutive, ligand-independent STAT1 and/or STAT3 and ERK1/2 phosphorylation. Moreover, these receptor combinations induced transcription of the STAT3 target genes c-myc and Pim-1 and factor-independent growth of stably transduced Ba/F3-gp130 cells. Here, we establish the IL-15/IL-15Rα-sushi system as a new system to mimic constitutive and ligand-independent activation of homo- and heterodimeric receptor complexes, which might be applicable to other heterodimeric receptor families. A mutated IL-15 protein, which was still able to bind the IL-15Rα-sushi domain, but not to β- and γ-receptor chains, in combination with the 2A peptide technology may be used to translate our in vitro data into the in vivo situation to assess the tumorigenic potential of gp130-heterodimeric receptor complexes. The American Society for Cell Biology 2010-08-01 /pmc/articles/PMC2912364/ /pubmed/20554759 http://dx.doi.org/10.1091/mbc.E10-03-0240 Text en © 2010 by The American Society for Cell Biology |
spellingShingle | Articles Suthaus, Jan Tillmann, Anna Lorenzen, Inken Bulanova, Elena Rose-John, Stefan Scheller, Jürgen Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth |
title | Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth |
title_full | Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth |
title_fullStr | Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth |
title_full_unstemmed | Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth |
title_short | Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth |
title_sort | forced homo- and heterodimerization of all gp130-type receptor complexes leads to constitutive ligand-independent signaling and cytokine-independent growth |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912364/ https://www.ncbi.nlm.nih.gov/pubmed/20554759 http://dx.doi.org/10.1091/mbc.E10-03-0240 |
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