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Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor
Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune respo...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2001
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195877/ https://www.ncbi.nlm.nih.gov/pubmed/11136824 |
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author | You, Min Flick, Leah M. Yu, Dehua Feng, Gen-Sheng |
author_facet | You, Min Flick, Leah M. Yu, Dehua Feng, Gen-Sheng |
author_sort | You, Min |
collection | PubMed |
description | Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune responses. Production of interleukin (IL)-6 in response to IL-1α or tumor necrosis factor (TNF)-α was nearly abolished in homozygous mutant (Shp-2(−/)−) fibroblast cells. The targeted Shp-2 mutation has no significant effect on the activation of the three types of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (Erk), c-Jun NH(2)-terminal kinase (Jnk), and p38, by IL-1/TNF, indicating that Shp-2 does not work through MAP kinase pathways in mediating IL-1/TNF-induced IL-6 synthesis. In contrast, IL-1/TNF-stimulated nuclear factor (NF)-κB DNA binding activity and inhibitor of κB (IκB) phosphorylation was dramatically decreased in Shp-2(−/)− cells, while the expression and activity of NF-κB–inducing kinase (NIK), Akt, and IκB kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2(−/)− cells rescued NF-κB activation and IL-6 production in response to IL-1/TNF stimulation. Furthermore, Shp-2 tyrosine phosphatase was detected in complexes with IKK as well as with IL-1 receptor. Thus, this SH2-containing enzyme is an important cytoplasmic factor required for efficient NF-κB activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-κB pathway in a MAP kinase–independent fashion. |
format | Text |
id | pubmed-2195877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2001 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21958772008-04-14 Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor You, Min Flick, Leah M. Yu, Dehua Feng, Gen-Sheng J Exp Med Original Article Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune responses. Production of interleukin (IL)-6 in response to IL-1α or tumor necrosis factor (TNF)-α was nearly abolished in homozygous mutant (Shp-2(−/)−) fibroblast cells. The targeted Shp-2 mutation has no significant effect on the activation of the three types of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (Erk), c-Jun NH(2)-terminal kinase (Jnk), and p38, by IL-1/TNF, indicating that Shp-2 does not work through MAP kinase pathways in mediating IL-1/TNF-induced IL-6 synthesis. In contrast, IL-1/TNF-stimulated nuclear factor (NF)-κB DNA binding activity and inhibitor of κB (IκB) phosphorylation was dramatically decreased in Shp-2(−/)− cells, while the expression and activity of NF-κB–inducing kinase (NIK), Akt, and IκB kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2(−/)− cells rescued NF-κB activation and IL-6 production in response to IL-1/TNF stimulation. Furthermore, Shp-2 tyrosine phosphatase was detected in complexes with IKK as well as with IL-1 receptor. Thus, this SH2-containing enzyme is an important cytoplasmic factor required for efficient NF-κB activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-κB pathway in a MAP kinase–independent fashion. The Rockefeller University Press 2001-01-01 /pmc/articles/PMC2195877/ /pubmed/11136824 Text en © 2001 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Original Article You, Min Flick, Leah M. Yu, Dehua Feng, Gen-Sheng Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor |
title | Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor |
title_full | Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor |
title_fullStr | Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor |
title_full_unstemmed | Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor |
title_short | Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor |
title_sort | modulation of the nuclear factor κb pathway by shp-2 tyrosine phosphatase in mediating the induction of interleukin (il)-6 by il-1 or tumor necrosis factor |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195877/ https://www.ncbi.nlm.nih.gov/pubmed/11136824 |
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