Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 368K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by You, M. Articles by Feng, G.-S. Search for Related Content PubMed PubMed Citation Articles by You, M. Articles by Feng, G.-S. Social Bookmarking                            What's this?

Original Article

Modulation of the Nuclear Factor b Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor

^a From The Burnham Institute, La Jolla, California 92037
^b Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202
^c Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
^d Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037.858-713-6274858-713-6265

gfeng{at}burnham.org

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-1 or tumor necrosis factor (TNF)- 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 NH₂-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)-B DNA binding activity and inhibitor of B (IB) phosphorylation was dramatically decreased in Shp-2^–/– cells, while the expression and activity of NF-B–inducing kinase (NIK), Akt, and IB kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2^–/– cells rescued NF-B 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-B activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-B pathway in a MAP kinase–independent fashion.

Key Words: tyrosine phosphatase • IL-1 • IL-6 • TNF • Shp-2

Abbreviations used in this paper: AP, activator protein; EMSA, electrophoretic mobility shift assay; Erk, extracellular signal-regulated kinase; IB, inhibitor of B; IKK, IB kinase; IRAK, IL-1 receptor–associated serine/threonine kinase; Jnk, c-Jun NH₂-terminal kinase; MAP, mitogen-activated protein; MBP, myelin basic protein; NF, nuclear factor; NIK, NF-B–inducing kinase; SH, src homology.

L.M. Flick's present address is Eli Lilly and Co., Greenfield, IN 46140.

© 2001 The Rockefeller University Press

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS