Induction of Jak/STAT signaling by activation of the type 1 TNF receptor

Dan Qun Guo, James D. Dunbar, Chuan Yang, Lawrence Pfeffer, David B. Donner

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114 Citations (Scopus)

Abstract

Cellular responses to TNF are initiated by either of two cell surface receptors, the type 1 TNF receptor (TNFR1) and the type 2 TNF receptor (TNFR2). Although neither receptor contains an intrinsic protein tyrosine kinase, such activity has been implicated in TNF action. In this study, we show that murine TNF induces the tyrosine phosphorylation and activation of the intracellular Janus tyrosine kinases Jak1, Jak2, and Tyk2 in murine 3T3- L1 adipocytes. Activation of Jak kinases by TNF was associated with tyrosine phosphorylation of STAT1, STAT3, STAT5, and STAT6, but not STAT2 or STAT4, showing that TNF acts on a specific subset of these latent cytoplasmic transcription factors in 3T3-L1 adipocytes. Agonist antiserum to TNFR1 induced Jak kinase and STAT protein phosphorylation. Phosphorylation of Jak proteins was also induced by human TNF, which selectively binds to TNFR1 on murine cells. 35S-labeled Jak kinases were precipitated from a cell-free system and from lysates of 3T3-L1 adipocytes by a glutathione S-transferase fusion protein containing the cytoplasmic domain of TNFR1. These results suggest that the cytoplasmic domain of TNFR1 can directly interact with and form signaling complexes with Jak kinases. Jak2 was precipitated from HeLa cells by antiserum to TNFR1, directly demonstrating their association in vivo. Thus, TNF activates a Jak/STAT signal-transduction cascade by acting through TNFR1.

Original languageEnglish (US)
Pages (from-to)2742-2750
Number of pages9
JournalJournal of Immunology
Volume160
Issue number6
StatePublished - Mar 15 1998

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Receptors, Tumor Necrosis Factor, Type I
Tumor Necrosis Factor Receptors
Phosphorylation
Adipocytes
Phosphotransferases
Protein-Tyrosine Kinases
Tyrosine
Immune Sera
Receptors, Tumor Necrosis Factor, Type II
Janus Kinases
Cell-Free System
Cell Surface Receptors
Glutathione Transferase
HeLa Cells
Protein Kinases
Signal Transduction
Proteins
Transcription Factors

All Science Journal Classification (ASJC) codes

  • Immunology

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Induction of Jak/STAT signaling by activation of the type 1 TNF receptor. / Guo, Dan Qun; Dunbar, James D.; Yang, Chuan; Pfeffer, Lawrence; Donner, David B.

In: Journal of Immunology, Vol. 160, No. 6, 15.03.1998, p. 2742-2750.

Research output: Contribution to journalArticle

Guo, DQ, Dunbar, JD, Yang, C, Pfeffer, L & Donner, DB 1998, 'Induction of Jak/STAT signaling by activation of the type 1 TNF receptor', Journal of Immunology, vol. 160, no. 6, pp. 2742-2750.
Guo, Dan Qun ; Dunbar, James D. ; Yang, Chuan ; Pfeffer, Lawrence ; Donner, David B. / Induction of Jak/STAT signaling by activation of the type 1 TNF receptor. In: Journal of Immunology. 1998 ; Vol. 160, No. 6. pp. 2742-2750.
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