Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2).
Tumor necrosis factor (TNF) elicits its biological activities by stimulation of two receptors, TNFR1 and TNFR2, both belonging to the TNF receptor superfamily. Whereas TNFR1-mediated signal transduction has been intensively studied and is understood in detail, especially with respect to activation of the classical NFkappaB pathway, cell death induction, and MAP kinase signaling, TNFR2-associated signal transduction is poorly defined. Here, we demonstrate in various tumor cell lines and primary T-cells that TNFR2, but not TNFR1, induces activation of the alternative NFkappaB pathway. In accord with earlier findings demonstrating that only membrane TNF, but not soluble TNF, properly activates TNFR2, we further show by use of TNFR1- and TNFR2-specific mutants of soluble TNF and membrane TNF that soluble ligand trimers fail to activate the alternative NFkappaB pathway. In accord with the known inhibitory role of TRAF2 in the alternative NFkappaB pathway, TNFR2-, but not TNFR1-specific TNF induced depletion of cytosolic TRAF2. Thus, we identified activation of the alternative NFkappaB pathway as a TNF signaling effect that can be specifically assigned to TNFR2 and membrane TNF.
Rauert
Hilka
H
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
Wicovsky
Andreas
A
Müller
Nicole
N
Siegmund
Daniela
D
Spindler
Volker
V
Waschke
Jens
J
Kneitz
Christian
C
Wajant
Harald
H
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
D052003:NF-kappa B p52 Subunit; D020033:Protein Isoforms; D021122:Protein Subunits; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D048069:Tumor Necrosis Factors; D051841:Transcription Factor RelB