A novel domain in the CD30 cytoplasmic tail mediates NFkappaB activation |
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Authors: | Horie R; Aizawa S; Nagai M; Ito K; Higashihara M; Ishida T; Inoue J; Watanabe T |
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Institution: | First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan. |
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Abstract: | About 100 amino acid residues in the C-terminal region are conserved among
human, rat and murine CD30, a member of the tumor necrosis factor receptor
(TNFR) superfamily, and can be separated into three subdomains with
relatively higher conservation (D1, D2 and D3). Activation of NFkappaB by
CD30 was shown to be mediated through interaction of TNFR- associated
factor (TRAF) 1, 2 and 5 with the D2 and D3 subdomains. However, the
function of the other conserved subdomain, D1, remained to be determined.
Deletion of the D2 and D3 subdomains abolished interactions with TRAF2 and
5 but it did not affect NFkappaB activation. Reporter gene assays using
deletion and mutant constructs of CD30 revealed that the D1 subdomain is
sufficient for NFkappaB activation, without interaction with TRAF2 or 5,
and that each subdomain alone can activate NFkappaB. Electrophoretic
mobility shift assays revealed constitutive and CD30-induced NFkappaB
activation in stable transformants of 293 cells expressing CD30 or a
deletion mutant lacking D2 and D3 subdomains. Deletion of C-terminal 19
amino acid residues of the D1 subdomain abolished activation of NFkappaB.
Substitution of alanine for one of the two threonine residues (amino acid
position 524 and 529), one of which is a potential phosphorylation site in
the D1 subdomain, also abolished the NFkappaB activation. Overexpression of
the TRAF domain of TRAF2 or 5 had a dominant negative effect on the
NFkappaB activation mediated by the D1 subdomain, thereby suggesting
involvement of TRAF proteins in the signaling. Thus, the C- terminal 100
amino acid region of CD30 is composed of three independent functional
subdomains, two of which contain binding sites for TRAF proteins. A novel
domain in the cytoplasmic tail mediates NFkappaB activation, without direct
interaction of TRAF2 or 5. Our observations suggest involvement of an
unknown TRAF protein(s) in the signal transduction pathway of CD30.
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