TRAF2 recruitment via T61 in CD30 drives NFκB activation and enhances hESC survival and proliferation.

Thakar, Nilay Y., Ovchinnikov, Dmitry A., Hastie, Marcus L., Kobe, Bostjan, Gorman, Jeffrey J. and Wolvetang, Ernst J. (2015) TRAF2 recruitment via T61 in CD30 drives NFκB activation and enhances hESC survival and proliferation.. Molecular Biology of the Cell, 26 5: 993-1006. doi:10.1091/mbc.E14-08-1290

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Author Thakar, Nilay Y.
Ovchinnikov, Dmitry A.
Hastie, Marcus L.
Kobe, Bostjan
Gorman, Jeffrey J.
Wolvetang, Ernst J.
Title TRAF2 recruitment via T61 in CD30 drives NFκB activation and enhances hESC survival and proliferation.
Journal name Molecular Biology of the Cell   Check publisher's open access policy
ISSN 1059-1524
1939-4586
Publication date 2015-01-07
Year available 2015
Sub-type Article (original research)
DOI 10.1091/mbc.E14-08-1290
Open Access Status File (Publisher version)
Volume 26
Issue 5
Start page 993
End page 1006
Total pages 27
Place of publication Bethesda, MD, United States
Publisher American Society for Cell Biology
Collection year 2016
Language eng
Formatted abstract
CD30 (TNFRSF8), a tumor necrosis factor receptor family protein, and CD30 variant (CD30v), a ligand-independent form encoding only the cytoplasmic signaling domain, are concurrently overexpressed in transformed human embryonic stem cells (hESCs) or hESCs cultured in the presence of ascorbate. CD30 and CD30v are thought to increase hESC survival and proliferation through NFκB activation, but how this occurs is largely unknown. Here we demonstrate that hESCs that endogenously express CD30v and hESCs that artificially overexpress CD30v, exhibit increased ERK phosphorylation levels, activation of the canonical NFκB pathway, down-regulation of the non-canonical NFκB pathway, and reduced expression of the full-length CD30 protein. We further find that CD30v, surprisingly, resides predominantly in the nucleus of hESC. We demonstrate that alanine substitution of a single threonine residue at position 61 (T61) in CD30v abrogates CD30v-mediated NFκB activation, CD30v-mediated resistance to apoptosis and CD30v-enhanced proliferation, as well as restores normal G2/M-checkpoint arrest upon H2O2 treatment while maintaining its unexpected subcellular distribution. Using an affinity purification strategy and LC-MS, we identified TRAF2 as the predominant protein that interacts with WT CD30v but not the T61A-mutant form in hESCs. The identification of Thr61 as a critical residue for TRAF2 recruitment and canonical NFκB signaling by CD30v reveals the substantial contribution this molecule makes to overall NFκB activity, cell cycle changes and survival in hESCs.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 7 January 2015.

 
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Created: Fri, 16 Jan 2015, 13:22:55 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences