Journal
CELLULAR SIGNALLING
Volume 20, Issue 6, Pages 1044-1051Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.01.015
Keywords
NUMBL; TAB2; NF-kappa B signaling pathway
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The cytokines TNF alpha and IL-1 beta induce inflammation through activation of transcription factors NF-kappa B. TAB2 is an adapter protein that facilitates TNF alpha and IL-1 beta-mediated NF-kappa B activation. In this work, using yeast two-hybrid system TAB2 was identified to interact with NUMBL. The interaction was further confirmed in vitro and in vivo. PTB domain of NUMBL and C-terminal region are required for their interaction. Overexpression of NUMBL inhibited TNF alpha, IL-1 beta-induced activation of NF-kappa B signaling pathway. NUMBL also inhibited TAB2, TAK1, TRAF6 and RIP-induced activation of NF-kappa B in a dose-dependent manner. We found that NUMBL can impair TAB2 binding to TRAF6 or RIP and inhibit ubiquitination of TRAF6 enhanced by TAB2. Taken together, our data suggest that NUMBL is involved in negative regulation of NF-kappa B signaling through its interaction with TAB2. These findings also reveal the new functions of NUMBL and implicate that NUMBL potentially links Notch pathway to NF-kappa B pathway. (C) 2008 Elsevier Inc. All rights reserved.
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