Journal
CELL REPORTS
Volume 2, Issue 5, Pages 1286-1299Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2012.09.028
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Funding
- National Research Foundation grant of Korea [2009-0081756, 2012R1A3A2026438]
- Ministry of Land, Transport and Maritime Affairs [20046001]
- National Multiple Sclerosis Foundation
- NIH [AI63419]
- National Research Foundation of Korea [2012R1A3A2026438, 2009-0081756, 과C6B2606] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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TGF-beta 1 is a multifunctional cytokine that mediates diverse biological processes. However, the mechanisms by which the intracellular signals of TGF-beta 1 are terminated are not well understood. Here, we demonstrate that DRAK2 serves as a TGF-beta 1-inducible antagonist of TGF-beta signaling. TGF-beta 1 stimulation rapidly induces DRAK2 expression and enhances endogenous interaction of the type I TGF-beta receptor with DRAK2, thereby blocking R-Smads recruitment. Depletion of DRAK2 expression markedly augmented the intensity and the extent of TGF-beta 1 responses. Furthermore, a high level of DRAK2 expression was observed in basal-like and HER2-enriched breast tumors and cell lines, and depletion of DRAK2 expression suppressed the tumorigenic ability of breast cancer cells. Thus, these studies define a function for DRAK2 as an intrinsic intracellular antagonist participating in the negative feedback loop to control TGF-beta 1 responses, and aberrant expression of DRAK2 increases tumorigenic potential, in part, through the inhibition of TGF-beta 1 tumor suppressor activity.
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