DRAK2 Participates in a Negative Feedback Loop to Control TGF-β/Smads Signaling by Binding to Type I TGF-β Receptor

Kyung Min Yang, Wonjoo Kim, Eunjin Bae, Jungsoo Gim, Brian M. Weist, Yunshin Jung, Ja Shil Hyun, Jennifer B. Hernandez, Sun Hee Leem, Taesung Park, Joon Jeong, Craig M. Walsh, Seong Jin Kim

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31 Citations (Scopus)


TGF-β1 is a multifunctional cytokine that mediates diverse biological processes. However, the mechanisms by which the intracellular signals of TGF-β1 are terminated are not well understood. Here, we demonstrate that DRAK2 serves as a TGF-β1-inducible antagonist of TGF-β signaling. TGF-β1 stimulation rapidly induces DRAK2 expression and enhances endogenous interaction of the type I TGF-β receptor with DRAK2, thereby blocking R-Smads recruitment. Depletion of DRAK2 expression markedly augmented the intensity and the extent of TGF-β1 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-β1 responses, and aberrant expression of DRAK2 increases tumorigenic potential, in part, through the inhibition of TGF-β1 tumor suppressor activity.

Original languageEnglish
Pages (from-to)1286-1299
Number of pages14
JournalCell Reports
Issue number5
Publication statusPublished - 2012 Nov 29

Bibliographical note

Funding Information:
We demonstrated that the transcriptional regulation of DRAK2 by TGF-β1 is mediated through a rapid and direct Smad3-dependent signaling mechanism. TGF-β1 treatment rapidly induces DRAK2 expression, resulting in increased interactions between endogenous TβRI and DRAK2. This interaction was found to occur in the cytoplasm and near the plasma membrane. The ability of the DRAK2 promoter to respond to TGF-β1 is therefore believed to play a central role in the negative autoregulation of TGF-β signaling. However, they do not rule out the possibility that this protein kinase may fulfill other functions in normal physiology. In addition to suppressing TGF-β signaling within the cytosol, DRAK2 is predominantly localized in the nucleus in the breast cancer cells analyzed, even in the presence of TGF-β1. Although this has not yet been directly investigated, a possible nuclear role for DRAK2 may be in the regulation of transcription. This observation is supported by the microarray analysis of genes regulated by DRAK2. Furthermore, DRAK2 is known to be induced by combinatory network of proinflammatory cytokines, such as IFN-γ with IL-1β or TNF-α with IL-1β ( Mao et al., 2009 ). Thus, DRAK2 not only is a TGF-β1-induced antagonist but is also involved in fine-tuning the cellular response to TGF-β1, by integrating different signaling pathways.

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology


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