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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Abstract

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
Volume2
Issue number5
DOIs
Publication statusPublished - 2012 Nov 29

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, K. M., Kim, W., Bae, E., Gim, J., Weist, B. M., Jung, Y., Hyun, J. S., Hernandez, J. B., Leem, S. H., Park, T., Jeong, J., Walsh, C. M., & Kim, S. J. (2012). DRAK2 Participates in a Negative Feedback Loop to Control TGF-β/Smads Signaling by Binding to Type I TGF-β Receptor. Cell Reports, 2(5), 1286-1299. https://doi.org/10.1016/j.celrep.2012.09.028