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.
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bone Morphogenetic Proteins / metabolism
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Female
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HEK293 Cells
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HeLa Cells
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Humans
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Mice
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Mice, SCID
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Molecular Sequence Data
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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RNA, Small Interfering / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction / drug effects
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Smad Proteins / metabolism*
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1 / pharmacology
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Transplantation, Heterologous
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Apoptosis Regulatory Proteins
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Bone Morphogenetic Proteins
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RNA, Small Interfering
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Suppressor Proteins
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Protein Serine-Threonine Kinases
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STK17B protein, human
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Receptor, Transforming Growth Factor-beta Type I