title: DRAK2 participates in a negative feedback loop to control TGF-β/Smads signaling by binding to type I TGF-β receptor.
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.
authors.affiliation: CHA Cancer Institute, CHA University of Medicine and Science, Seoul 135-081, Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Yang
authors.forename: Wonjoo
authors.initials: W
authors.lastname: Kim
authors.forename: Eunjin
authors.initials: E
authors.lastname: Bae
authors.forename: Jungsoo
authors.initials: J
authors.lastname: Gim
authors.forename: Brian M
authors.initials: BM
authors.lastname: Weist
authors.forename: Yunshin
authors.initials: Y
authors.lastname: Jung
authors.forename: Ja-Shil
authors.initials: JS
authors.lastname: Hyun
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Hernandez
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Leem
authors.forename: Taesung
authors.initials: T
authors.lastname: Park
authors.forename: Joon
authors.initials: J
authors.lastname: Jeong
authors.forename: Craig M
authors.initials: CM
authors.lastname: Walsh
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D019485:Bone Morphogenetic Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C115489:STK17B protein, human; D000077293:Receptor, Transforming Growth Factor-beta Type I