title: Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation.
abstract: We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation.
authors.affiliation: From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papoutsoglou
authors.affiliation: From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Varun
authors.initials: V
authors.lastname: Maturi
authors.affiliation: From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Tsubakihara
authors.affiliation: the Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland, and.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
authors.affiliation: From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden,; the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE-751 23 Uppsala, Sweden. Electronic address: aris.moustakas@imbim.uu.se.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D018345:Mice, Knockout; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C556015:PARPBP protein, human; D051901:Smad4 Protein; D051902:Smad5 Protein; D000246:Adenosine Diphosphate Ribose; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase
keywords: ADP-ribosylation; SMAD transcription factor; bone morphogenetic protein (BMP); signal transduction; transcription