title: A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor.
abstract: Bone morphogenetic protein (BMP) signaling regulates many different biological processes, including cell growth, differentiation, and embryogenesis. BMPs bind to heterogeneous complexes of transmembrane serine/threonine (Ser/Thr) kinase receptors known as the BMP type I and II receptors (BMPRI and BMPRII). BMPRII phosphorylates and activates the BMPRI kinase, which in turn activates the Smad proteins. The cytoplasmic region of BMPRII contains a "tail" domain (BMPRII-TD) with no enzymatic activity or known regulatory function. The discovery of mutations associated with idiopathic pulmonary artery hypertension mapping to BMPRII-TD underscores its importance. Here, we report that Tribbles-like protein 3 (Trb3) is a novel BMPRII-TD-interacting protein. Upon BMP stimulation, Trb3 dissociates from BMPRII-TD and triggers degradation of Smad ubiquitin regulatory factor 1 (Smurf1), which results in the stabilization of BMP receptor-regulated Smads and potentiation of the Smad pathway. Downregulation of Trb3 inhibits BMP-mediated cellular responses, including osteoblast differentiation of C2C12 cells and maintenance of the smooth muscle phenotype of pulmonary artery smooth muscle cells. Thus, Trb3 is a critical component of a novel mechanism for regulation of the BMP pathway by BMPRII.
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Mun Chun
authors.initials: MC
authors.lastname: Chan
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nguyen
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Davis
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Keyong
authors.initials: K
authors.lastname: Du
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lagna
authors.forename: Akiko
authors.initials: A
authors.lastname: Hata
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry* / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000037:antagonists & inhibitors; D017434:Protein Structure, Tertiary; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474830:TRB3 protein, mouse; C474831:TRIB3 protein, human; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II