A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor.
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.
Chan
Mun Chun
MC
Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Nguyen
Peter H
PH
Davis
Brandi N
BN
Ohoka
Nobumichi
N
Hayashi
Hidetoshi
H
Du
Keyong
K
Lagna
Giorgio
G
Hata
Akiko
A
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
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