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.
Mesh Terms:
Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein Receptors, Type II, Bone Morphogenetic Proteins, COS Cells, Cell Cycle Proteins, Cercopithecus aethiops, Down-Regulation, Humans, Mice, Myocytes, Smooth Muscle, NIH 3T3 Cells, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Pulmonary Artery, Repressor Proteins, Signal Transduction, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein Receptors, Type II, Bone Morphogenetic Proteins, COS Cells, Cell Cycle Proteins, Cercopithecus aethiops, Down-Regulation, Humans, Mice, Myocytes, Smooth Muscle, NIH 3T3 Cells, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Pulmonary Artery, Repressor Proteins, Signal Transduction, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Mol. Cell. Biol.
Date: Aug. 01, 2007
PubMed ID: 17576816
View in: Pubmed Google Scholar
Download Curated Data For This Publication
140791
Switch View:
- Interactions 4