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Molecular and Cellular Biology, August 2007, p. 5776-5789, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00218-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Novel Regulatory Mechanism of the Bone Morphogenetic Protein (BMP) Signaling Pathway Involving the Carboxyl-Terminal Tail Domain of BMP Type II Receptor

Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111,¹ Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111,² Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-cho, Nagoya, Aichi, Japan,³ Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111⁴

Received 6 February 2007/ Returned for modification 30 March 2007/ Accepted 6 June 2007

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.

Published ahead of print on 18 June 2007.