A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor
A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor
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DOI：
10.1128/mcb.00218-07
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Hata, Akiko
中科院分区：
文献类型：
--
作者：
Chan, Mun Chun;Nguyen, Peter H.;Hata, Akiko
骨形态发生蛋白（BMP）信号调节许多不同的生物过程，包括细胞生长，分化和胚胎发生。BMP与跨膜丝氨酸/苏氨酸（Ser/Thr）激酶受体的异质复合物结合，所述跨膜丝氨酸/苏氨酸激酶受体被称为BMP I型和H型受体（BMPRI和BMPRII）。BMPRH磷酸化并激活BMPRI激酶，其进而激活Smad蛋白。BMPRH的胞质区域含有一个没有酶活性或已知调节功能的“尾”结构域（BMPRII-TD）。与BMPRH-TD相关的特发性肺动脉高压突变的发现强调了其重要性。在这里，我们报告，Tribb-like蛋白3（Trb 3）是一种新的BMPRII-TD相互作用蛋白。在BMP刺激后，Trb 3从BMPRII-TD解离并触发Smad泛素调节因子I（Smurf 1）的降解，这导致BMP受体调节的Smad的稳定和Smad途径的增强。Trb 3的下调抑制BMP介导的细胞应答，包括C2 C12细胞的成骨细胞分化和肺动脉平滑肌细胞的平滑肌表型的维持。因此，Trb 3是BMPRH调节BMP途径的新机制的关键组分。
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 H receptors (BMPRI and BMPRII). BMPRH phosphorylates and activates the BMPRI kinase, which in turn activates the Smad proteins. The cytoplasmic region of BMPRH 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 BMPRH-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 I (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 BMPRH.