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 proteins (BMPs) are members of the transforming growth factor ␤ (TGF␤) family of growth factors performing multiple essential functions in embryos and adult metazoans (19,20). The BMP receptors initiate a cascade of Ser/Thr phosphorylation upon binding of BMPs, starting with the BMP type II receptor (BMRPII) kinase phosphorylating and activating the BMPRI kinase, which phosphorylates and activates downstream signal transducers, the Smad proteins, and thus modulates gene expression (2,3,7,30,31). Several proteins are known as specific negative regulators of the BMP signaling pathway: secreted BMP antagonists (chordin and noggin), antagonistic Smads (Smad6 and Smad7), and the E3 ubiquitin ligase for BMP-specific Smad proteins (Smurf1) (3,7,30).Heterozygous mutations of the gene encoding BMPRII have been identified among patients with idiopathic pulmonary artery hypertension (IPAH), a disease characterized by elevated pulmonary artery (PA) pressure and eventually right ventricular failure (1,10,28,36,46). PAs from IPAH patients are characterized by increased muscularization of small arteries and thickening or fibrosis of the intima, resulting in obstruction of PAs and increased pressure. It was also reported that a mutant form of BMPRII found in IPAH, when overexpressed in a smooth muscle cell (SMC)-restricted fashion in transgenic mice, causes an increase in PA pressure and pulmonary arterial muscularization, suggesting that BMPRII mutation in SMCs is sufficient to produce pulmonary hypertension (48). Several BMPRII mutations are found within the extracellular and the kinase domains as well as the long carboxyl (C)-terminal "tail" domain (BMPRII-TD), which has neither enzymatic activity nor homology to known domains (28,46). The finding of BMPRII-TD mutations in IPAH suggests that BMPRII-TD might have a regulatory role in the BMP pathway. It has been shown that BMPRII-TD participates in mediating BMP-induced apoptosis in PA SMCs (PASMCs) (24, 37). Several proteins have been shown to interact with BMPRII-TD, including LIM kinase 1 (LIMK1) and 25,29), but little is known about the role of these proteins in the regulation of the BMP signaling pathway. Recently, it has been found that BMPRII-TD interacts with Eps15R, a component of clathrin-coated pits (CCPs) that regulates endocytosis of the BMP receptor complex and affects downstream signaling (15). It is unclear whether endocytosis of the BMP receptors via CCPs plays a role in the regulation of the BMP pathway in vascular cells.In a search for novel BMPRII-TD-interacting proteins, we isolated the mammalian homolog of Drosophila Tribbles, Trb3 (5, 17, 33). Trb3 contains a variant Ser/Thr kinase domain which lacks the key residues for catalytic activity and ATP binding domain (e.g., DLKLRK in Trb3 instead of DLKPEN) (33). Thus, it is believed to be a nonfunctional kinase. In Drosophila, tribbles appears to play a role in the regulation of the cell cycle and cell migration by inhibiting string and slbo, the homologs of CDC25 and C/EBP, respectively ...

Developmental roles of tribbles protein family members

“…In BMP-responsive osteoblasts, Trib3 is bound to the intracellular portion of the BMPRII receptor at the cell cortex and is released upon ligand binding. In the cytoplasm, Trib3 binds and degrades SMURF1, an E3 ubiquitin ligase specific for the BMP mediator Smad, effectively stabilizing Smads (Chan et al, 2007). In TGFb-responsive HepG2 cells, Trib3 binds the MH domain of Smad3, enters the nucleus, and acts as a co-factor to modulate target gene expression (Hua et al, 2011).…”

Trb3 Regulates LR Axis Formation in Zebrafish Embryos

“…Overexpression of the TGF-β activator (TARAM-A*) and the antagonist, Lefty1 confirmed that TGF-β signaling is required for trb3 expression in the embryos. Studies have shown that Trb3 physically interacts with the BMP type II receptor in mammalian cells and thereby regulates BMP signaling (Chan et al, 2007). BMPs and their receptors belong to the TGF-β super family and are critical for ventral patterning in vertebrates (von Bubnoff and Cho, 2001).…”

“…Over-expression of trb3 reduces level of smurf1 transcripts Studies in the pulmonary artery smooth muscle cells (PASMCs) show that TRB3 regulates Smurf1 in association with BMP signaling components (Chan et al, 2007). We thus examined the putative correlation between Smurf1 and Trb3 in zebrafish embryogenesis.…”

“…It also regulates cell cycle via negative modulation of Slbo and String in Drosophila (Mata et al, 2002). TRB3 acts as an adopter/mediator molecule in the photomorphogenic protein 1 (COP1) that mediates degradation of acetyl-coenzyme A carboxylase (ACC) (Qi et al, 2006) and downregulates SMAD specific E3 ubiquitin regulatory factors 1/2 (Smurf1/2) (Chan at al., 2007;Hua et al, 2011). TRB3 is a key molecule in muscle differentiation via PKB/Akt signaling pathways (Kato and Du, 2007), a potent target of various physiological responses like hypoxia (Rzymski et al, 2008), ER stress (Avery et al, 2010), oxidative stress and nutrient deficiency in various cell types (Jousse et al, 2007).…”

“…TRB3 is a key molecule in muscle differentiation via PKB/Akt signaling pathways (Kato and Du, 2007), a potent target of various physiological responses like hypoxia (Rzymski et al, 2008), ER stress (Avery et al, 2010), oxidative stress and nutrient deficiency in various cell types (Jousse et al, 2007). Tribbles family members have been reported to interact with BMPRII tail domain (BMPRII-TD) in the pulmonary artery smooth muscle cells (PASMCs) (Chan et al, 2007).…”