FRET Reveals Novel Protein-Receptor Interaction of Bone Morphogenetic Proteins Receptors and Adaptor Protein 2 at the Cell Surface

Bragdon, Beth; Thinakaran, Shayamala; Bonor, Jeremy; Underhill, T. Michael; Petersen, Nils O.; Nohe, Anja

doi:10.1016/j.bpj.2009.05.061

Cited by 27 publications

(54 citation statements)

References 42 publications

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“…The mutants were named as the following: mutant CK2 (MCK2) at binding site 1 (MCK2.1 (aa 218S-A)), site 2 (MCK2.2 (aa 325S-A)), and site 3 (MCK2.3 (aa 214S-A)). As reported overexpression of MCK2.1, MCK2.2, and MCK2.3 in C2C12 cells reveal that only MCK2.2 and MCK2.3 are able to induce osteogenesis as measured by an increase in mineralization compared to the overexpression of BMPRIa (Bragdon et al 2009;2011;. Similar results were obtained using peptides CK2.2 and CK2.3 that release CK2 from BMPRIa (Bragdon et al 2009;2011;.…”

Section: Mutation Of Aa213-217at Bmpria Induced Adipogenesis In Additsupporting

confidence: 82%

Inhibition of CK2 binding to BMPRIa induces C2C12 differentiation into osteoblasts and adipocytes

Moseychuk

Akkiraju

Dutta

et al. 2013

Journal of Cell Communication and Signaling

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BMP2 is a growth factor that regulates the cell fate of mesenchymal stem cells into osteoblast and adipocytes. However, the detailed signaling pathways and mechanism are unknown. We previously reported a new interaction of Casein kinase II (CK2) with the BMP receptor type-Ia (BMPRIa) and demonstrated using mimetic peptides CK2.1, CK2.2 and CK2.3 that the release of CK2 from BMPRIa activates Smad signaling and osteogenesis. Previously, we showed that mutation of these CK2 sites on BMPRIa (MCK2.1 (476S-A), MCK2.2 (324S-A) and MCK2.3 (214S-A)) induced osteogenesis. However, one mutant MCK2.1 induced osteogenesis similar to overexpression of wild type BMPRIa, suggesting that the effect of this mutant on mineralization was due to overexpression. In this paper we investigated the signaling pathways involved in the CK2-BMPRIa mediated osteogenesis and identified a new signaling pathway activating adipogenesis dependent on the BMPRIa and CK2 association. Further the mechanism for adipogenesis and osteogenesis is specific to the CK2 interaction site on BMPRIa. In detail our data show that overexpression of MCK2.2 induced osteogenesis was dependent on Caveolin-1 (Cav1) and the activation of the Smad and mTor pathways, while overexpression of MCK2.3 induced osteogenesis was independent of Caveolin-1 without activation of Smad pathway. However, MCK2.3 induced osteogenesis via the MEK pathway. The adipogenesis induced by the overexpression of MCK2.2 in C2C12 cells was dependent on the p38 and ERK pathways as well as Caveolin-1. These data suggest that signaling through BMPRIa used two different signaling pathways to induce osteogenesis dependent on CK2. Additionally the data supports a signaling pathway initiated in caveolae and one outside of caveolae to induce mineralization. Moreover, they reveal the signaling pathway of BMPRIa mediated adipogenesis.

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Section: Mutation Of Aa213-217at Bmpria Induced Adipogenesis In Additsupporting

confidence: 82%

Inhibition of CK2 binding to BMPRIa induces C2C12 differentiation into osteoblasts and adipocytes

Moseychuk

Akkiraju

Dutta

et al. 2013

Journal of Cell Communication and Signaling

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“…In this study, disruption of caveolae and CCPs decreased the Smad phosphorylation and downstream Smad signaling response to BMP2 stimulation when BMPR2 was overexpressed. Recently, disruption of cells with CPZ or EH29 was shown to activate Smad phosphorylation (3). Therefore, the decrease in activation may be due to the overexpression of BMPR2 in these cells.…”

Section: Discussionmentioning

confidence: 99%

Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension

Nohe

Bragdon

Tian

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Bone morphogenetic proteins (BMPs) are pleiotrophic growth factors that influence diverse processes such as skeletal development, hematopoiesis, and neurogenesis. They play crucial roles in diseases such as pulmonary arterial hypertension (PAH). In PAH, mutants of the BMP type II receptors (BMPR2) were detected, and their functions were impaired during BMP signaling. It is thought that expression levels of these receptors determine the fate of BMP signaling, with low levels of expression leading to decreased Smad activation in PAH. However, our studies demonstrate, for the first time, that the localization of receptors on the plasma membrane, in this case BMPR2, was misdirected. Three BMPR2 mutants, D485G, N519K, and R899X, which are known to be involved in PAH, were chosen as our model system. Our results show that all three BMPR2 mutants decreased BMP-dependent Smad phosphorylation and Smad signaling. Although the three mutants reached the cell membrane and their expression was lower than that of BMPR2, they formed smaller clusters and associated differently with membrane domains, such as caveolae and clathrin-coated pits. The disruption of these domains restored the Smad signaling of D485G and N519K to the level of wild-type BMPR2, showing that these mutants were trapped in the domains, rather than just expressed at a lower level on the surface. Therefore, new treatment options for PAH should also target receptor localization, rather than just expression level.

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“…However, long term BMP2 usage increases osteoclastogenesis and osteoclast activity, reducing the anabolic effects of BMP2 and raising concerns that bone loss could increase due to this catabolic action 4 . We recently identified a novel BMP type I receptor (BMPRIa) interacting protein, Casein Kinase 2 (CK2), that is released upon BMP2 stimulation 5 . CK2 interacts with more than 300 substrates that regulates cell growth, proliferation, differentiation, apoptosis, and tumorigenesis 6 .…”

Section: Introductionmentioning

confidence: 99%

Systemic Injection of CK2.3, a Novel Peptide Acting Downstream of Bone Morphogenetic Protein Receptor BMPRIa, Leads to Increased Trabecular Bone Mass

Akkiraju

Bonor

Olli

et al. 2014

Journal Orthopaedic Research

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Bone Morphogenetic Protein 2 (BMP2) regulates bone integrity by driving both osteogenesis and osteoclastogenesis. However, BMP2 as a therapeutic has significant drawbacks. We have designed a novel peptide CK2.3 that blocks the interaction of Casein Kinase 2 (CK2) with Bone Morphogenetic Protein Receptor type Ia (BMPRIa), thereby activating BMP signaling pathways in the absence of ligand. Here, we show that CK2.3 induced mineralization in primary osteoblast cultures isolated from calvaria and bone marrow stromal cells (BMSCs) of 8 week old mice. Further, systemic tail vein injections of CK2.3 in 8 week old mice resulted in increased bone mineral density (BMD) and mineral apposition rate (MAR). In situ immunohistochemistry of the femur found that CK2.3 injection induced phosphorylation of extracellular signal-related kinase (ERK), but not Smad in osteocytes and osteoblasts, suggesting that CK2.3 signaling occurred through Smad independent pathway. Finally mice injected with CK2.3 exhibited decreased osteoclast differentiation and osteoclast activity. These data indicate that the novel mimetic peptide CK2.3 activated BMPRIa downstream signaling to enhance bone formation without the increase in osteoclast activity that accompanies BMP 2 stimulation.

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FRET Reveals Novel Protein-Receptor Interaction of Bone Morphogenetic Proteins Receptors and Adaptor Protein 2 at the Cell Surface

Cited by 27 publications

References 42 publications

Inhibition of CK2 binding to BMPRIa induces C2C12 differentiation into osteoblasts and adipocytes

Inhibition of CK2 binding to BMPRIa induces C2C12 differentiation into osteoblasts and adipocytes

Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension

Systemic Injection of CK2.3, a Novel Peptide Acting Downstream of Bone Morphogenetic Protein Receptor BMPRIa, Leads to Increased Trabecular Bone Mass

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