Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development

Holtzhausen, Alisha; Golzio, Christelle; How, Tam; Lee, Yong–Hun; Schiemann, William P.; Katsanis, Nicholas; Blobe, Gerard C.

doi:10.1096/fj.13-239178

Cited by 84 publications

(88 citation statements)

References 55 publications

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“…In accordance with the stimulatory effect of BMPs in murine primary pituitary cells, it has been shown that BMP2 acts synergistically with Activin A to regulate FSHb expression in LbT2 cells (Lee et al 2007, Wang et al 2014. BMP2 has been previously reported to induce non-canonical phosphorylation of Smad3 (Holtzhausen et al 2014, Wang et al 2014) consistent with our results showing that BMP2 triggers Smad3 phosphorylation in LbT2 cells (Fig. 3F).…”

Section: Discussionsupporting

confidence: 91%

Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215

Jung

Ahn

Shim

et al. 2014

Journal of Endocrinology

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Activins and bone morphogenetic proteins (BMPs) share activin type 2 signaling receptors but utilize different type 1 receptors and Smads. We designed AB215, a potent BMP2-like Activin A/BMP2 chimera incorporating the high-affinity type 2 receptor-binding epitope of Activin A. In this study, we compare the signaling properties of AB215 and BMP2 in HEK293T cells and gonadotroph LbT2 cells in which Activin A and BMP2 synergistically induce FSHb. In HEK293T cells, AB215 is more potent than BMP2 and competitively blocks Activin A signaling, while BMP2 has a partial blocking activity. Activin A signaling is insensitive to BMP pathway antagonism in HEK293T cells but is strongly inhibited by constitutively active (CA) BMP type 1 receptors. By contrast, the potencies of AB215 and BMP2 are indistinguishable in LbT2 cells and although AB215 blocks Activin A signaling, BMP2 has no inhibitory effect. Unlike HEK293T, Activin A signaling is strongly inhibited by BMP pathway antagonism in LbT2 cells but is largely unaffected by CA BMP type 1 receptors. BMP2 increases phospho-Smad3 levels in LbT2 cells, in both the absence and the presence of Activin A treatment, and augments Activin A-induced FSHb. AB215 has the opposite effect and sharply decreases basal phospho-Smad3 levels and blocks Smad2 phosphorylation and FSHb induction resulting from Activin A treatment. These findings together demonstrate that while AB215 activates the BMP pathway, it has opposing effects to those of BMP2 on FSHb induction in LbT2 cells apparently due to its ability to block Activin A signaling. Key Words" transforming growth factor beta (TGFb)" activin " bone morphogenetic protein (BMP)" protein structure " signal transduction

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Section: Discussionsupporting

confidence: 91%

Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215

Jung

Ahn

Shim

et al. 2014

Journal of Endocrinology

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“…[10] More recently, it was shown that BMP-2 also could signal through heteromeric complexes consisting of TGFBR2/ALK5/ALK3, leading to SMAD2 phosphorylation, and BMPR2/ALK5/ALK3 or BMPRII/ALK7/ALK6 leading to Smad3 phosphorylation. [11] BMPs also share all type 2 receptors with activin A, which should be kept in mind when developing targeted therapies to these TGF-β family members. [3,12] Additionally, TGF-β family type 3 receptors and coreceptors exist that contribute to regulation and fine-tuning of formation of the ligand-receptor complex.…”

Section: Bmp Signal Transductionmentioning

confidence: 99%

The role of bone morphogenetic proteins in myeloma cell survival

Holien

Sundan

2014

Cytokine & Growth Factor Reviews

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“…BMP9 has been implied in tumourigenesis (7)(8)(9)(10)(11)(12)(13)16,(19)(20)(21)(22). The proliferative effect of BMP9 on tumours varies considerably.…”

Section: Discussionmentioning

confidence: 99%

“…The proliferative effect of BMP9 on tumours varies considerably. BMP9 promotes the proliferation of ovarian cancer cells (21) and hepatocellular carcinoma cells (22), but it inhibits the proliferation of colon cancer cells (19), breast cancer cells (20) and gastric cancer cells (16). However, the proliferative effect of BMP9 on OS is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies also indicated that BMP9 failed to induce osteogenic differentiation in OS (8,9,(11)(12)(13). Aberrant expression of BMP9 might result in many human tumours, such as colon cancer (19), breast cancer (20), ovarian cancer (21), hepatocellular carcinoma (22) and gastric cancer (16). These data indicate that the abnormal osteogenic differentiation related to BMP9 might be one of the determinants in the pathogenesis of OS.…”

Section: Introductionmentioning

confidence: 86%

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All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway

Meng

et al. 2017

International Journal of Oncology

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Abstract. Osteosarcoma (OS) is the most common malignant bone tumour and is considered to be a disease caused by a dysfunction in differentiation. Bone morphogenetic protein 9 (BMP9) is the most potent osteogenic factor in mesenchymal stem cells, but it cannot induce osteogenic differentiation in OS cells; this might be one of the determinants in the pathogenesis of OS. All-trans retinoic acid (ATRA) can induce osteogenic differentiation of OS cells and potentiate BMP9-induced osteogenesis in preadipocytes. However, the concomitant effect of ATRA and BMP9 in OS cells is unclear; therefore, in the present study, we focused on this topic. The results showed that BMP9 significantly promoted the proliferation of human OS 143B cells and did not induce osteogenic differentiation of cells in vitro (p<0.01). ATRA inhibited proliferation and induced osteogenesis in 143B cells; these effects could be enhanced by BMP9 overexpression (p<0.05). ATRA could significantly increase the level of phosphorylated p38 MAPK (p-p38) in 143B cells, while BMP9 did not have any significant effect. Notably, BMP9 overexpression enhanced the ability of ATRA to increase the levels of p-p38. Both the osteogenic differentiation and the anti-proliferative activity of BMP9 in the presence of ATRA decreased upon treatment with a specific inhibitor of p38 MAPK (SB203580) (p<0.01). This study indicates that the osteogenic differentiation ability of BMP9 in 143B cells can be restored by ATRA, and the combination of BMP9 and ATRA generated a stronger anti-proliferative effect on 143B cells than ATRA alone. This result may be due to the activation of the p38 MAPK pathway.

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Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development

Cited by 84 publications

References 55 publications

Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215

Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215

The role of bone morphogenetic proteins in myeloma cell survival

All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway

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