P335 Hgs physically interacts with BMP-receptor-associated Smad5 and attenuates BMP signaling

TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment.

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Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce AIF-caspase independent cell death.

10.21203/rs.3.rs-20532/v1 ◽

2020 ◽

Author(s):

Arindam Mondal ◽

Rachel NeMoyer ◽

Elaine Langenfeld ◽

Danea Glover ◽

Michael Scott ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cell Lines ◽

Nuclear Translocation ◽

Bmp Signaling ◽

Lung Carcinomas ◽

Bmp Receptor ◽

Cell Death Pathway ◽

Morphogenetic Protein ◽

Receptor Inhibitor

Abstract Background: BMP is an evolutionary conserved morphogen that is reactivated in lung carcinomas. BMP receptor inhibitors promote cell death of lung carcinomas by mechanisms not fully elucidated. The studies here reveal novel mechanisms by which the “survivin” inhibitor Ym155 in combination with the BMP inhibitor JL5 synergistically induces death of lung cancer cells.Methods: This study examines the mechanism by which Ym155 in combination with JL5 downregulates BMP signaling and induces cell death of non-small cell lung carcinomas (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC.Results: We found that Ym155, which is reported to be a survivin inhibitor, potently inhibits BMP signaling by causing BMPR2 mislocalization into the cytoplasm and its decreased expression. Ym155 mediated cell death is not caused by the inhibition of survivin but involves Ym155 binding to mitochondrial DNA leading to depletion of ATP. The combination of Ym155 and the BMP receptor inhibitor JL5 synergistically causes the downregulation of BMP Smad-1/5 dependent and independent signaling and the induction of cell death of lung cancer cell lines and primary lung tumors. Cell death involves the nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus causing DNA double stranded breaks independent of caspase activation, which occurs only when JL5 and Ym155 are used in combination. Knockdown of BMPR2 together with Ym155 also induced AIF localization to the nucleus.Conclusions: These studies suggest that inhibition of BMPR2 together with Ym155 can induce AIF caspase-independent cell death. AIF caspase-independent cell is an evolutionary conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight how to target AIF caspase-independent cell death using BMP inhibitors.

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Abstract 382: The Bone Morphogenetic Protein Pathway Mediates the Effects of H11 Kinase/Hsp22 on Cardiac Cell Growth and Survival

Circulation ◽

10.1161/circ.118.suppl_18.s_295-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Xiangzhen Sui ◽

Dan Li ◽

Nadia Hedhli ◽

Hongyu Qiu ◽

Vinciane Gaussin ◽

...

Keyword(s):

Cell Growth ◽

Bone Morphogenetic Protein ◽

Bmp Signaling ◽

Cardiac Cell ◽

Growth And Survival ◽

Over Expression ◽

Bmp Receptor ◽

Morphogenetic Protein ◽

Bmp Pathway ◽

Cell Growth And Survival

The bone morphogenetic protein (BMP) pathway is a major signaling mechanism during cardiac development but it has no clear function in the post-natal heart. Here, we tested the hypothesis that BMP mediates the physiological effect of the cardiac chaperone H11Kinase/Hsp22 (H11K). Expression of H11K increases during both cardiac ischemia and overload, and its cardiac-specific over-expression in a transgenic (TG) mouse is sufficient to provide major protection against ischemia and to promote cardiac cell growth, which involves the activation of phosphatidylinositol-3-kinase (PI3K) and of its effector Akt. We tested whether H11K-induced activation of PI3K is mediated by BMP. Microarray comparison between hearts from TG and wild type (WT) mice showed an up-regulation of the BMP receptor subunits Alk3 and BMPR-II, as well as of the BMP receptor ligand BMP4, which was confirmed at the protein level (P<0.01 vs WT). Activation of the BMP pathway in TG mice was confirmed by increased phosphorylation of the canonical BMP effectors Smad 1/5/8 (P<0.01 vs WT). The mechanism was further studied in isolated cardiac myocytes. Adeno-mediated over-expression of H11K was accompanied by significant 2–3-fold increase in PI3K activity, phospho-Akt, Smad 1/5/8 phosphorylation and cell growth as measured by [3H]phenylalanine incorporation, and by a 70% reduction in H2O2-mediated apoptosis (all values, P<0.01 vs control). All these changes mediated by H11K in myocytes were abolished upon addition of the BMP antagonist noggin. In pull-down experiments, H11K co-precipitated with both Alk3 and BMPR-II, and increased the association of these two subunits into a functional receptor. Accordingly, Smad 1/5/8 phosphorylation in presence of BMP4 was enhanced by 5-fold upon H11K over-expression, whereas it was decreased by 3-fold upon H11K knockdown (both, P<0.01 vs control), which shows that H11K potentiates the BMP receptor signaling pathway. Therefore, potentiation of the BMP receptor pathway by H11K promotes the activation of the PI3K/Akt pathway and dictates the physiological effects of H11K on cardiac cell growth and survival, which shows a novel role for BMP signaling in post-natal heart. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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Investigating Bone Morphogenetic Protein (BMP) Signaling in a Newly Established Human Cell Line Expressing BMP Receptor Type II

The Tohoku Journal of Experimental Medicine ◽

10.1620/tjem.222.121 ◽

2010 ◽

Vol 222 (2) ◽

pp. 121-129 ◽

Cited By ~ 6

Author(s):

Tada-aki Kudo ◽

Hiroyasu Kanetaka ◽

Akira Watanabe ◽

Ayako Okumoto ◽

Masanobu Asano ◽

...

Keyword(s):

Cell Line ◽

Bone Morphogenetic Protein ◽

Human Cell ◽

Human Cell Line ◽

Bmp Signaling ◽

Receptor Type ◽

Type Ii ◽

Bmp Receptor ◽

Morphogenetic Protein

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BMP signaling in rats with TNBS-induced colitis following BMP7 therapy

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00244.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. G1151-G1162 ◽

Cited By ~ 16

Author(s):

Ivana Maric ◽

Natalia Kucic ◽

Tamara Turk Wensveen ◽

Ivana Smoljan ◽

Blazenka Grahovac ◽

...

Keyword(s):

Bone Morphogenetic Proteins ◽

Chronic Phase ◽

Acute Stage ◽

Tissue Growth ◽

Bmp Signaling ◽

Rat Colon ◽

Trinitrobenzene Sulfonic Acid ◽

Opposite Pattern ◽

Bmp Receptor ◽

Experimental Inflammatory Bowel Disease

Beyond stimulating bone formation, bone morphogenetic proteins (BMPs) are important in development, inflammation, and malignancy of the gut. We have previously shown that BMP7 has a regenerative, anti-inflammatory, and antiproliferative effect on experimental inflammatory bowel disease (IBD) in rats. To further investigate the BMP signaling pathway we monitored the effect of BMP7 therapy on the BMP signaling components in the rat colon during different stages of experimentally induced colitis by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed a significantly decreased BMP7 expression in the acute phase, followed by a significantly increased BMP2 and decreased BMP6 expression during the chronic phase of colitis. BMP7 therapy influenced the expression of several BMPs with the most prominent effect on downregulation of BMP2 and upregulation of BMP4 in the chronic phase of colitis. Importantly, connective tissue growth factor and noggin expression were elevated in the acute stage and significantly decreased upon BMP7 therapy. BMP receptor I expression was unchanged, whereas BMP receptor II was decreased at day 2 and increased at days 14 and 30 of TNBS inflammation. However, an opposite pattern of expression following BMP7 therapy has been observed. BMP7 increased the expression of BR-Smad including Smad3 and Smad4. Inhibitory Smads were increased in colitis and significantly decreased following BMP7 therapy at later stages of the disease. We suggest that BMP signaling was altered during TNBS-induced colitis and was recovered with BMP7 administration, suggesting that IBD is a reversible process.

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BMP signaling is a therapeutic target in ovarian cancer

Cell Death Discovery ◽

10.1038/s41420-020-00377-w ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Tomohiko Fukuda ◽

Risa Fukuda ◽

Ryo Tanabe ◽

Daizo Koinuma ◽

Hiroo Koyama ◽

...

Keyword(s):

Ovarian Cancer ◽

Kinase Inhibitors ◽

Bmp Signaling ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Bmp Receptor ◽

Tcga Dataset ◽

Sphere Formation

AbstractBMP signaling has been found to have tumor-promoting as well as tumor-suppressing effects in different types of tumors. In this study, we investigated the effects of BMP signaling and of BMP inhibitors on ovarian cancer (OC) cells in vitro and in vivo. High expression of BMP receptor 2 (BMPR2) correlated with poor overall survival of OC patients in the TCGA dataset. Both BMP2 and BMPR2 enhanced OC cell proliferation, whereas BMP receptor kinase inhibitors inhibited OC cell growth in cell culture as well as in a mouse model. BMP2 also augmented sphere formation, migration, and invasion of OC cells, and induced EMT. High BMP2 expression was observed after chemotherapy of OC patients in the GSE109934 dataset. In accordance, carboplatin, used for the treatment of OC patients, increased BMP2 secretion from OC cells, and induced EMT partially via activation of BMP signaling. Our data suggest that BMP signaling has tumor-promoting effects in OC, and that BMP inhibitors might be useful therapeutic agents for OC patients. Considering that carboplatin treatment augmented BMP2 secretion, the possibility to use a combination of BMP inhibitors and carboplatin in the treatment of OC patients, would be worth exploring.

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Granulosa Cell-expressed BMPR1A and BMPR1B have Unique Functions in Regulating Fertility but Act Redundantly to Suppress Ovarian Tumor Development

Endocrine Reviews ◽

10.1210/edrv.31.2.9999 ◽

2010 ◽

Vol 31 (2) ◽

pp. 263-263

Author(s):

Mark A. Edson ◽

Caterina Clementi ◽

Roopa L. Nalam ◽

Heather L. Franco ◽

Francesco J. DeMayo ◽

...

Keyword(s):

Granulosa Cell ◽

Granulosa Cells ◽

Transforming Growth Factor ◽

Tumor Development ◽

Bmp Signaling ◽

Conditional Knockout ◽

Type I ◽

Bmp Receptor ◽

Bmp Receptors ◽

Ovarian Tumorigenesis

ABSTRACT Bone morphogenetic proteins (BMPs) have diverse roles in development and reproduction. Although several BMPs are produced by oocytes, thecal cells, and granulosa cells of developing follicles, the in vivo functions of most of these ligands are unknown. BMP signals are transduced by multiple type I and type II transforming growth factor β (TGFβ) family receptors, and of the type I receptors, BMP receptor 1A (BMPR1A) and BMP receptor 1B (BMPR1B) are known to be expressed in rodent granulosa cells. Female mice homozygous null for Bmpr1b are sterile due to compromised cumulus expansion, but the function of BMPR1A in the ovary is unknown. To further decipher a role for BMP signaling in mouse granulosa cells, we deleted Bmpr1a in the granulosa cells of the ovary and found Bmpr1a conditional knockout females to be subfertile with reduced spontaneous ovulation. To explore the redundant functions of BMP receptor signaling in the ovary, we generated Bmpr1a Bmpr1b double mutant mice, which developed granulosa cell tumors that have evidence of increased TGFβ and hedgehog signaling. Thus, similar to SMAD1 and SMAD5, which have redundant roles in suppressing granulosa cell tumor development in mice, two type I BMP receptors, BMPR1A and BMPR1B, function together to prevent ovarian tumorigenesis. These studies support a role for a functional BMP signaling axis as a tumor suppressor pathway in the ovary, with BMPR1A and BMPR1B acting downstream of BMP ligands and upstream of BMP receptor SMADs.

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