The C. elegans SMOC-1 protein acts cell non-autonomously to promote bone morphogenetic protein signaling

ABSTRACTBone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) null mutants have a small body size, while overexpression of smoc-1 led to a long body size and increased expression of the RAD-SMAD BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFβ-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell non-autonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1’s function in modulating BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans.ARTICLE SUMMARYBMP signaling is critical for development and homeostasis in metazoans, and is under tight regulation. We report the identification and characterization of a Secreted MOdular Calcium binding protein SMOC-1 as a positive modulator of BMP signaling in C. elegans. We established that SMOC-1 antagonizes the function of LON-2/glypican and acts through the DBL-1/BMP ligand to promote BMP signaling. We identified smoc-1-expressing cells, and demonstrated that SMOC-1 acts cell non-autonomously and in a positive feedback loop to regulate BMP signaling. We also provide evidence suggesting that the function of SMOC proteins in the BMP pathway is conserved from worms to humans.

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Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines

Cancer Science ◽

10.1111/j.1349-7006.2008.00993.x ◽

2009 ◽

Vol 100 (1) ◽

pp. 103-110 ◽

Cited By ~ 14

Author(s):

Shin Hamada ◽

Kennichi Satoh ◽

Morihisa Hirota ◽

Wataru Fujibuchi ◽

Atsushi Kanno ◽

...

Keyword(s):

Epithelial Cell ◽

Pancreatic Duct ◽

Bone Morphogenetic Protein ◽

Cell Lines ◽

Calcium Binding ◽

Binding Protein ◽

Calcium Binding Protein ◽

Duct Epithelial Cell ◽

Morphogenetic Protein ◽

Epithelial Cell Lines

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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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Role of autocrine bone morphogenetic protein Signaling in trophoblast stem cells

Biology of Reproduction ◽

10.1093/biolre/ioab213 ◽

2021 ◽

Author(s):

Jennie Au ◽

Daniela F Requena ◽

Hannah Rishik ◽

Sampada Kallol ◽

Chandana Tekkatte ◽

...

Keyword(s):

Stem Cells ◽

Bone Morphogenetic Protein ◽

Bmp Signaling ◽

Human Trophoblast ◽

Trophoblast Stem Cells ◽

Trophoblast Stem ◽

Morphogenetic Protein ◽

Bmp Pathway

Abstract The Bone Morphogenetic Protein (BMP) pathway is involved in numerous developmental processes, including cell growth, apoptosis, and differentiation. In mouse embryogenesis, BMP signaling is a well-known morphogen for both mesoderm induction and germ cell development. Recent evidence points to a potential role in development of the extra-embryonic compartment, including trophectoderm-derived tissues. In this study, we investigated the effect of BMP signaling in both mouse and human trophoblast stem cells (TSC) in vitro, evaluating the expression and activation of the BMP signaling response machinery, and the effect of BMP signaling manipulation during TSC maintenance and differentiation. Both mTSC and hTSC expressed various BMP ligands and the receptors BMPR1A and BMPR2, necessary for BMP response, and displayed maximal active BMP signaling when undifferentiated. We also observed a conserved modulatory role of BMP signaling during trophoblast differentiation, whereby maintenance of active BMP signaling blunted differentiation of TSC in both species. Conversely, the effect of BMP signaling on the undifferentiated state of TSC appeared to be species-specific, with SMAD-independent signaling important in maintenance of mTSC, and a more subtle role for both SMAD-dependent and -independent BMP signaling in hTSC. Altogether, these data establish an autocrine role for the BMP pathway in the trophoblast compartment. As specification and correct differentiation of the extra-embryonic compartment are fundamental for implantation and early placental development, insights on the role of the BMP signaling in early development might prove useful in the setting of in vitro fertilization as well as targeting trophoblast-associated placental dysfunction.

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Feedback regulation of BMP signaling by C. elegans cuticle collagens

10.1101/686592 ◽

2019 ◽

Author(s):

Uday Madaan ◽

Lionel Faure ◽

Albar Chowdhury ◽

Shahrear Ahmed ◽

Emma J. Ciccarelli ◽

...

Keyword(s):

Body Size ◽

Regulation Of Gene Expression ◽

Feedback Regulation ◽

Bmp Signaling ◽

Physical Separation ◽

C Elegans ◽

Morphogenetic Protein ◽

Cellular Responsiveness ◽

Collagen Genes ◽

Cuticle Collagens

AbstractCellular responsiveness to environmental cues, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway allowing this responsiveness is the bone morphogenetic protein (BMP) signaling pathway. Due to their broad and potent functions, BMPs and their signaling pathways are highly regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a major regulator of body size. We have previously shown that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We have now obtained evidence of feedback regulation of DBL-1/BMP by collagen genes. We analyzed four DBL-1-regulated collagen genes that affect body size. Here we show that inactivation of any one of these cuticle collagen genes reduces DBL-1/BMP signaling, as measured by a Smad activity reporter. Furthermore, we find that depletion of these collagens reduces GFP::DBL-1 fluorescence, and acts unexpectedly at the level of dbl-1 transcription. We therefore conclude that cuticle, a type of ECM, impinges on DBL-1/BMP expression and signaling. In contrast to other characterized examples, however, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact-independent, due to the physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel mechanism of regulation of BMP signaling, with broader implications for mechanical regulation of gene expression in general.

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