scholarly journals BMP pathway regulation of insulin signaling components promotes lipid storage in Caenorhabditis elegans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (10) ◽  
pp. e1009836
Author(s):  
James F. Clark ◽  
Emma J. Ciccarelli ◽  
Peter Kayastha ◽  
Gehan Ranepura ◽  
Katerina K. Yamamoto ◽  
...  
Keyword(s):  
Bmp Signaling ◽  
Lipid Homeostasis ◽  
Signaling Crosstalk ◽  
Morphogenetic Protein ◽  
Autophagy Induction ◽  
Bmp Pathway ◽  
Dauer Formation ◽  
Pathway Regulation ◽  
And Function ◽  
Modes Of Interaction

A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not fully understood. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing additional IIS functions including dauer formation, aging, and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

scholarly journals Mechanism of Interaction of BMP and Insulin Signaling in C. elegans Development and Homeostasis

2019 ◽  
Author(s):  
James F. Clark ◽  
Emma J. Ciccarelli ◽  
Gehan Ranepura ◽  
Muhammad S. Hasan ◽  
Alicia Meléndez ◽  
...  
Keyword(s):  
Bmp Signaling ◽  
Lipid Homeostasis ◽  
Signaling Crosstalk ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Autophagy Induction ◽  
Dauer Formation ◽  
And Function ◽  
Modes Of Interaction ◽  
Molecular Components

AbstractA small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not known. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is specifically regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing two additional IIS functions, dauer formation and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

scholarly journals Loss of mismatch repair signaling impairs the WNT–bone morphogenetic protein crosstalk and the colonic homeostasis

2019 ◽  
Vol 12 (6) ◽  
pp. 410-423
Author(s):  
Katrine Nørgaard ◽  
Carolin Müller ◽  
Nadja Christensen ◽  
María L Chiloeches ◽  
Cesilie L Madsen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Mismatch Repair ◽  
Goblet Cells ◽  
Bmp Signaling ◽  
Colonic Epithelium ◽  
Signaling Crosstalk ◽  
Dna Mismatch ◽  
Morphogenetic Protein ◽  
And Function ◽  
Deficient Mice

Abstract The fine balance between proliferation, differentiation, and apoptosis in the colonic epithelium is tightly controlled by the interplay between WNT, Notch, and bone morphogenetic protein (BMP) signaling. How these complex networks coordinate the colonic homeostasis, especially if cancer predisposing mutations such as mutations in the DNA mismatch repair (MMR) are present, is unclear. Inactivation of the MMR system has long been linked to colorectal cancer; however, little is known about its role in the regulation of the colonic homeostasis. It has been shown that loss of MMR promotes the proliferation of colon epithelial cells that renders them highly susceptible to transformation. The mechanism through which MMR mediates this effect, yet, remains to be determined. Using an MMR-deficient mouse model, we show that increased methylation of Dickkopf1 impacts its expression, and consequently, the ability to negatively regulate WNT signaling. As a result, excessive levels of active β-catenin promote strong crypt progenitor-like phenotype and abnormal proliferation. Under these settings, the development and function of the goblet cells are affected. MMR-deficient mice have fewer goblet cells with enlarged mucin-loaded vesicles. We further show that MMR inactivation impacts the WNT–BMP signaling crosstalk.

scholarly journals A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Jonathan W. Lowery ◽  
Brice Brookshire ◽  
Vicki Rosen
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Human Organ ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Bmp Pathway ◽  
Wide Perspective ◽  
The Relationship

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-βfamily of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-βpathways.

scholarly journals Bu-M-P-ing Iron: How BMP Signaling Regulates Muscle Growth and Regeneration

2020 ◽  
Vol 8 (1) ◽  
pp. 4
Author(s):  
Matthew J Borok ◽  
Despoina Mademtzoglou ◽  
Frederic Relaix
Keyword(s):  
Skeletal Muscle ◽  
Bone Formation ◽  
Postnatal Development ◽  
Recent Work ◽  
Muscle Regeneration ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Different Tissues

The bone morphogenetic protein (BMP) pathway is best known for its role in promoting bone formation, however it has been shown to play important roles in both development and regeneration of many different tissues. Recent work has shown that the BMP proteins have a number of functions in skeletal muscle, from embryonic to postnatal development. Furthermore, complementary studies have recently demonstrated that specific components of the pathway are required for efficient muscle regeneration.

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

Circulation ◽  
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.

BMP Signaling in Development, Stem Cells, and Diseases of the Gastrointestinal Tract

2020 ◽  
Vol 82 (1) ◽  
pp. 251-273 ◽  
Author(s):  
Yongchun Zhang ◽  
Jianwen Que
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Digestive System ◽  
Bmp Signaling ◽  
Gi Tract ◽  
Multiple Organs ◽  
Morphogenetic Protein ◽  
New Findings ◽  
Bmp Pathway ◽  
Disease Initiation

The bone morphogenetic protein (BMP) pathway is essential for the morphogenesis of multiple organs in the digestive system. Abnormal BMP signaling has also been associated with disease initiation and progression in the gastrointestinal (GI) tract and associated organs. Recent studies using animal models, tissue organoids, and human pluripotent stem cells have significantly expanded our understanding of the roles played by BMPs in the development and homeostasis of GI organs. It is clear that BMP signaling regulates GI function and disease progression that involve stem/progenitor cells and inflammation in a tissue-specific manner. In this review we discuss these new findings with a focus on the esophagus, stomach, and intestine.

scholarly journals Synergistic interaction between the fibroblast growth factor and bone morphogenetic protein signaling pathways in lens cells

2015 ◽  
Vol 26 (13) ◽  
pp. 2561-2572 ◽  
Author(s):  
Bruce A. Boswell ◽  
Linda S. Musil
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Bone Morphogenetic Protein ◽  
Primary Cultures ◽  
Bmp Signaling ◽  
Fibroblast Growth ◽  
Lens Development ◽  
Morphogenetic Protein ◽  
Lens Cells ◽  
And Function

Fibroblast growth factors (FGFs) play a central role in two processes essential for lens transparency—fiber cell differentiation and gap junction–mediated intercellular communication (GJIC). Using serum-free primary cultures of chick lens epithelial cells (DCDMLs), we investigated how the FGF and bone morphogenetic protein (BMP) signaling pathways positively cooperate to regulate lens development and function. We found that culturing DCDMLs for 6 d with the BMP blocker noggin inhibits the canonical FGF-to-ERK pathway upstream of FRS2 activation and also prevents FGF from stimulating FRS2- and ERK-independent gene expression, indicating that BMP signaling is required at the level of FGF receptors. Other experiments revealed a second type of BMP/FGF interaction by which FGF promotes expression of BMP target genes as well as of BMP4. Together these studies reveal a novel mode of cooperation between the FGF and BMP pathways in which BMP keeps lens cells in an optimally FGF-responsive state and, reciprocally, FGF enhances BMP-mediated gene expression. This interaction provides a mechanistic explanation for why disruption of either FGF or BMP signaling in the lens leads to defects in lens development and function.

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

2018 ◽  
Author(s):  
Melisa S. DeGroot ◽  
Herong Shi ◽  
Alice Eastman ◽  
Alexandra N. McKillop ◽  
Jun Liu
Keyword(s):  
Body Size ◽  
Bone Morphogenetic Protein ◽  
Calcium Binding ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Bmp Signaling ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Positive Modulator ◽  
Bmp Pathway

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.

scholarly journals Aberrant BMP2 Signaling in Patients Diagnosed with Osteoporosis

2020 ◽  
Vol 21 (18) ◽  
pp. 6909 ◽  
Author(s):  
Hilary W. Durbano ◽  
Daniel Halloran ◽  
John Nguyen ◽  
Victoria Stone ◽  
Sean McTague ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Osteoblast Activity ◽  
Morphogenetic Protein ◽  
Osteogenic Response ◽  
Type Ia ◽  
Bmp Pathway ◽  
Negative Side Effects ◽  
Potent Growth

The most common bone disease in humans is osteoporosis (OP). Current therapeutics targeting OP have several negative side effects. Bone morphogenetic protein 2 (BMP2) is a potent growth factor that is known to activate both osteoblasts and osteoclasts. It completes these actions through both SMAD-dependent and SMAD-independent signaling. A novel interaction between the BMP type Ia receptor (BMPRIa) and casein kinase II (CK2) was discovered, and several CK2 phosphorylation sites were identified. A corresponding blocking peptide (named CK2.3) was designed to further elucidate the phosphorylation site’s function. Previously, CK2.3 demonstrated an increased osteoblast activity and decreased osteoclast activity in a variety of animal models, cell lines, and isolated human osteoblasts. It is hypothesized that CK2.3 completes these actions through the BMP signaling pathway. Furthermore, it was recently discovered that BMP2 did not elicit an osteogenic response in osteoblasts from patients diagnosed with OP, while CK2.3 did. In this study, we explore where in the BMP pathway the signaling disparity or defect lies in those diagnosed with OP. We found that osteoblasts isolated from patients diagnosed with OP did not activate SMAD or ERK signaling after BMP2 stimulation. When OP osteoblasts were stimulated with BMP2, both BMPRIa and CK2 expression significantly decreased. This indicates a major disparity within the BMP signaling pathway in patients diagnosed with osteoporosis.

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