scholarly journals It Takes Two to Tango: Endothelial TGFβ/BMP Signaling Crosstalk with Mechanobiology

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1965 ◽  
Author(s):  
Christian Hiepen ◽  
Paul-Lennard Mendez ◽  
Petra Knaus
Keyword(s):  
Shear Stress ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Research Field ◽  
Bmp Signaling ◽  
Growth Factor Signaling ◽  
Mechanical Stimuli ◽  
Signaling Crosstalk

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGFβ) superfamily of cytokines. While some ligand members are potent inducers of angiogenesis, others promote vascular homeostasis. However, the precise understanding of the molecular mechanisms underlying these functions is still a growing research field. In bone, the tissue in which BMPs were first discovered, crosstalk of TGFβ/BMP signaling with mechanobiology is well understood. Likewise, the endothelium represents a tissue that is constantly exposed to multiple mechanical triggers, such as wall shear stress, elicited by blood flow or strain, and tension from the surrounding cells and to the extracellular matrix. To integrate mechanical stimuli, the cytoskeleton plays a pivotal role in the transduction of these forces in endothelial cells. Importantly, mechanical forces integrate on several levels of the TGFβ/BMP pathway, such as receptors and SMADs, but also global cell-architecture and nuclear chromatin re-organization. Here, we summarize the current literature on crosstalk mechanisms between biochemical cues elicited by TGFβ/BMP growth factors and mechanical cues, as shear stress or matrix stiffness that collectively orchestrate endothelial function. We focus on the different subcellular compartments in which the forces are sensed and integrated into the TGFβ/BMP growth factor signaling.

scholarly journals LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Carl Herdenberg ◽  
Pascal M. Mutie ◽  
Ola Billing ◽  
Ahmad Abdullah ◽  
Rona J. Strawbridge ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lipid Metabolism ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Bmp Signaling ◽  
Null Mouse ◽  
Growth Factor Signaling

AbstractLeucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-β) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease.

scholarly journals Disruption of Smad4 in Odontoblasts Causes Multiple Keratocystic Odontogenic Tumors and Tooth Malformation in Mice

2009 ◽  
Vol 29 (21) ◽  
pp. 5941-5951 ◽  
Author(s):  
Yuanrong Gao ◽  
Guan Yang ◽  
Tujun Weng ◽  
Juan Du ◽  
Xuejiu Wang ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Odontogenic Tumors ◽  
High Recurrence Rate ◽  
Signal Molecules ◽  
Cystic Tumors ◽  
Keratocystic Odontogenic Tumors

ABSTRACT Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocyte-specific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-β/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment.

scholarly journals Regulation of TEAD Transcription Factors in Cancer Biology

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 600 ◽  
Author(s):  
Hyunbin Huh ◽  
Dong Kim ◽  
Han-Sol Jeong ◽  
Hyun Park
Keyword(s):  
Transcription Factors ◽  
Growth Factor ◽  
Tumor Progression ◽  
Transforming Growth Factor Beta ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Transforming Growth Factor ◽  
Clinicopathological Parameters ◽  
Transcriptional Output

Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics.

dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp

Development ◽  
1997 ◽  
Vol 124 (20) ◽  
pp. 4113-4120 ◽  
Author(s):  
S.M. Jackson ◽  
H. Nakato ◽  
M. Sugiura ◽  
A. Jannuzi ◽  
R. Oakes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Cellular Responses ◽  
Growth Factor Signaling ◽  
Tgf Beta ◽  
Morphogenetic Protein

Decapentaplegic (Dpp) is a Drosophila member of the Transforming Growth Factor-beta (TGF-beta)/Bone Morphogenetic Protein (BMP) superfamily of growth factors. Dpp serves as a classical morphogen, where concentration gradients of this secreted factor control patterning over many cell dimensions. Regulating the level of Dpp signaling is therefore critical to its function during development. One type of molecule proposed to modulate growth factor signaling at the cell surface are integral membrane proteoglycans. We show here that division abnormally delayed (dally), a Drosophila member of the glypican family of integral membrane proteoglycans is required for normal Dpp signaling during development, affecting cellular responses to this morphogen. Ectopic expression of dally+ can alter the patterning activity of Dpp, suggesting a role for dally+ in modulating Dpp signaling strength. These findings support a role for members of the glypican family in controlling TGF-beta/BMP activity in vivo by affecting signaling at the cell surface.

scholarly journals P.106 Thrombospondin 1 mediates transforming growth factor beta induced premature senescence in primary glioblastoma cells

2016 ◽  
Vol 43 (S2) ◽  
pp. S45-S45
Author(s):  
R Kumar ◽  
I Lorimer
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Global Gene Expression ◽  
Premature Senescence ◽  
Primary Glioblastoma ◽  
Thrombospondin 1 ◽  
Growth Factor Beta ◽  
Novel Therapeutic Strategies

Background: Glioblastoma is the most common primary malignant brain tumor. Primary Glioblastoma (PriGO) cells are key drivers of glioblastoma. Senescence is the irreversible growth arrest of cells with continued metabolic activity. Recently, I discovered PriGO cells undergo premature senescence in response to Fetal Bovine Serum (FBS). Determining the underlying molecular mechanisms may allow development of novel therapeutic strategies to decrease the malignant potential of glioblastoma. Methods: Global gene expression changes in PriGO cells treated with serum were analyzed and compared to untreated cells. Senescence was determined by the Senescence-Associated-Beta-Galactosidase (SA-B-Gal) assay. Results: PriGO cells treated with serum demonstrated increased expression of genes in the Transforming Growth Factor Beta (TGF-B) pathway, such as Thrombospondin 1 (TSP1), compared to untreated cells. TGF-B treatment of PriGO cells significantly increased senescence compared to untreated cells. Treatment of PriGO cells with serum and the TGF-B inhibitor SB431542 led to a decrease in senescence compared to serum only treated cells. Treatment of PriGO cells with serum and the TSP1 inhibitor LSKL led to a reduction in senescence compared to serum only treated cells. Conclusions: Our data identifies TGF-B as an important component of serum responsible for inducing senescence in PriGO cells. Furthermore, TGF-B induced senescence in PriGO cells is in part mediated by TSP1.

scholarly journals Feedback regulation of BMP signaling by Caenorhabditis elegans cuticle collagens

2020 ◽  
Vol 31 (8) ◽  
pp. 825-832 ◽  
Author(s):  
Uday Madaan ◽  
Lionel Faure ◽  
Albar Chowdhury ◽  
Shahrear Ahmed ◽  
Emma J. Ciccarelli ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Feedback Regulation ◽  
Bmp Signaling ◽  
Reciprocal Interactions ◽  
Growth Factor Beta ◽  
Cuticle Collagens

Transforming growth factor beta (TGF-β) and related signals can be regulated by the extracellular matrix (ECM). We identify a novel contact-independent regulation of DBL-1 TGF-β/BMP–related signaling by collagens in Caenorhabditis elegans. These collagens are transcriptional targets of the pathway, indicating reciprocal interactions between DBL-1 signaling and the ECM.

scholarly journals Pericyte-Endothelial Interactions in the Retinal Microvasculature

2020 ◽  
Vol 21 (19) ◽  
pp. 7413
Author(s):  
Hu Huang
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Neurovascular Unit ◽  
Blood Retinal Barrier ◽  
Vascular Disorders ◽  
Pathological Conditions ◽  
Retinal Microvasculature

Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the retinal microvessels. Formation, maturation, and stabilization of the micro-vasculatures require pericyte-endothelial interactions, which are perturbed in many retinal vascular disorders, such as retinopathy of prematurity, retinal vein occlusion, and diabetic retinopathy. Understanding the cellular and molecular mechanisms of pericyte-endothelial interaction and perturbation can facilitate the design of therapeutic intervention for the prevention and treatment of retinal vascular disorders. Pericyte-endothelial interactions are indispensable for the integrity and functionality of retinal neurovascular unit (NVU), including vascular cells, retinal neurons, and glial cells. The essential autocrine and paracrine signaling pathways, such as Vascular endothelial growth factor (VEGF), Platelet-derived growth factor subunit B (PDGFB), Notch, Angipointein, Norrin, and Transforming growth factor-beta (TGF-β), have been well characterized for the regulation of pericyte-endothelial interactions in the neo-vessel formation processes (vasculogenesis and angiogenesis) during embryonic development. They also play a vital role in stabilizing and remodeling mature vasculature under pathological conditions. Awry signals, aberrant metabolisms, and pathological conditions, such as oxidative stress and inflammation, can disrupt the communication between pericytes and endothelial cells, thereby resulting in the breakdown of the blood-retinal barrier (BRB) and other microangiopathies. The emerging evidence supports extracellular exosomes’ roles in the (mis)communications between the two cell types. This review summarizes the essential knowledge and updates about new advancements in pericyte-EC interaction and communication, emphasizing the retinal microvasculature.

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