scholarly journals TGFβ family signaling and development

Development ◽  
2021 ◽  
Vol 148 (5) ◽  
Author(s):  
Shunji Jia ◽  
Anming Meng
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Dorsoventral Patterning ◽  
Tgfβ Signaling ◽  
Evolutionarily Conserved ◽  
Transduction Mechanisms

ABSTRACT The transforming growth factor β (TGFβ) signaling family is evolutionarily conserved in metazoans. The signal transduction mechanisms of TGFβ family members have been expansively investigated and are well understood. During development and homeostasis, numerous TGFβ family members are expressed in various cell types with temporally changing levels, playing diverse roles in embryonic development, adult tissue homeostasis and human diseases by regulating cell proliferation, differentiation, adhesion, migration and apoptosis. Here, we discuss the molecular mechanisms underlying signal transduction and regulation of the TGFβ subfamily pathways, and then highlight their key functions in mesendoderm induction, dorsoventral patterning and laterality development, as well as in the formation of several representative tissues/organs.

scholarly journals Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

2004 ◽  
Vol 24 (6) ◽  
pp. 2546-2559 ◽  
Author(s):  
Joshua P. Frederick ◽  
Nicole T. Liberati ◽  
David S. Waddell ◽  
Yigong Shi ◽  
Xiao-Fan Wang
Keyword(s):  
Growth Factor ◽  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Specific Cell ◽  
Smad Proteins ◽  
Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

scholarly journals Msk is required for nuclear import of TGF-β/BMP-activated Smads

2007 ◽  
Vol 178 (6) ◽  
pp. 981-994 ◽  
Author(s):  
Lan Xu ◽  
Xiaohao Yao ◽  
Xiaochu Chen ◽  
Peiyuan Lu ◽  
Biliang Zhang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Bone Morphogenetic Proteins ◽  
Nuclear Import ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Nuclear Accumulation ◽  
Smad Proteins ◽  
Evolutionarily Conserved ◽  
Drosophila Cells

Nuclear translocation of Smad proteins is a critical step in signal transduction of transforming growth factor β (TGF-β) and bone morphogenetic proteins (BMPs). Using nuclear accumulation of the Drosophila Smad Mothers against Decapentaplegic (Mad) as the readout, we carried out a whole-genome RNAi screening in Drosophila cells. The screen identified moleskin (msk) as important for the nuclear import of phosphorylated Mad. Genetic evidence in the developing eye imaginal discs also demonstrates the critical functions of msk in regulating phospho-Mad. Moreover, knockdown of importin 7 and 8 (Imp7 and 8), the mammalian orthologues of Msk, markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-β. Biochemical studies further suggest that Smads are novel nuclear import substrates of Imp7 and 8. We have thus identified new evolutionarily conserved proteins that are important in the signal transduction of TGF-β and BMP into the nucleus.

TGFβ2 mediates the effects of Hedgehog on hypertrophic differentiation and PTHrP expression

Development ◽  
2002 ◽  
Vol 129 (8) ◽  
pp. 1913-1924 ◽  
Author(s):  
Jesus Alvarez ◽  
Philip Sohn ◽  
Xin Zeng ◽  
Thomas Doetschman ◽  
David J. Robbins ◽  
...  
Keyword(s):  
Growth Plate ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Signaling Cascade ◽  
Tgfβ Signaling ◽  
Organ Cultures ◽  
Embryonic Mouse ◽  
Metatarsal Bones ◽  
Pthrp Expression

The development of endochondral bones requires the coordination of signals from several cell types within the cartilage rudiment. A signaling cascade involving Indian hedgehog (Ihh) and parathyroid hormone related peptide (PTHrP) has been described in which hypertrophic differentiation is limited by a signal secreted from chondrocytes as they become committed to hypertrophy. In this negative-feedback loop, Ihh inhibits hypertrophic differentiation by regulating the expression of Pthrp, which in turn acts directly on chondrocytes in the growth plate that express the PTH/PTHrP receptor. Previously, we have shown that PTHrP also acts downstream of transforming growth factor β (TGFβ) in a common signaling cascade to regulate hypertrophic differentiation in embryonic mouse metatarsal organ cultures. As members of the TGFβ superfamily have been shown to mediate the effects of Hedgehog in several developmental systems, we proposed a model where TGFβ acts downstream of Ihh and upstream of PTHrP in a cascade of signals that regulate hypertrophic differentiation in the growth plate. This report tests the hypothesis that TGFβ signaling is required for the effects of Hedgehog on hypertrophic differentiation and expression of Pthrp. We show that Sonic hedgehog (Shh), a functional substitute for Ihh, stimulates expression of Tgfb2 and Tgfb3 mRNA in the perichondrium of embryonic mouse metatarsal bones grown in organ cultures and that TGFβ signaling in the perichondrium is required for inhibition of differentiation and regulation of Pthrp expression by Shh. The effects of Shh are specifically dependent on TGFβ2, as cultures from Tgfb3-null embryos respond to Shh but cultures from Tgfb2-null embryos do not. Taken together, these data suggest that TGFβ2 acts as a signal relay between Ihh and PTHrP in the regulation of cartilage hypertrophic differentiation.

scholarly journals Urokinase-type plasminogen activator induces tyrosine phosphorylation of a 78-kDa protein in H-157 cells

1999 ◽  
Vol 277 (2) ◽  
pp. L301-L309 ◽  
Author(s):  
G. Jayarama Bhat ◽  
Jagadambika J. Gunaje ◽  
Steven Idell
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Plasminogen Activator ◽  
Tyrosine Phosphorylation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Upa Receptor ◽  
Type Plasminogen Activator ◽  
Transduction Mechanisms

Studies from our laboratory have shown that exposure of human lung epithelial cells to urokinase plasminogen activator (uPA) induces their proliferation. This effect of uPA is likely to occur via activation of signal transduction pathways. To elucidate uPA-induced signal transduction mechanisms, we exposed H-157 cells to uPA and determined the induced tyrosine phosphorylation profile of proteins. We demonstrate that, in these cells, uPA prominently induced tyrosine phosphorylation of a 78-kDa protein. This effect was observed as early as 30 min and was sustained for at least 24 h. Treatment of cells with agents that abrogate uPA receptor (uPAR) function, including neutralizing anti-uPAR antibody, phosphatidylinositol-specific phospholipase C, or a selective antagonist that blocks the association of uPA with uPAR (Å5 compound), all failed to prevent uPA-induced tyrosine phosphorylation. B-428, an active site inhibitor of uPA activity, prevented the uPA effect. Treatment of cells with hepatocyte growth factor, vascular endothelial growth factor, or transforming growth factor-β, all of which are known to be activated by a uPA-dependent pathway, did not stimulate tyrosine phosphorylation of the 78-kDa protein. uPA induced an increase in [3H]thymidine incorporation into DNA, and cell numbers were unaffected in the presence of Å5. These results demonstrate that, in H-157 cells, uPA induces tyrosine phosphorylation of a 78-kDa protein via a proteolysis-dependent but uPAR-independent mechanism. This novel signaling pathway represents a putative mechanism by which uPA could influence epithelial cell proliferation.

scholarly journals The TGF-β Family: Signaling Pathways, Developmental Roles, and Tumor Suppressor Activities

2002 ◽  
Vol 2 ◽  
pp. 892-925 ◽  
Author(s):  
Aaron N. Johnson ◽  
Stuart J. Newfeld
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Suppressor Activity ◽  
Wide Range ◽  
Tumor Suppressor Activity ◽  
Multicellular Organisms

Intercellular communication is a critical process for all multicellular organisms, and communication among cells is required for proper embryonic development and adult physiology. Members of the Transforming Growth Factor-β (TGF-β) family of secreted proteins communicate information between cells via a complex signaling pathway, and family members are capable of inducing a wide range of cellular responses. The purpose of this review is to provide the reader with a broad introduction to our current understanding of three aspects of the TGF-β family. These are the molecular mechanisms utilized by TGF-β signaling pathways, the developmental roles played by TGF-β family members in a variety of species, and the growing list of cancers in which various TGF-β signaling pathways display tumor suppressor activity.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 975
Author(s):  
Kara Corps ◽  
Monica Stanwick ◽  
Juliann Rectenwald ◽  
Andrew Kruggel ◽  
Sarah B. Peters
Keyword(s):  
Transforming Growth Factor ◽  
Skeletal Development ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Skeletal Deformities ◽  
Tooth Abnormalities ◽  
Pathological Analysis ◽  
Diaphragmatic Muscle ◽  
Proliferation And Differentiation ◽  
Tgfβ Receptor

Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

scholarly journals A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jian Zhang ◽  
Yongjun Zheng ◽  
Jimmy Lee ◽  
Jieyu Hua ◽  
Shilong Li ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Skin Wound ◽  
Large Animal ◽  
Skin Wounds ◽  
Tgfβ Signaling ◽  
Pulsatile Release ◽  
Ecm Extracellular Matrix

AbstractEffective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-β (TGFβ) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFβ signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFβ can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.

scholarly journals Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 634
Author(s):  
Bailee H. Sliker ◽  
Paul M. Campbell
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Fibroblast Activation Protein ◽  
Cancer Associated Fibroblasts ◽  
Cell Type ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
New Research ◽  
Tumor Types

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

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