scholarly journals Specification of BMP Signaling

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1579 ◽  
Author(s):  
Joachim Nickel ◽  
Thomas D. Mueller
Keyword(s):  
Growth Factors ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Current View ◽  
Receptor Subtypes ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Tgfβ Signaling ◽  
Receptor Complexes

Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.

Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin

1994 ◽  
Vol 14 (6) ◽  
pp. 3810-3821
Author(s):  
J Cárcamo ◽  
F M Weis ◽  
F Ventura ◽  
R Wieser ◽  
J L Wrana ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Amino Acid Sequence Identity ◽  
Transforming Growth Factor ◽  
Type I ◽  
Type Ii ◽  
Tgf Beta ◽  
Transcriptional Responses ◽  
Receptor Complexes ◽  
Growth Inhibitory ◽  
Growth Factor Beta

Transforming growth factor beta (TGF-beta) and activin bind to receptor complexes that contain two distantly related transmembrane serine/threonine kinases known as receptor types I and II. The type II receptors determine ligand binding specificity, and each interacts with a distinct repertoire of type I receptors. Here we identify a new type I receptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. ActR-IB has the structural and binding properties of a type I receptor: it binds activin only in the presence of an activin type II receptor and forms a heteromeric noncovalent complex with activin type II receptors. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a common set of growth-inhibitory and transcriptional responses in association with their corresponding ligands and type II receptors. The transcriptional responses include elevated expression of fibronectin and plasminogen activator inhibitor 1. Although T beta R-I and ActR-IB are nearly identical in their kinase domains (90% amino acid sequence identity), their corresponding type II receptor kinase domains are very different from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin correlates with the presence of similar type I kinases in their complex. Indeed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) whose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, we conclude that the type I receptor subunits are primary specifiers of signals sent by TGF-beta and activin receptor complexes.

scholarly journals Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation.

1997 ◽  
Vol 17 (3) ◽  
pp. 1682-1691 ◽  
Author(s):  
J J Lebrun ◽  
W W Vale
Keyword(s):  
Cell Line ◽  
Transforming Growth Factor ◽  
Erythroid Differentiation ◽  
Stable Cell Line ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Tgf Beta ◽  
Activin Receptor ◽  
Antagonistic Effects

Activins and inhibins belong to the transforming growth factor beta (TGF-beta)-like superfamily and exert their effects on a broad range of cellular targets by modulating cell differentiation and proliferation. Members of this family interact with two structurally related classes of receptors (type I and type II), both containing a serine/threonine kinase domain. When expressed alone, the type II but not the type I activin receptor can bind activin. However, the presence of a type I receptor is required for signaling. For TGF-beta1, ligand binding to the type II receptor results in the recruitment and transphosphorylation of the type I receptor. Transient overexpression of the two types of activin receptor results in ligand-independent receptor heteromerization and activation. Nevertheless, activin addition to the transfected cells increased complex formation between the two receptors, suggesting a mechanism of action similar to that observed for the TGF-beta receptor. In the present study, we generated a stable cell line, overexpressing the two types of activin receptor upon induction, in the human erythroleukemia cell line K562. We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner. Using this stable line, we analyzed the effects of activin and inhibin on human erythroid differentiation. Our results indicate that activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. Finally, using cell lines that can be induced to overexpress ActRII and ActRIB or ActRIB only, we show that the inhibin antagonistic effects on activin-induced biological responses are mediated through a competition for the type II activin receptor but also require the presence of an inhibin-specific binding component.

scholarly journals CIN85 modulates TGFβ signaling by promoting the presentation of TGFβ receptors on the cell surface

2015 ◽  
Vol 210 (2) ◽  
pp. 319-332 ◽  
Author(s):  
Ihor Yakymovych ◽  
Mariya Yakymovych ◽  
Guangxiang Zang ◽  
Yabing Mu ◽  
Anders Bergh ◽  
...  
Keyword(s):  
Cell Surface ◽  
Transforming Growth Factor ◽  
Adaptor Protein ◽  
Dominant Negative Mutant ◽  
Type I ◽  
Dependent Manner ◽  
Tgfβ Signaling ◽  
Transcriptional Responses ◽  
Tgfβ Receptors ◽  
Smad2 Phosphorylation

Members of the transforming growth factor β (TGFβ) family initiate cellular responses by binding to TGFβ receptor type II (TβRII) and type I (TβRI) serine/threonine kinases, whereby Smad2 and Smad3 are phosphorylated and activated, promoting their association with Smad4. We report here that TβRI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGFβ stimulation in a TRAF6-dependent manner. Small interfering RNA–mediated knockdown of CIN85 resulted in accumulation of TβRI in intracellular compartments and diminished TGFβ-stimulated Smad2 phosphorylation. Overexpression of CIN85 instead increased the amount of TβRI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGFβ receptors. CIN85 enhanced TGFβ-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGFβ receptors and thereby positively regulates TGFβ signaling.

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

2007 ◽  
Vol 292 (2) ◽  
pp. L537-L549 ◽  
Author(s):  
Miguel A. Alejandre-Alcázar ◽  
Grazyna Kwapiszewska ◽  
Irwin Reiss ◽  
Oana V. Amarie ◽  
Leigh M. Marsh ◽  
...  
Keyword(s):  
Bronchopulmonary Dysplasia ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Lung Epithelial Cells ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii

Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O2 between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O2, and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-β type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-β signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O2 as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O2. After exposure to 85% O2, primary alveolar type II cells were more susceptible to TGF-β-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O2 significantly enhanced the TGF-β-stimulated production of the α1 subunit of type I collagen (Iα1), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-β/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.

scholarly journals Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin.

1994 ◽  
Vol 14 (6) ◽  
pp. 3810-3821 ◽  
Author(s):  
J Cárcamo ◽  
F M Weis ◽  
F Ventura ◽  
R Wieser ◽  
J L Wrana ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Amino Acid Sequence Identity ◽  
Transforming Growth Factor ◽  
Type I ◽  
Type Ii ◽  
Tgf Beta ◽  
Transcriptional Responses ◽  
Receptor Complexes ◽  
Growth Inhibitory ◽  
Growth Factor Beta

Transforming growth factor beta (TGF-beta) and activin bind to receptor complexes that contain two distantly related transmembrane serine/threonine kinases known as receptor types I and II. The type II receptors determine ligand binding specificity, and each interacts with a distinct repertoire of type I receptors. Here we identify a new type I receptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. ActR-IB has the structural and binding properties of a type I receptor: it binds activin only in the presence of an activin type II receptor and forms a heteromeric noncovalent complex with activin type II receptors. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a common set of growth-inhibitory and transcriptional responses in association with their corresponding ligands and type II receptors. The transcriptional responses include elevated expression of fibronectin and plasminogen activator inhibitor 1. Although T beta R-I and ActR-IB are nearly identical in their kinase domains (90% amino acid sequence identity), their corresponding type II receptor kinase domains are very different from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin correlates with the presence of similar type I kinases in their complex. Indeed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) whose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, we conclude that the type I receptor subunits are primary specifiers of signals sent by TGF-beta and activin receptor complexes.

scholarly journals The TGFβ type I receptor TGFβRI functions as an inhibitor of BMP signaling in cartilage

2019 ◽  
Vol 116 (31) ◽  
pp. 15570-15579 ◽  
Author(s):  
Weiguang Wang ◽  
Hyelim Chun ◽  
Jongseung Baek ◽  
Joshua Elyahu Sadik ◽  
Anna Shirazyan ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bmp Signaling ◽  
Type I ◽  
Type Ii ◽  
Tgfβ Signaling ◽  
Major Function ◽  
High Affinity ◽  
Bmp Receptor ◽  
Tgfβ Receptor ◽  
Intracellular Mediators

The type I TGFβ receptor TGFβRI (encoded by Tgfbr1) was ablated in cartilage. The resulting Tgfbr1Col2 mice exhibited lethal chondrodysplasia. Similar defects were not seen in mice lacking the type II TGFβ receptor or SMADs 2 and 3, the intracellular mediators of canonical TGFβ signaling. However, we detected elevated BMP activity in Tgfbr1Col2 mice. As previous studies showed that TGFβRI can physically interact with ACVRL1, a type I BMP receptor, we generated cartilage-specific Acvrl1 (Acvrl1Col2) and Acvrl1/Tgfbr1 (Acvrl1/Tgfbr1Col2) knockouts. Loss of ACVRL1 alone had no effect, but Acvrl1/Tgfbr1Col2 mice exhibited a striking reversal of the chondrodysplasia seen in Tgfbr1Col2 mice. Loss of TGFβRI led to a redistribution of the type II receptor ACTRIIB into ACVRL1/ACTRIIB complexes, which have high affinity for BMP9. Although BMP9 is not produced in cartilage, we detected BMP9 in the growth plate, most likely derived from the circulation. These findings demonstrate that the major function of TGFβRI in cartilage is not to transduce TGFβ signaling, but rather to antagonize BMP signaling mediated by ACVRL1.

scholarly journals Utilizing the ABC Transporter for Growth Factor Production by fleQ Deletion Mutant of Pseudomonas fluorescens

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 679
Author(s):  
Benedict-Uy Fabia ◽  
Joshua Bingwa ◽  
Jiyeon Park ◽  
Nguyen-Mihn Hieu ◽  
Jung-Hoon Ahn
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Pseudomonas Fluorescens ◽  
Abc Transporter ◽  
Transforming Growth Factor Beta ◽  
Deletion Mutant ◽  
Transforming Growth Factor ◽  
Gene Knockout ◽  
Type I ◽  
Double Deletion

Pseudomonas fluorescens, a gram-negative bacterium, has been proven to be a capable protein manufacturing factory (PMF). Utilizing its ATP-binding cassette (ABC) transporter, a type I secretion system, P. fluorescens has successfully produced recombinant proteins. However, besides the target proteins, P. fluorescens also secretes unnecessary background proteins that complicate protein purification and other downstream processes. One of the background proteins produced in large amounts is FliC, a flagellin protein. In this study, the master regulator of flagella gene expression, fleQ, was deleted from P. fluorescens Δtp, a lipase and protease double-deletion mutant, via targeted gene knockout. FleQ directs flagella synthesis, so the new strain, P. fluorescens ΔfleQ, does not produce flagella-related proteins. This not only simplifies purification but also makes P. fluorescens ΔfleQ an eco-friendly expression host because it will not survive outside a controlled environment. Six recombinant growth factors, namely, insulin-like growth factors I and II, beta-nerve growth factor, fibroblast growth factor 1, transforming growth factor beta, and tumor necrosis factor beta, prepared using our supercharging method, were successfully secreted by P. fluorescens ΔfleQ. Our findings demonstrate the potential of P. fluorescens ΔfleQ, combined with our supercharging process, as a PMF.

scholarly journals Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher Agnew ◽  
Pelin Ayaz ◽  
Risa Kashima ◽  
Hanna S. Loving ◽  
Prajakta Ghatpande ◽  
...  
Keyword(s):  
Md Simulations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Type I ◽  
Type Ii ◽  
Exchange Mass Spectrometry ◽  
Receptor Complexes ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Smad Proteins

AbstractUpon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

Sign in / Sign up

Export Citation Format

Share Document