scholarly journals The Serine/Threonine Transmembrane Receptor ALK2 Mediates Müllerian Inhibiting Substance Signaling

2001 ◽  
Vol 15 (6) ◽  
pp. 936-945 ◽  
Author(s):  
Jenny A. Visser ◽  
Robert Olaso ◽  
Miriam Verhoef-Post ◽  
Piet Kramer ◽  
Axel P. N. Themmen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Effector Proteins ◽  
Dominant Negative ◽  
Type I ◽  
Type Ii ◽  
Morphogenetic Protein ◽  
Gene Assay

Abstract Müllerian inhibiting substance (MIS or anti-Müllerian hormone) is a member of the transforming growth factor-β family and plays a pivotal role in proper male sexual differentiation. Members of this family signal by the assembly of two related serine/threonine kinase receptors, referred to as type I or type II receptors, and downstream cytoplasmic Smad effector proteins. Although the MIS type II receptor (MISRII) has been identified, the identity of the type I receptor is unclear. Here we report that MIS activates a bone morphogenetic protein-like signaling pathway, which is solely dependent on the presence of the MISRII and bioactive MIS ligand. Among the multiple type I candidates tested, only ALK2 resulted in significant enhancement of the MIS signaling response. Furthermore, dominant-negative and antisense strategies showed that ALK2 is essential for MIS-induced signaling in two independent assays, the cellular Tlx-2 reporter gene assay and the Müllerian duct regression organ culture assay. In contrast, ALK6, the other candidate MIS type I receptor, was not required. Expression analyses revealed that ALK2 is present in all MIS target tissues including the mesenchyme surrounding the epithelial Müllerian duct. Collectively, we conclude that MIS employs a bone morphogenetic protein-like signaling pathway and uses ALK2 as its type I receptor. The use of this ubiquitously expressed type I receptor underscores the role of the MIS ligand and the MIS type II receptor in establishing the specificity of the MIS signaling cascade.

Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation

1999 ◽  
Vol 112 (20) ◽  
pp. 3519-3527 ◽  
Author(s):  
T. Ebisawa ◽  
K. Tada ◽  
I. Kitajima ◽  
K. Tojo ◽  
T.K. Sampath ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Transforming Growth Factor ◽  
C2c12 Cells ◽  
Nuclear Accumulation ◽  
Type I ◽  
Type Ii ◽  
Weakly Bound ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Bone morphogenetic protein (BMP)-6 is a member of the transforming growth factor (TGF)-(β) superfamily, and is most similar to BMP-5, osteogenic protein (OP)-1/BMP-7, and OP-2/BMP-8. In the present study, we characterized the endogenous BMP-6 signaling pathway during osteoblast differentiation. BMP-6 strongly induced alkaline phosphatase (ALP) activity in cells of osteoblast lineage, including C2C12 cells, MC3T3-E1 cells, and ROB-C26 cells. The profile of binding of BMP-6 to type I and type II receptors was similar to that of OP-1/BMP-7 in C2C12 cells and MC3T3-E1 cells; BMP-6 strongly bound to activin receptor-like kinase (ALK)-2 (also termed ActR-I), together with type II receptors, i.e. BMP type II receptor (BMPR-II) and activin type II receptor (ActR-II). In addition, BMP-6 weakly bound to BMPR-IA (ALK-3), to which BMP-2 also bound. In contrast, binding of BMP-6 to BMPR-IB (ALK-6), and less efficiently to ALK-2 and BMPR-IA, together with BMPR-II was detected in ROB-C26 cells. Intracellular signalling was further studied using C2C12 and MC3T3-E1 cells. Among the receptor-regulated Smads activated by BMP receptors, BMP-6 strongly induced phosphorylation and nuclear accumulation of Smad5, and less efficiently those of Smad1. However, Smad8 was constitutively phosphorylated, and no further phosphorylation or nuclear accumulation of Smad8 by BMP-6 was observed. These findings indicate that in the process of differentiation to osteoblasts, BMP-6 binds to ALK-2 as well as other type I receptors, and transduces signals mainly through Smad5 and possibly through Smad1.

scholarly journals Integrin β1Signaling Is Necessary for Transforming Growth Factor-β Activation of p38MAPK and Epithelial Plasticity

2001 ◽  
Vol 276 (50) ◽  
pp. 46707-46713 ◽  
Author(s):  
Neil A. Bhowmick ◽  
Roy Zent ◽  
Mayshan Ghiassi ◽  
Maureen McDonnell ◽  
Harold L. Moses
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Type I ◽  
Type Ii

Transforming growth factor-β (TGF-β) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-β-meditated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-β regulation of various β1integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-β and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-β type II receptor, we blocked TGF-β-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-β type II receptor expression inhibited TGF-β signaling to the SMAD and AKT pathways, but did not block TGF-β-mediated p38MAPK activation. Interestingly, blocking integrin β1function inhibited TGF-β-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-β-mediated EMT. In summary, TGF-β-mediated p38MAPK activation is dependent on functional integrin β1, and p38MAPK activity is required but is not sufficient to induce EMT.

scholarly journals Smad6 Recruits Transcription Corepressor CtBP To Repress Bone Morphogenetic Protein-Induced Transcription

2003 ◽  
Vol 23 (24) ◽  
pp. 9081-9093 ◽  
Author(s):  
Xia Lin ◽  
Yao-Yun Liang ◽  
Baohua Sun ◽  
Min Liang ◽  
Yujiang Shi ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Feedback Mechanism ◽  
Binding Motif ◽  
Physical Interaction ◽  
Type I ◽  
Negative Feedback Mechanism ◽  
Morphogenetic Protein ◽  
Repressor Activity

ABSTRACT Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor β-Smad signal transduction pathways in a negative-feedback mechanism. Previously it has been thought that inhibitory Smads bind to the type I receptor and block the phosphorylation of receptor-activated Smads, thereby inhibiting the initiation of Smad signaling. Conversely, few studies have suggested the possible nuclear functions of inhibitory Smads. Here, we present compelling evidence demonstrating that Smad6 repressed bone morphogenetic protein-induced Id1 transcription through recruiting transcriptional corepressor C-terminal binding protein (CtBP). A consensus CtBP-binding motif, PLDLS, was identified in the linker region of Smad6. Our findings show that mutation in the motif abolished the Smad6 binding to CtBP and subsequently its repressor activity of transcription. We conclude that the nuclear functions and physical interaction of Smad6 and CtBP provide a novel mechanism for the transcriptional regulation by inhibitory Smads.

scholarly journals Myostatin Signals through a Transforming Growth Factor β-Like Signaling Pathway To Block Adipogenesis

2003 ◽  
Vol 23 (20) ◽  
pp. 7230-7242 ◽  
Author(s):  
A. Rebbapragada ◽  
H. Benchabane ◽  
J. L. Wrana ◽  
A. J. Celeste ◽  
L. Attisano
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Signal Transduction Pathway ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Type I ◽  
Type Ii ◽  
Transduction Pathway

ABSTRACT Myostatin, a transforming growth factor β (TGF-β) family member, is a potent negative regulator of skeletal muscle growth. In this study we characterized the myostatin signal transduction pathway and examined its effect on bone morphogenetic protein (BMP)-induced adipogenesis. While both BMP7 and BMP2 activated transcription from the BMP-responsive I-BRE-Lux reporter and induced adipogenic differentiation, myostatin inhibited BMP7- but not BMP2-mediated responses. To dissect the molecular mechanism of this antagonism, we characterized the myostatin signal transduction pathway. We showed that myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TβRI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-β-like signaling pathway. We demonstrated that myostatin prevents BMP7 but not BMP2 binding to its receptors and that BMP7-induced heteromeric receptor complex formation is blocked by competition for the common type II receptor, ActRIIB. Thus, our results reveal a strikingly specific antagonism of BMP7-mediated processes by myostatin and suggest that myostatin is an important regulator of adipogenesis.

scholarly journals mRNA expression of type I and type II receptors for activin, transforming growth factor-beta, and bone morphogenetic protein in the murine erythroleukemic cell line, F5-5.fl

2000 ◽  
pp. 705-710 ◽  
Author(s):  
H Machida ◽  
K Ogawa ◽  
M Funaba ◽  
T Mizutani ◽  
M Tsujimoto
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Type I ◽  
Type Ii ◽  
Tgf Beta ◽  
Morphogenetic Protein ◽  
Growth Factor Beta

OBJECTIVE: Intracellular signaling of activin and transforming growth factor-beta (TGF-beta) is thought to be mediated by the same molecules (Smad2/3 and Smad4). Although differentiation of murine erythroleukemia F5-5.fl cells is induced by activin, it is not induced by TGF-beta, suggesting that at some point TGF-beta signaling is defective. The aim of this study was to investigate the unresponsiveness of F5-5.fl cells to TGF-beta. DESIGN: mRNA expression of ligands, receptors, and signal mediators for the TGF-beta family was examined in F5-5.fl cells using RT-PCR. RESULTS: Activin induced erythrodifferentiation of F5-5.fl cells in a dose-dependent manner. Neither TGF-beta1 nor bone morphogenetic protein (BMP)-4 affected the differentiation of F5-5.fl cells in the presence or absence of activin. Although mRNAs of TGF-betas (TGF-beta1, TGF-beta2 and TGF-beta3) were detected, those of inhibin/activin (alpha-, betaA- and betaB-subunits) and BMPs (BMP-2, BMP-4 and BMP-7) could not be detected in the cells, suggesting that neither activins nor BMPs are produced in F5-5.fl cells. The expression of both type I (ALK-4/ActRIB) and type II (ActRII) receptors for activin was detected in F5-5.fl cells. In contrast, while the expression of type I receptor for TGF-beta (ALK-5/TbetaRI) was detected, that of type II receptor (TbetaRII) was not. The mRNA of all Smads examined was detected in F5-5.fl cells. CONCLUSIONS: A defect in the type II receptor might cause unresponsiveness to TGF-beta in F5-5.fl cells. An erythrodifferentiation assay using F5-5.fl cells would be useful for measuring net activin activity because it would not be necessary to consider endogenous activins and BMPs.

The bone morphogenetic protein system and the regulation of ovarian follicle development in mammals

Zygote ◽  
2015 ◽  
Vol 24 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Rodrigo O.D.S. Rossi ◽  
José J.N. Costa ◽  
Anderson W.B. Silva ◽  
Márcia V.A. Saraiva ◽  
Robert Van den Hurk ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Ovarian Follicle ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Serine Threonine Kinase ◽  
Ovarian Follicle Development ◽  
Functional Studies ◽  
Morphogenetic Protein

SummaryThe bone morphogenetic protein (BMP) family consists of several growth factor proteins that belong to the transforming growth factor-β (TGF-β) superfamily. BMPs bind to type I and type II serine–threonine kinase receptors, and transduce signals through the Smad signalling pathway. BMPs have been identified in mammalian ovaries, and functional studies have shown that they are involved in the regulation of oogenesis and folliculogenesis. This review summarizes the role of the BMP system during formation, growth and maturation of ovarian follicles in mammals.

scholarly journals Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

2007 ◽  
Vol 38 (2) ◽  
pp. 315-330 ◽  
Author(s):  
Katharine B Lee ◽  
Vishal Khivansara ◽  
Michelle M Santos ◽  
Pankaj Lamba ◽  
Tony Yuen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Mrna Levels ◽  
Signaling Mechanism ◽  
Morphogenetic Protein

Transforming growth factor β superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LβT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LβT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LβT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other’s effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2’s effects. In summary, BMPs regulate Fshb transcription in LβT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.

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