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Results: 11 to 19 of 19

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Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility.
Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL
(2004) J Biol Chem 279: 24505-13
MeSH Terms: Actins, Activin Receptors, Type I, Adenoviridae, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Blotting, Northern, Breast Neoplasms, Bromodeoxyuridine, Butadienes, Cell Cycle, Cell Division, Cell Line, Cell Line, Tumor, Cell Movement, Chromones, DNA, Complementary, Disease Progression, Enzyme Inhibitors, Epithelial Cells, Gene Expression Regulation, Genes, Reporter, Green Fluorescent Proteins, Humans, Imidazoles, Immunoblotting, Integrin beta1, Ligands, Luminescent Proteins, Microscopy, Fluorescence, Models, Genetic, Morpholines, Nitriles, Phosphatidylinositol 3-Kinases, Precipitin Tests, Protein-Serine-Threonine Kinases, Pseudopodia, Pyridines, Receptor, ErbB-2, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Retroviridae, Signal Transduction, Transcription, Genetic, Transforming Growth Factor beta, Trastuzumab, Wound Healing, rac1 GTP-Binding Protein
Show Abstract · Added March 5, 2014
We have examined overexpression of the human epidermal growth factor receptor 2 (HER2) to determine if it modifies the anti-proliferative effect of transforming growth factor (TGF)-beta against MCF-10A human mammary epithelial cells. Exogenous TGF-beta inhibited cell proliferation and induced Smad-dependent transcriptional reporter activity in both MCF-10A/HER2 and MCF-10A/vector control cells. Ligand-induced reporter activity was 7-fold higher in HER2-overexpressing cells. In wound closure and transwell assays, TGF-beta induced motility of HER2-transduced, but not control cells. The HER2-blocking antibody trastuzumab (Herceptin) prevented TGF-beta-induced cell motility. Expression of a constitutively active TGF-beta type I receptor (ALK5(T204D)) induced motility of MCF-10A/HER2 but not MCF-10A/vector cells. TGF-beta-induced motility was blocked by coincubation with either the phosphatidylinositol 3-kinase inhibitor LY294002, the mitogen-activated protein kinase (MAPK) inhibitor U0126, the p38 MAPK inhibitor SB202190, and an integrin beta(1) blocking antibody. Rac1 activity was higher in HER2-overexpressing cells, where both Rac1 and Pak1 proteins were constitutively associated with HER2. Both exogenous TGF-beta and transduction with constitutively active ALK5 enhanced this association. TGF-beta induced actin stress fibers as well as lamellipodia within the leading edge of wounds. Herceptin blocked basal and TGF-beta-stimulated Rac1 activity but did not repress TGF-beta-stimulated transcriptional reporter activity. These data suggest that 1) overexpression of HER2 in nontumorigenic mammary epithelial is permissive for the ability of TGF-beta to induce cell motility and Rac1 activity, and 2) HER2 and TGF-beta signaling cooperate in the induction of cellular events associated with tumor progression.
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47 MeSH Terms
Transforming growth factor beta (TGFbeta ) signaling via differential activation of activin receptor-like kinases 2 and 5 during cardiac development. Role in regulating parasympathetic responsiveness.
Ward SM, Desgrosellier JS, Zhuang X, Barnett JV, Galper JB
(2002) J Biol Chem 277: 50183-9
MeSH Terms: Activin Receptors, Type I, Alkaline Phosphatase, Animals, Blotting, Western, Chick Embryo, Enzyme Activation, Gene Expression Regulation, Developmental, Genes, Reporter, Heart, Luciferases, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases, Proteins, RNA, Messenger, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Ribonucleases, Signal Transduction, Time Factors, Transforming Growth Factor beta
Show Abstract · Added February 21, 2016
Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 days in ovo, transforming growth factor beta (TGFbeta) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of Galpha(i2). Here in atrial cells 5 days in ovo, TGFbeta increased carbamylcholine inhibition of beat rate 2.5-fold and increased expression of Galpha(i2). TGFbeta also stimulated Galpha(i2) mRNA expression and promoter activity at day 5 while inhibiting them at day 14 in ovo. Over the same time course expression of type I TGFbeta receptors, chick activin receptor-like kinase 2 and 5 increased with a 2.3-fold higher increase in activin receptor-like kinase 2. Constitutively active activin receptor-like kinase 2 inhibited Galpha(i2) promoter activity, whereas constitutively active activin receptor-like kinase 5 stimulated Galpha(i2) promoter activity independent of embryonic age. In 5-day atrial cells, TGFbeta stimulated the p3TP-lux reporter, which is downstream of activin receptor-like kinase 5 and had no effect on the activity of the pVent reporter, which is downstream of activin receptor-like kinase 2. In 14-day cells, TGFbeta stimulated both pVent and p3TP-lux. Thus TGFbeta exerts opposing effects on parasympathetic response and Galpha(i2) expression by activating different type I TGFbeta receptors at distinct stages during cardiac development.
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20 MeSH Terms
The novel type I serine-threonine kinase receptor Alk8 binds TGF-beta in the presence of TGF-betaRII.
de Caestecker MP, Bottomley M, Bhattacharyya S, Payne TL, Roberts AB, Yelick PC
(2002) Biochem Biophys Res Commun 293: 1556-65
MeSH Terms: Activin Receptors, Type I, Amino Acid Sequence, Animals, Blotting, Northern, Blotting, Western, Bone Morphogenetic Proteins, Cell Line, Cross-Linking Reagents, Humans, In Situ Hybridization, Ligands, Luciferases, Mice, Molecular Sequence Data, Mutation, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tissue Distribution, Transforming Growth Factor beta, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 5, 2011
The TGF-beta superfamily consists of an array of ligands including BMP, TGF-beta, activin, and nodal subfamilies. The extensive range of biological effects elicited by TGF-beta family signaling is due in part to the large numbers and promiscuity of types I and II TGF-beta family member receptors. Alk8 is a novel type I TGF-beta family member receptor first identified in zebrafish [Dev. Dyn. 211 (4) (1998) 352], which participates in BMP signaling pathways [Development 128 (6) (2001) 849; Development 128 (6) (2001) 859; Mech. Dev. 100 (2) (2001) 275; J. Dent. Res. 80 (11) (2001) 1968]. Here we report that Alk8 also forms active signaling complexes with TGF-beta in the presence of TGF-betaRII. These results expand the signaling repertoire of zAlk8 by demonstrating an ability to participate in two distinct TGF-beta subfamily signaling pathways.
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27 MeSH Terms
Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension.
De Caestecker M, Meyrick B
(2001) Respir Res 2: 193-7
MeSH Terms: Activin Receptors, Type I, Bone Morphogenetic Protein Receptors, Type I, Bone Morphogenetic Protein Receptors, Type II, Bone Morphogenetic Proteins, Humans, Hypertension, Pulmonary, Mutation, Protein-Serine-Threonine Kinases, Receptors, Growth Factor
Show Abstract · Added January 5, 2011
Several recent papers have shown that both familial primary pulmonary hypertension (FPPH) and sporadic primary pulmonary hypertension (PPH) may have a common etiology that is associated with the inheritance and/or spontaneous development of germline mutations in the bone morphogenetic protein receptor (BMPR) type II gene. Because BMPR-II is a ubiquitously expressed receptor for a family of secreted growth factors known as the bone morphogenetic proteins (BMPs), these findings suggest that BMPs play an important role in the maintenance of normal pulmonary vascular physiology. In the present commentary we discuss the implications of these findings in the context of BMP receptor biology, and relate these data to the genetics and pulmonary pathophysiology of patients with PPH.
2 Communities
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9 MeSH Terms
Zebrafish nma is involved in TGFbeta family signaling.
Tsang M, Kim R, de Caestecker MP, Kudoh T, Roberts AB, Dawid IB
(2000) Genesis 28: 47-57
MeSH Terms: Activin Receptors, Type I, Amino Acid Sequence, Animals, Body Patterning, Bone Morphogenetic Proteins, Embryo, Nonmammalian, Female, Gene Expression Regulation, Developmental, In Situ Hybridization, Membrane Proteins, Microinjections, Molecular Sequence Data, Mutation, Protein-Serine-Threonine Kinases, RNA, Radiation Hybrid Mapping, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Sequence Homology, Amino Acid, Signal Transduction, Xenopus, Xenopus Proteins, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 5, 2011
Bone morphogenetic proteins (BMP) are members of the TGFbeta superfamily of secreted factors with important regulatory functions during embryogenesis. We have isolated the zebrafish gene, nma, that encodes a protein with high sequence similarity to human NMA and Xenopus Bambi. It is also similar to TGFbeta type I serine/theronine kinase receptors in the extracellular ligand-binding domain but lacks a cytoplasmic kinase domain. During development, nma expression is similar to that of bmp2b and bmp4, and analysis in the dorsalized and ventralized zebrafish mutants swirl and chordino indicates that nma is regulated by BMP signaling. Overexpression of nma during zebrafish and Xenopus development resulted in phenotypes that appear to be based on inhibition of BMP signaling. Biochemically, NMA can associate with TGFbeta type II receptors and bind to TGFbeta ligand. We propose that nma is a BMP-regulated gene whose function is to attenuate BMP signaling during development through interactions with type II receptors and ligands.
2 Communities
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25 MeSH Terms
Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation.
Lai YT, Beason KB, Brames GP, Desgrosellier JS, Cleggett MC, Shaw MV, Brown CB, Barnett JV
(2000) Dev Biol 222: 1-11
MeSH Terms: Activin Receptors, Type II, Amino Acid Sequence, Animals, Atrioventricular Node, Base Sequence, COS Cells, Chick Embryo, DNA Primers, DNA, Complementary, Immune Sera, Molecular Sequence Data, Morphogenesis, Protein-Serine-Threonine Kinases, Receptors, Growth Factor, Sequence Homology, Amino Acid
Show Abstract · Added February 21, 2016
Epithelial-mesenchymal transformation in the atrioventricular (AV) cushion of the tubular heart is a critical step in the formation of the valves and membranous septa. Transforming growth factor beta (TGFbeta) ligands are a primary signal of this transformation. To investigate the expression and function of specific Type I TGFbeta receptors during AV cushion transformation, we cloned and characterized the chicken homologues of two mammalian activin receptor-like kinases (ALK), ALK2 and ALK5, and generated specific, polyclonal antibodies against the extracellular binding domains of each. Both the chicken ALK2 (ChALK2) and the chicken ALK5 (ChALK5) cDNAs encode proteins that bind TGFbeta1 in the presence of the Type II TGFbeta receptor. However, as expected, only ChALK5 stimulated the TGFbeta-responsive PAI-1 promoter. These data establish that ChALK2 and ChALK5 are the chicken homologues of the mammalian receptors ALK2 and ALK5. Both ChALK2 and ChALK5 are expressed by AV endocardial cells. AV cushion explants harvested from stage 13-18 embryos were incubated with antisera to ChALK2 or ChALK5. Anti-ChALK2 antisera inhibited mesenchyme formation by 34-50% while neutralizing anti-ChALK5 antisera were without effect. These data demonstrate that ChALK2 can mediate transformation in the AV cushion.
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15 MeSH Terms
CBFa(AML/PEBP2)-related elements in the TGF-beta type I receptor promoter and expression with osteoblast differentiation.
Ji C, Casinghino S, Chang DJ, Chen Y, Javed A, Ito Y, Hiebert SW, Lian JB, Stein GS, McCarthy TL, Centrella M
(1998) J Cell Biochem 69: 353-63
MeSH Terms: Activin Receptors, Type I, Animals, Binding Sites, Cell Differentiation, Cells, Cultured, Core Binding Factor Alpha 1 Subunit, Neoplasm Proteins, Osteoblasts, Phenotype, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Transcription Factors
Show Abstract · Added June 10, 2010
Organization of the transforming growth factor-beta (TGF-beta) type I receptor (TRI) promoter predicts constitutive transcription, although its activity increases with differentiation status in cultured osteoblasts. Several sequences in the rat TRI promoter comprise cis-acting elements for CBFa (AML/PEBP2alpha) transcription factors. By gel mobility shift and immunological analyses, a principal osteoblast-derived nuclear factor that binds to these sites is CBFa1 (AML-3/PEBP2alphaA). Rat CBFa1 levels parallel expression of the osteoblast phenotype and increase under conditions that promote mineralized bone nodule formation in vitro. Fusion of CBFa binding sequence from the TRI promoter to enhancer-free transfection vector increases reporter gene expression in cells that possess abundant CBFa1, and overexpression of CBFa increase the activity of transfected native TRI promoter/reporter plasmid. Consequently, phenotype-restricted use of cis-acting elements for CBFa transcription factors can contribute to the high levels of TRI that parallel osteoblast differentiation and to the potent effects of TGF-beta on osteoblast function.
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16 MeSH Terms
Characterization of the interaction of FKBP12 with the transforming growth factor-beta type I receptor in vivo.
Okadome T, Oeda E, Saitoh M, Ichijo H, Moses HL, Miyazono K, Kawabata M
(1996) J Biol Chem 271: 21687-90
MeSH Terms: Activin Receptors, Type I, Alkyl and Aryl Transferases, Amino Acid Isomerases, Base Sequence, Carrier Proteins, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Gene Amplification, HeLa Cells, Heat-Shock Proteins, Humans, Molecular Sequence Data, Phosphorylation, Point Mutation, Polymerase Chain Reaction, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Tacrolimus, Tacrolimus Binding Proteins, Transferases
Show Abstract · Added May 27, 2014
The type I transforming growth factor-beta receptor (TbetaR-I) is the efferent component of the receptor complex, which presumably phosphorylates intracellular targets. FKBP12, a binding protein for FK506 and rapamycin, is shown to associate with the cytoplasmic region of TbetaR-I in vitro. In this report, we investigated the interaction of FKBP12 with TbetaR-I in vivo. FKBP12 interacts with TbetaR-I in mammalian cells as well as in yeast. Ligand addition does not affect the interaction, and both constitutively active and kinase-negative mutants of TbetaR-I bind FKBP12. FKBP12 dissociates from TbetaR-I in the presence of a high concentration of FK506. The juxtamembrane region of TbetaR-I, containing the major phosphorylation sites by the type II receptor, is required for the interaction. One of the deletion mutants in this region, which was shown to mediate transcriptional response, does not bind FKBP12, suggesting that FKBP12 is not directly involved in TGF-beta signaling. Furthermore TbetaR-I does not phosphorylate FKBP12 in vitro. FKBP12 may not be a direct substrate of TbetaR-I but possibly modulates the TbetaR-I function through its interaction with the regulatory domain of the kinase.
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21 MeSH Terms
Interaction of the transforming growth factor-beta type I receptor with farnesyl-protein transferase-alpha.
Kawabata M, Imamura T, Miyazono K, Engel ME, Moses HL
(1995) J Biol Chem 270: 29628-31
MeSH Terms: Activin Receptors, Type I, Alkyl and Aryl Transferases, Glutathione Transferase, HeLa Cells, Humans, Kinetics, Mutagenesis, Site-Directed, Phosphorylation, Point Mutation, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Recombinant Fusion Proteins, Transferases, beta-Galactosidase
Show Abstract · Added February 17, 2014
Transforming growth factor-beta 1 (TGF-beta 1) is the prototype of a large family of molecules that regulate a variety of biological processes. The type I (T beta R-I) and type II (T beta R-II) receptors for TGF-beta 1 are transmembrane serine/threonine kinases, forming a heteromeric signaling complex. Recent studies have shown that T beta R-II is a constitutively active kinase and phosphorylates T beta R-I upon ligand binding, suggesting that T beta R-I is the effector subunit of the receptor complex, which transduces signals to intracellular targets. This model has been further confirmed by the identification of constitutively active T beta R-I that mediates TGF-beta 1-specific cellular responses in the absence of ligand and T beta R-II. To investigate signaling by TGF-beta 1, we have sought to isolate proteins that interact with the cytoplasmic region of T beta R-I. One of the proteins identified was the alpha subunit of farnesyl-protein transferase (FT alpha) that modifies a series of peptides including Ras. T beta R-I specifically interacts with FT alpha in the yeast two-hybrid system. Glutathione S-transferase-T beta R-I fusion proteins bind FT alpha translated in vitro. T beta R-I also phosphorylates FT alpha. We further show that the constitutively active T beta R-I interacted with FT alpha very strongly whereas an inactive form of T beta R-I did not. These results suggest that FT alpha may be one of the substrates of the activated T beta R-I kinase.
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15 MeSH Terms