The Experts below are selected from a list of 15966 Experts worldwide ranked by ideXlab platform
Wylie Vale - One of the best experts on this subject based on the ideXlab platform.
-
cell type specific modulation of pituitary cells by Activin inhibin and follistatin
Molecular and Cellular Endocrinology, 2012Co-Authors: Louise M. Bilezikjian, Ezra Wiater, Nicholas J Justice, Alissa N Blackler, Wylie ValeAbstract:Activins are multifunctional proteins and members of the TGF-β superfamily. Activins are expressed locally in most tissues and, analogous to the actions of other members of this large family of pleiotropic factors, play prominent roles in the regulation of diverse biological processes in both differentiated and embryonic stem cells. They have an essential role in maintaining tissue homeostasis in the adult and are known to contribute to the developmental programs in the embryo. Activins are further implicated in the growth and metastasis of tumor cells. Through distinct modes of action, inhibins and follistatins function as antagonists of Activin and several other TGF-β family members, including a subset of BMPs/GDFs, and modulate cellular responses and the signaling cascades downstream of these ligands. In the pituitary, the Activin pathway is known to regulate key aspects of gonadotrope functions and also exert effects on other pituitary cell types. As in other tissues, Activin is produced locally by pituitary cells and acts locally by exerting cell-type specific actions on gonadotropes. These local actions of Activin on gonadotropes are modulated by the autocrine/paracrine actions of locally secreted follistatin and by the feedback actions of gonadal inhibin. Knowledge about the mechanism of Activin, inhibin and follistatin actions is providing information about their importance for pituitary function as well as their contribution to the pathophysiology of pituitary adenomas. The aim of this review is to highlight recent findings and summarize the evidence that supports the important functions of Activin, inhibin and follistatin in the pituitary.
-
Activin a bone morphogenetic protein bmp chimeras exhibit bmp like activity and antagonize Activin and myostatin
Journal of Biological Chemistry, 2008Co-Authors: Radhika V Korupolu, Wylie Vale, Uwe Muenster, Jessica Read, Wolfgang H. FischerAbstract:Activins and bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta family of growth and differentiation factors that induce signaling in target cells by assembling type II and type I receptors at the cell surface. Ligand residues involved in type II binding are located predominantly in the C-terminal region that forms an extended beta-sheet, whereas residues involved in type I binding are located in the alpha-helical and preceding loop central portion of the molecule. To test whether the central residues are sufficient to determine specificity toward type I receptors, Activin A/BMP chimeras were constructed in which the central residues (45-79) of Activin A were replaced with corresponding residues of BMP2 and BMP7. The chimeras were assessed for Activin type II receptor (Act RII) binding, Activin-like bioactivity, and BMP-like activity as well as antagonistic properties toward Activin A and myostatin. ActA/BMP7 chimera retained Act RII binding affinity comparable with wild type Activin A, whereas ActA/BMP2 chimera showed a slightly reduced affinity toward Act RII. Both the chimeras were devoid of significant Activin bioactivity in 293T cells in the A3 Lux reporter assay up to concentrations 10-fold higher than the minimal effective Activin A concentration (approximately 4 nM). In contrast, these chimeras showed BMP-like activity in a BRE-Luc assay in HepG2 cells as well as induced osteoblast-like phenotype in C2C12 cells expressing alkaline phosphatase. Furthermore, both the chimeras activated Smad1 but not Smad2 in C2C12 cells. Also, both the chimeras antagonized ligands that signal via Activin type II receptor, such as Activin A and myostatin. These data indicate that Activin residues in the central region determine its specificity toward type I receptors. ActA/BMP chimeras can be useful in the study of receptor specificities and modulation of transforming growth factor-beta members, Activins, and BMPs.
-
Pituitary actions of ligands of the TGF-β family: Activins and inhibins
Reproduction, 2006Co-Authors: Louise M. Bilezikjian, Amy L Blount, Cindy Donaldson, Wylie ValeAbstract:: Activins, as members of the transforming growth factor-beta superfamily, control and orchestrate many physiological processes and are vital for the development, growth and functional integrity of most tissues, including the pituitary. Activins produced by pituitary cells work in conjunction with central, peripheral, and other local factors to influence the function of gonadotropes and maintain a normal reproductive axis. Follistatin, also produced by the pituitary, acts as a local buffer to bind Activin and modulate its bioactivity. On the other hand, inhibins of gonadal origin provide an endocrine feedback signal to antagonize Activin signaling in cells that express the inhibin co-receptor, betaglycan, such as gonadotropes. This review highlights the pituitary roles of Activin and the mechanisms through which these actions are modulated by inhibin and follistatin.
-
antagonists of Activin signaling mechanisms and potential biological applications
Trends in Endocrinology and Metabolism, 2005Co-Authors: Craig A. Harrison, Wylie Vale, Peter C. Gray, David RobertsonAbstract:Activins are members of the transforming growth factor-β (TGF-β) superfamily that control many physiological processes such as cell proliferation and differentiation, immune responses, wound repair and various endocrine activities. Activins elicit these diverse biological responses by signaling via type I and type II receptor serine kinases. Recent studies have revealed details of the roles of inhibin, betaglycan, follistatin and its related protein follistatin-related gene (FLRG), Cripto and BAMBI in antagonizing Activin action, and exogenous antagonists against the Activin type I (SB-431542 and SB-505124) and type II (Activin-M108A) receptors have been developed. Understanding how Activin signaling is controlled extracellularly is the first step in providing treatment for wound healing and for disorders such as cachexia and cancer, which result from a deregulated Activin pathway.
-
Activins and inhibins physiological roles signaling mechanisms and regulation
2005Co-Authors: Peter C. Gray, Craig A. Harrison, Ezra Wiater, Louise M. Bilezikjian, Wylie ValeAbstract:Activins and inhibins belong to the transforming growth factor β (TGFβ) superfamily, which also includes the TGF-β (Massague 1998), bone morphogenetic protein (BMP) (Wozney et al. 1988), growth and differentiation (GDF) and nodal-related families (Schier et al. 2000). In human there are now known to be 42 members of the TGF-β superfamily (reviewed in Shi et al. 2003). This review summarizes the physiological roles of Activins and inhibins, focusing on Activin actions in the central nervous system (CNS). In addition, we outline the molecular basis for Activin signal transduction and regulation, emphasizing recent advances regarding the structural basis for ligand/receptor interactions and the roles of betaglycan and Cripto in attenuating Activin signaling.
Martin M Matzuk - One of the best experts on this subject based on the ideXlab platform.
-
Activins and inhibins: novel regulators of thymocyte development.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Paula Licona-limón, Martin M Matzuk, Germán R. Alemán-muench, Jesús Chimal-monroy, Marina Macías-silva, Eduardo A. García-zepeda, Teresa I. Fortoul, Gloria SoldevilaAbstract:Activins and inhibins are members of the transforming growth factor-{beta} superfamily that act on different cell types and regulate a broad range of cellular processes including proliferation, differentiation, and apoptosis. Here, we provide the first evidence that Activins and inhibins regulate specific checkpoints during thymocyte development. We demonstrate that both Activin A and inhibin A promote the DN3-DN4 transition in vitro, although they differentially control the transition to the DP stage. Whereas Activin A induces the accumulation of a CD8{sup +}CD24{sup hi}TCR{beta}{sup lo} intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both Activin A and inhibin A appear to promote CD8{sup +}SP differentiation. Moreover, inhibin {alpha} null mice have delayed in vitro T cell development, showing both a decrease in the DN-DP transition and reduced thymocyte numbers, further supporting a role for inhibins in the control of developmental signals taking place during T cell differentiation in vivo.
-
Intraovarian Activins Are Required for Female Fertility
Molecular endocrinology (Baltimore Md.), 2007Co-Authors: Stephanie A. Pangas, Carolina J. Jorgez, Mai Tran, Julio E. Agno, Chester W. Brown, T. Rajendra Kumar, Martin M MatzukAbstract:Activins have diverse roles in multiple physiological processes including reproduction. Mutations and loss of heterozygosity at the human Activin receptor ACVR1B and ACVR2 loci are observed in pituitary, pancreatic, and colorectal cancers. Functional studies support intraovarian roles for Activins, although clarifying the in vivo roles has remained elusive due to the perinatal death of Activin βA knockout mice. To study the roles of Activins in ovarian growth, differentiation, and cancer, a tissue-specific knockout system was designed to ablate ovarian production of Activins. Mice lacking ovarian Activin βA were intercrossed to Inhbb homozygous null mice to produce double Activin knockouts. Whereas ovarian βA knockout females are subfertile, βB/βA double mutant females are infertile. Strikingly, the Activin βA and βB/βA-deficient ovaries contain increased numbers of functional corpora lutea but do not develop ovarian tumors. Microarray analysis of isolated granulosa cells identifies significant changes in...
-
Activins are critical modulators of growth and survival
Molecular Endocrinology, 2003Co-Authors: Chester W. Brown, Dianne E Houstonhawkins, Martin M MatzukAbstract:Activins betaA and betaB (encoded by Inhba and Inhbb genes, respectively) are related members of the TGF-beta superfamily. Previously, we generated mice with an Inhba knock-in allele (InhbaBK) that directs the expression of Activin betaB protein in the spatiotemporal pattern of Activin betaA. These mice were small and had shortened life spans, both influenced by the dose of the hypomorphic InhbaBK allele. To understand the mechanism(s) underlying these abnormalities, we now examine growth plates, liver, and kidney and analyze IGF-I, GH, and major urinary proteins. Our studies show that Activins modulate the biological effects of IGF-I without substantial effects on GH, and that Activin signaling deficiency also has modest effects on hepatic and renal function. To assess the relative influences of Activin betaA and Activin betaB, we produced mice that express Activin betaB from the InhbaBK allele, and not from its endogenous Inhbb locus. InhbaBK/BK, Inhbb-/- mice have failure of eyelid fusion at birth and demonstrate more severe effects on somatic growth and survival than either of the corresponding single homozygous mutants, showing that somatic growth and life span are supported by both Activins betaA and betaB, although Activin betaA plays a more substantial role.
-
follistatin is a modulator of gonadal tumor progression and the Activin induced wasting syndrome in inhibin deficient mice
Endocrinology, 2000Co-Authors: Sherry C Cipriano, Rajendra T Kumar, Lei Chen, Martin M MatzukAbstract:Inhibins and Activins are dimeric proteins belonging to the transforming growth factor-β superfamily. Follistatin is an Activin-binding protein that antagonizes the function of Activin via binding to its β-subunits. Previously, we demonstrated that mice deficient in inhibin develop ovarian and testicular sex cord-stromal tumors of granulosa and Sertoli cell origin, with 100% penetrance as early as 4 weeks of age. Overproduction of Activins in the serum directly causes a cachexia-like wasting syndrome that results in lethality of these mice at an early stage after the onset of the tumors. In an independent set of studies, overexpression of mouse follistatin using the mouse metallothionein I promoter in transgenic mice led to gonadal defects and eventual infertility, primarily due to local effects of follistatin in these tissues. Activin has a positive growth effect on gonadal tumor cells in culture and directly causes the cancer cachexia-like syndrome in inhibin-deficient mice via interaction with Activin ...
-
Activin signaling through Activin receptor type ii causes the cachexia like symptoms in inhibin deficient mice
Molecular Endocrinology, 1996Co-Authors: Katherine A Coerver, Jennie P. Mather, Teresa K. Woodruff, Allan Bradley, Milton J Finegold, Martin M MatzukAbstract:Activins and inhibins, members of the transforming growth factor-p superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in cY-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parieta1 cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant Activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibit+deficient mice secrete high levels of Activins. In addition, Northern blot analysis has localized Activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced Activins act through ActRll to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of Activin signaling through ActRll in viva, we generated compound homozygous mutant mice deficient in both cu-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of Activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of Activin signaling through ActRll
Louise M. Bilezikjian - One of the best experts on this subject based on the ideXlab platform.
-
cell type specific modulation of pituitary cells by Activin inhibin and follistatin
Molecular and Cellular Endocrinology, 2012Co-Authors: Louise M. Bilezikjian, Ezra Wiater, Nicholas J Justice, Alissa N Blackler, Wylie ValeAbstract:Activins are multifunctional proteins and members of the TGF-β superfamily. Activins are expressed locally in most tissues and, analogous to the actions of other members of this large family of pleiotropic factors, play prominent roles in the regulation of diverse biological processes in both differentiated and embryonic stem cells. They have an essential role in maintaining tissue homeostasis in the adult and are known to contribute to the developmental programs in the embryo. Activins are further implicated in the growth and metastasis of tumor cells. Through distinct modes of action, inhibins and follistatins function as antagonists of Activin and several other TGF-β family members, including a subset of BMPs/GDFs, and modulate cellular responses and the signaling cascades downstream of these ligands. In the pituitary, the Activin pathway is known to regulate key aspects of gonadotrope functions and also exert effects on other pituitary cell types. As in other tissues, Activin is produced locally by pituitary cells and acts locally by exerting cell-type specific actions on gonadotropes. These local actions of Activin on gonadotropes are modulated by the autocrine/paracrine actions of locally secreted follistatin and by the feedback actions of gonadal inhibin. Knowledge about the mechanism of Activin, inhibin and follistatin actions is providing information about their importance for pituitary function as well as their contribution to the pathophysiology of pituitary adenomas. The aim of this review is to highlight recent findings and summarize the evidence that supports the important functions of Activin, inhibin and follistatin in the pituitary.
-
Pituitary actions of ligands of the TGF-β family: Activins and inhibins
Reproduction, 2006Co-Authors: Louise M. Bilezikjian, Amy L Blount, Cindy Donaldson, Wylie ValeAbstract:: Activins, as members of the transforming growth factor-beta superfamily, control and orchestrate many physiological processes and are vital for the development, growth and functional integrity of most tissues, including the pituitary. Activins produced by pituitary cells work in conjunction with central, peripheral, and other local factors to influence the function of gonadotropes and maintain a normal reproductive axis. Follistatin, also produced by the pituitary, acts as a local buffer to bind Activin and modulate its bioactivity. On the other hand, inhibins of gonadal origin provide an endocrine feedback signal to antagonize Activin signaling in cells that express the inhibin co-receptor, betaglycan, such as gonadotropes. This review highlights the pituitary roles of Activin and the mechanisms through which these actions are modulated by inhibin and follistatin.
-
Activins and inhibins physiological roles signaling mechanisms and regulation
2005Co-Authors: Peter C. Gray, Craig A. Harrison, Ezra Wiater, Louise M. Bilezikjian, Wylie ValeAbstract:Activins and inhibins belong to the transforming growth factor β (TGFβ) superfamily, which also includes the TGF-β (Massague 1998), bone morphogenetic protein (BMP) (Wozney et al. 1988), growth and differentiation (GDF) and nodal-related families (Schier et al. 2000). In human there are now known to be 42 members of the TGF-β superfamily (reviewed in Shi et al. 2003). This review summarizes the physiological roles of Activins and inhibins, focusing on Activin actions in the central nervous system (CNS). In addition, we outline the molecular basis for Activin signal transduction and regulation, emphasizing recent advances regarding the structural basis for ligand/receptor interactions and the roles of betaglycan and Cripto in attenuating Activin signaling.
-
Activins and Inhibins and Their Signaling
Annals of the New York Academy of Sciences, 2004Co-Authors: Wylie Vale, Craig A. Harrison, Ezra Wiater, Peter C. Gray, Louise M. Bilezikjian, Senyon ChoeAbstract:: Activins and inhibins, which were discovered by virtue of their abilities to stimulate or inhibit, respectively, the secretion of FSH, are members of the transforming growth factor-beta (TGFbeta) superfamily and exert a broad range of effects on the diffentiation, proliferation and functions of numerous cell types. Activins interact with two structurally related classes of serine/threonine kinase receptors (type I and type II). Inhibin antagonizes Activin by binding to the proteoglycan, betaglycan, and forming a stable complex with and, thereby, sequestering type II Activin receptors while excluding type I receptors. If betaglycan is present, inhibin can also antagonize those bone morphogenic proteins (BMPs) whose signaling is dependent upon access to type II Activin receptors. Recent insights regarding the structures of ligands, receptors and their signaling complexes are providing the basis for the development of therapeutics capable of modulating fertility and numerous pathophysiologic processes.
-
autocrine paracrine regulation of pituitary function by Activin inhibin and follistatin
Molecular and Cellular Endocrinology, 2004Co-Authors: Louise M. Bilezikjian, Amy L Blount, Wolfgang H. Fischer, Cindy Donaldson, Angela M O Leal, Wylie ValeAbstract:The precise regulation of the anterior pituitary is achieved by the cell-specific and combined actions of central, peripheral and local factors. Activins, inhibins, and follistatins were first discovered as gonadal factors with actions on FSH production from pituitary gonadotropes. With the realization that these factors are expressed in a wide array of tissues, including the pituitary, it became apparent that the functional importance of Activins, inhibins, and follistatins extends beyond the reproductive axis and that they often exert their effects by autocrine/paracrine mechanisms. As members of the TGF-β superfamily, Activins and inhibins control and orchestrate many physiological processes and are vital for the development, the growth, and the functional integrity of most tissues, including the pituitary. Activins exert effects on multiple pituitary cell types but the best-characterized pituitary targets of the autocrine/paracrine function of Activins are the gonadotropes. The autocrine/paracrine function of the Activin-binding proteins, follistatins, constitutes an important local mechanism to modulate Activin bioactivity while the restricted actions of gonadal inhibins to betaglycan-expressing gonadotropes provides a secondary mode of regulation of cell-specific actions of Activins. The aim of this review is to highlight and evaluate experimental evidence that supports the roles of Activins, inhibins, and follistatins as autocrine, paracrine, and/or endocrine modulators of the pituitary.
Teresa K. Woodruff - One of the best experts on this subject based on the ideXlab platform.
-
structures of an actriib Activin a complex reveal a novel binding mode for tgf β ligand receptor interactions
The EMBO Journal, 2003Co-Authors: Thomas B Thompson, Teresa K. Woodruff, Theodore S JardetzkyAbstract:The TGF-β superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell fate specification in development to immune suppression. Activins define a major subgroup of TGF-β ligands that regulate cellular differentiation, proliferation, activation and apoptosis. Activins signal through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of Activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. ActRIIB binds to the outer edges of the Activin finger regions, with the two receptors juxtaposed in close proximity, in a mode that differs from TGF-β3 binding to type II receptors. The dimeric Activin A structure differs from other known TGF-β ligand structures, adopting a compact folded-back conformation. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface and suggests that diversity in the conformational arrangements of TGF-β ligand dimers could influence cellular signaling processes.
-
structures of an actriib Activin a complex reveal a novel binding mode for tgf β ligand receptor interactions
The EMBO Journal, 2003Co-Authors: Thomas B Thompson, Teresa K. Woodruff, Theodore S JardetzkyAbstract:The TGF-beta superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell fate specification in development to immune suppression. Activins define a major subgroup of TGF-beta ligands that regulate cellular differentiation, proliferation, activation and apoptosis. Activins signal through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of Activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. ActRIIB binds to the outer edges of the Activin finger regions, with the two receptors juxtaposed in close proximity, in a mode that differs from TGF-beta3 binding to type II receptors. The dimeric Activin A structure differs from other known TGF-beta ligand structures, adopting a compact folded-back conformation. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface and suggests that diversity in the conformational arrangements of TGF-beta ligand dimers could influence cellular signaling processes.
-
properties of inhibin binding to betaglycan inhbp p120 and the Activin type ii receptors
Molecular and Cellular Endocrinology, 2002Co-Authors: Stacey C Chapman, Daniel J Bernard, Jaroslav Jelen, Teresa K. WoodruffAbstract:Activin-stimulated FSH synthesis and release by the pituitary gonadotrope is antagonized by gonadally derived inhibins. The two isoforms of inhibin, inhibin A and B, bind to the Activin type II receptors, though at a lower affinity than the Activins, but do not stimulate intracellular signaling. Theoretically, therefore, inhibins can prevent Activin signaling through competitive binding if present at higher concentrations than the Activins. In reality, the inhibins have been shown to antagonize Activin signaling when the two ligand types are present at equimolar concentrations. These observations led to the hypothesis that inhibin binding proteins or co-receptors exist that either increase the affinity of the inhibins for the Activin receptors or propagate inhibin-specific intracellular signals. Two candidate inhibin co-receptors, betaglycan and InhBP/p120, interact with Activin receptors and augment inhibin antagonism of Activin action. Here, we report the effect of betaglycan and InhBP/p120 on both inhibin A and inhibin B binding to the Activin receptors ActRIIA and ActRIIB2. InhBP/p120 did not bind inhibin A or B when expressed alone or in combination with Activin receptors, requiring a re-examination of the role of this protein in inhibin biology. Both inhibins bound the Activin type II receptor, ActRIIB2. Inhibin B had a higher affinity for this receptor than inhibin A but an approximately 10-fold lower affinity than that of Activin A. Inhibin A and B bound betaglycan with high affinity; however, only inhibin A binding to ActRIIB2 was significantly enhanced in the presence of betaglycan. Both inhibin isoforms showed slight but significant binding to ActRIIA, yet this binding was potentiated in the presence of betaglycan. Additionally, the complex formed between the inhibins, ActRIIA, and betaglycan was resistant to disruption by Activin A, whereas Activin A potently competed for inhibin binding to ActRIIB2 and betaglycan. Collectively, these data show that the inhibin isoforms have different affinities for the Activin type II receptors but bind betaglycan with high affinity. A recently developed model of inhibin action proposes that inhibins form a high affinity, Activin-resistant ternary complex with Activin type II receptors and betaglycan, thereby providing a mechanism for inhibin antagonism of Activin signaling. Importantly, the results presented here clearly show that this model does not apply equally to both forms of inhibin nor to the different Activin type II receptor isoforms. Thus, it appears that the mechanisms of inhibin action may vary depending on the ligand and receptor types involved.
-
Activin signaling through Activin receptor type ii causes the cachexia like symptoms in inhibin deficient mice
Molecular Endocrinology, 1996Co-Authors: Katherine A Coerver, Jennie P. Mather, Teresa K. Woodruff, Allan Bradley, Milton J Finegold, Martin M MatzukAbstract:Activins and inhibins, members of the transforming growth factor-p superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in cY-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parieta1 cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant Activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibit+deficient mice secrete high levels of Activins. In addition, Northern blot analysis has localized Activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced Activins act through ActRll to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of Activin signaling through ActRll in viva, we generated compound homozygous mutant mice deficient in both cu-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of Activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of Activin signaling through ActRll
-
monoclonal antibody based elisas for measurement of Activins in biological fluids
Journal of Immunological Methods, 1993Co-Authors: Wai Lee T Wong, S. Garg, Teresa K. Woodruff, Laura N Bald, Brian M Fendly, James A LofgrenAbstract:Two sensitive monoclonal antibody (MAb)-based enzyme-linked immunosorbent assays (ELISAs), one for Activin A (homodimer of beta A subunits) and one for Activin B (homodimer of beta B subunits) in plasma have been developed. The Activin A ELISA had an effective range of 0.2-50 ng/ml while the Activin B ELISA's range was 0.1-25 ng/ml in human serum. Both ELISAs were specific with < 0.01% cross-reactivity with related hormones and follistatin (an Activin binding protein), however the presence of recombinant human follistatin caused a decrease in measured level of Activin A and B spiked human samples. The assay was linear across the standard curve range with intra- and interassay coefficients of variation were less than 15%. The level of Activins in female serum range from 0.3 to 10.4 ng/ml. In summary, we have developed a reliable, convenient and rapid MAb-based enzyme immunoassay for determination of Activin A and B levels in human serum which are also applicable for buffer, mouse and monkey serum matrices. This assay will be useful for studying the regulation and role of Activin A and B in health and disease.
Kunihiro Tsuchida - One of the best experts on this subject based on the ideXlab platform.
-
Multifunctional Roles of Activins in the Brain
Vitamins and hormones, 2011Co-Authors: Hiroshi Ageta, Kunihiro TsuchidaAbstract:Activins, which are members of the TGF-β superfamily, were initially isolated from gonads and served as modulators of follicle-stimulating hormone secretion. Activins regulate various biological functions, including induction of the dorsal mesoderm, craniofacial development, and differentiation of numerous cell types. Activin receptors are highly expressed in neuronal cells, and Activin mRNA expression is upregulated by neuronal activity. Activins also exhibit neuroprotective action during excitotoxic brain injury. However, very little is known about the functional roles of Activins in the brain. We recently generated various types of transgenic mice, demonstrating that Activins regulate spine formation, behavioral activity, anxiety, adult neurogenesis, late-phase long-term potentiation, and maintenance of long-term memory. The present chapter describes recent progress in the study of the role of Activin in the brain.
-
Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer
Endocrine JournalEndocrine Journal, 2008Co-Authors: Kunihiro TsuchidaAbstract:Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for Activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of Activins and nodal, Activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through Activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through Activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.
-
Activin isoforms signal through type i receptor serine threonine kinase alk7
Molecular and Cellular Endocrinology, 2004Co-Authors: Kunihiro Tsuchida, Masashi Nakatani, Osamu Hashimoto, Yoshihisa Hasegawa, Norio Yamakawa, Hiromu SuginoAbstract:Abstract Activins play a fundamental role in cell differentiation and development. Activin A signaling is mediated through a combination of Activin type II receptors (ActRIIs) and the Activin type IB receptor, ALK4. Signaling receptors of other Activin isoforms remain to be elucidated. Here, we found that Activin AB and Activin B are ligands for ALK7. ALK7 is an orphan receptor serine/threonine kinase expressed in neuroendocrine tissues including pancreatic islets. The combination of ActRIIA and ALK7, preferred by Activin AB and Activin B but not by Activin A, is responsible for Activin-mediated secretion of insulin from pancreatic β cell line, MIN6. In contrast, all Activins activate a combination of ActRIIA and ALK4 with various levels of potency. Thus, variation in Activin signaling through type I receptors is dependent upon homo- and heterodimeric assembly of Activin isoforms. Thus, the differential combination of receptor heterodimers mediates variation in Activin isoform signaling.
-
cloning and characterization of a transmembrane serine kinase that acts as an Activin type i receptor
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Kunihiro Tsuchida, Lawrence S MathewsAbstract:Abstract Activin type II receptors are transmembrane protein-serine/threonine kinases. By using a reverse-transcription PCR assay to screen for protein kinase sequences, we isolated a cDNA clone, Activin X1 receptor, from rat brain that encodes a 55-kDa transmembrane protein-serine kinase which is structurally related to other receptors in this kinase subfamily. The predicted protein consists of 509 amino acids, and the kinase domain shows 40% and 37% identity to the Activin and transforming growth factor beta type II receptors, respectively. No Activin-binding was observed when Activin X1 receptor was expressed alone in COS-M6 cells; however, coexpression with type II Activin receptors gave rise to a 68-kDa affinity-labeled complex in addition to the 85-kDa type II receptor complex. The size of this cross-linked band is consistent with the size of the type I Activin receptor; furthermore, Activin X1 receptor associated with type II receptors, as judged by coimmunoprecipitation with type II receptor antibodies. These data suggest that Activin X1 receptor can serve as an Activin type I receptor and that the diverse biological effects of Activins may be mediated by a complex formed by the interaction of two transmembrane protein-serine kinases.
