Dataset Information

Transforming Growth Factor-? Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding.

ABSTRACT: Transforming growth factor-? (TGF-?) family ligands are pleiotropic cytokines. Their physiological activities are not determined by a simple coupling of stimulus and response, but depend critically on context, i.e. the interplay of receptors, ligands, and regulators that form the TGF-? signal transduction system of a cell or tissue. How these different components combine to regulate signaling activities remains poorly understood. Here, we describe a ligand-mediated mechanism of signaling regulation. Based on the observation that the type II TGF-? family receptors ActRIIA, ActRIIB, and BMPRII interact with a large group of overlapping ligands at overlapping epitopes, we hypothesized high affinity ligands compete with low affinity ligands for receptor binding and signaling. We show activin A and other high affinity ligands directly inhibited signaling by the low affinity ligands BMP-2, BMP-7, and BMP-9. We demonstrate activin A functions as a competitive inhibitor that blocks the ligand binding epitope on type II receptors. We propose binding competition and signaling antagonism are integral functions of the TGF-? signal transduction system. These functions could help explain how activin A modulates physiological signaling during extraordinary cellular responses, such as injury and wound healing, and how activin A could elicit disease phenotypes such as cancer-related muscle wasting and fibrosis.

SUBMITTER: Aykul S

PROVIDER: S-EPMC4865925 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Transforming Growth Factor-β Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding.

Aykul Senem S Martinez-Hackert Erik E

The Journal of biological chemistry 20160309 20

Transforming growth factor-β (TGF-β) family ligands are pleiotropic cytokines. Their physiological activities are not determined by a simple coupling of stimulus and response, but depend critically on context, i.e. the interplay of receptors, ligands, and regulators that form the TGF-β signal transduction system of a cell or tissue. How these different components combine to regulate signaling activities remains poorly understood. Here, we describe a ligand-mediated mechanism of signaling regulat ...[more]

PMID: 26961869

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Project description:BACKGROUND: Endometrial remodelling is necessary for implantation in all mammalian species. The TGF beta super-family plays a crucial role in this event in humans and mice. However, the role of TGF beta super-family members during implantation is still unclear in ruminants. In the present study, the spacio-temporal expression of TGF beta super-family members including activin was explored in bovine trophoblasts and endometrial tissue during the peri-implantation period in order to elucidate whether it is essential for promoting cell proliferation at the implantation site. METHODS: Gene expression in the fetal membrane and endometrium of the gravid and non-gravid horn around Day 35 of gestation were analyzed with a custom-made oligo-microarray in cattle. The expression of activin and its related genes was also analyzed with quantitative RT-PCR. Activin-like activity in trophoblastic tissue and BT-1 cells was examined using a fibroblast cell proliferation test and Western blotting. RESULTS: The expression of various TGF beta super-family related genes including activin was detected in trophoblasts and the endometrium in cattle. The most intensive activin expression was found in the gravid horn endometrium, and rather intense expression was detected in the non-gravid trophoblastic tissue. Extracts from the fetal membrane including trophoblasts and purified activin both stimulated fibroblast proliferation effectively, and activin was immunologically detected in BT-1 cells, which have trophoblastic features. CONCLUSIONS: Specific expression of the activin gene (gene name: inhibin beta A) was found in the gravid horn endometrium during peri-implantation. An activin-like molecule, which was derived from the endometrium and trophoblasts, stimulated the proliferation of fibroblast cells. These results suggested that as in other species, the activity of TGF beta super-family members including activin-like molecules plays a pivotal role in endometrial remodelling, which is an essential process in implantation and placentogenesis during the peri-implantation period in cattle.

Dataset Information

Transforming Growth Factor-? Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding.

Publications

Transforming Growth Factor-β Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding.

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