Inactive Type II and Type I Receptors for TGFβ Are Dominant Inhibitors of TGFβ-dependent Transcription

Brand, Thomas; Schneider, Michael

doi:10.1074/jbc.270.14.8274

Cited by 48 publications

(19 citation statements)

References 65 publications

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“…Next, we blocked SMA-6 signaling in these regions using SMA-6(Δk), a dominant-negative isoform that lacks the intracellular kinase domain. Mutations disrupting the kinase domain of TGF-β receptors inhibit signal transduction of the corresponding pathway (31). Expression of sma-6(Δk) using the hypodermis-specific promoter dpy-7 in the wild-type animals resulted in decreased body length, similar to the phenotype of sma-6(wk7) mutant animals ( Fig.…”

Section: Dbl-1 Signals To the Hypodermis To Direct Aversive Olfactorymentioning

confidence: 67%

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning

Zhang¹,

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

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The TGF-β superfamily is conserved throughout metazoan, and its members play essential roles in development and disease. TGF-β has also been implicated in adult neural plasticity. However, the underlying mechanisms are not well understood. Here we report that DBL-1, a Caenorhabditis elegans TGF-β homolog known to control body morphology and immunity, is essential for aversive olfactory learning of potentially harmful bacteria food. We show that DBL-1 generated by the AVA command interneurons, which are critical for sensorimotor responses, regulates aversive olfactory learning, and that the activity of the type I TGF-β receptor SMA-6 in the hypodermis is needed during adulthood to generate olfactory plasticity. These spatial and temporal mechanisms are critical for the DBL-1 signaling to achieve its diverse functions in development and adult neural plasticity. Interestingly, aversive training decreases AVA calcium response, leading to an increase in the DBL-1 signal secreted from AVA, revealing an experience-dependent change that can underlie the role of TGF-β signaling in mediating plasticity.experience-dependent secretion | molecular and cellular mechanisms for TGF-beta pathway in learning

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Section: Dbl-1 Signals To the Hypodermis To Direct Aversive Olfactorymentioning

confidence: 67%

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning

Zhang¹,

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In these studies, we characterize separate activation and ligand-response domains within Smad4 using a functional assay based on the restoration of TGF-␤ responsiveness in a Smad4 null cell line by transient transfection with Smad4. We have shown that restoration of cellular responses to TGF-␤ by Smad4 in MDA-MB468 cells is dependent on TGF-␤ receptor function, as reporter gene activation is inhibited by co-transfection with a kinase-inactive TGF-␤ type II receptor mutant shown previously to exert a dominant negative effect on TGF-␤ -induced transcriptional responses in other systems (24). Furthermore, augmentation of basal reporter gene activation seen following co-transfection of Smad4 and the wild-type TGF-␤ type II receptor, and its reversal following incubation of the transfected cells with TGF-␤ neutralizing antibodies, indicates that restoration of cellular responses following transfection with Smad4 is dependent both on the level of receptor expression and the degree of autocrine or paracrine stimulation of this pathway resulting from the secretion of TGF-␤ into the culture medium.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Functional Domains within Smad4/DPC4

Caestecker

Hemmati

Larisch-Bloch

et al. 1997

Journal of Biological Chemistry

140

110

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Smad proteins are a family of highly conserved, intracellular proteins that signal cellular responses downstream of transforming growth factor-␤ (TGF-␤) family serine/threonine kinase receptors. One of these molecules, Smad4, originally identified as the candidate tumor suppressor gene dpc-4, reconstitutes TGF-␤-and activin-dependent transcriptional responses in Smad4 null cell lines and interacts in a ligand-dependent manner with other Smad family members in both TGF-␤, activin, and bone morphogenetic protein-2/-4 pathways. Here, we used an assay based on the restoration of liganddependent transcriptional responses in a Smad4 null cell line to characterize functional domain structures within Smad4. We showed that restoration of TGF-␤-induced transcriptional responses by Smad4 was inhibited by co-transfection with a kinase dead TGF-␤ type II receptor and that constitutive activation was blocked with TGF-␤ neutralizing antibodies, confirming the essential role of Smad4 in TGF-␤ signaling. Using a series of Smad4 mutation, deletion, and Smad1/Smad4 chimera constructs we identified a 47-amino acid deletion within the middle-linker region of Smad4 that is essential for the mediation of signaling responses. In addition, we showed that the NH 2 -terminal domain of Smad4 augments ligand-dependent activation associated with the middle-linker region, indicating that there is a distinct ligand-response domain within the N terminus of this molecule.

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“…However, no TGF-β responses have been described in cells lacking type I receptors. Overexpression of dominant-negative TβR-II receptor constructs can eliminate all TGF-β responses tested (79,184) or only part of the TGF-β responses tested (185), depending on the assay conditions. Responses requiring a low level of signaling activity may be triggered by a residual level of activity in cells expressing dominant-negative receptors.…”

Section: Signal Flow In the Receptor Complexmentioning

confidence: 99%

TGF-β SIGNAL TRANSDUCTION

Massagué

1998

Annu. Rev. Biochem.

4,589

3,715

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The transforming growth factor β (TGF-β) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-β signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-β and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders. CONTENTS

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Inactive Type II and Type I Receptors for TGFβ Are Dominant Inhibitors of TGFβ-dependent Transcription

Cited by 48 publications

References 65 publications

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning

Characterization of Functional Domains within Smad4/DPC4

TGF-β SIGNAL TRANSDUCTION

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