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PMID:17164348

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Citation

Tzachanis, D, Li, L, Lafuente, EM, Berezovskaya, A, Freeman, GJ and Boussiotis, VA (2007) Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-beta signaling in activated T lymphocytes. Blood 109:2944-52

Abstract

Quiescent T cells express Tob, an APRO gene family member, which functions as a transcriptional regulator. Subtractive hybridization identified Twisted gastrulation (Tsg) as one of the genes suppressed by Tob. Tsg is a secreted protein that interacts with Drosophila decapentaplegic (Dpp) and its vertebrate orthologs BMP2/4 and regulates morphogenetic effects in embryos. Here, we report the expression and function of Tsg in human T cells. Tsg mRNA was almost undetectable in unstimulated T cells and was up-regulated after activation by TCR/CD3 and either CD28, IL-2, or PMA. Tsg protein had no effect on responses of primary T cells to TCR/CD3 stimulation but had a potent inhibitory effect on proliferation and cytokine production of primed alloreactive CD4+ cells. Surprisingly, Tsg did not affect phosphorylation of the BMP-specific Smad1 but induced phosphorylation of the TGF-beta-specific Smad2 and mediated DNA binding on Smad3/4 consensus-binding sites, suggesting that it acted downstream of TGF-beta. In vitro association assays revealed a direct interaction of Tsg and TGF-beta proteins. Thus, Tsg functions as an agonist synergizing with TGF-beta to inhibit T-cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases.

Links

PubMed PMC1852213 Online version:10.1182/blood-2006-03-006510

Keywords

Base Sequence; Cytokines/biosynthesis; DNA Primers/genetics; Gene Expression; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Jurkat Cells; Lymphocyte Activation; Proteins/genetics; Proteins/metabolism; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Signal Transduction; T-Lymphocytes/immunology; T-Lymphocytes/metabolism; Transfection; Transforming Growth Factor beta/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TWSG1

involved_in

GO:0001818: negative regulation of cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWSG1

involved_in

GO:0007179: transforming growth factor beta receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000492)

Seeded From UniProt

complete

HUMAN:TWSG1

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q15796)
  • occurs_in:(CL:0000492)

Seeded From UniProt

complete

HUMAN:TWSG1

involved_in

GO:2000562: negative regulation of CD4-positive, alpha-beta T cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWSG1

involved_in

GO:2000515: negative regulation of CD4-positive, alpha-beta T cell activation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWSG1

enables

GO:0050431: transforming growth factor beta binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TGFR2

involved_in

GO:2000563: positive regulation of CD4-positive, alpha-beta T cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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