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PMID:14624253

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Citation

Roose, JP, Diehn, M, Tomlinson, MG, Lin, J, Alizadeh, AA, Botstein, D, Brown, PO and Weiss, A (2003) T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression. PLoS Biol. 1:E53

Abstract

Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligand-independent signaling by the precursors of mature antigen receptors regulates development of B and T lymphocytes. Here we describe a basal signal that controls gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG-2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results in constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or inhibition of signaling events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.

Links

PubMed PMC261890 Online version:10.1371/journal.pbio.0000053

Keywords

Adaptor Proteins, Signal Transducing; Animals; B-Lymphocytes/metabolism; Blotting, Northern; Blotting, Western; Cell Separation; DNA, Complementary/metabolism; DNA-Binding Proteins/metabolism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases/physiology; Flow Cytometry; Gene Expression Regulation; Homeodomain Proteins/metabolism; Humans; Immunoprecipitation; Jurkat Cells; Ligands; MAP Kinase Signaling System; Mice; Models, Biological; Molecular Sequence Data; Multigene Family; Oligonucleotide Array Sequence Analysis; Phosphoproteins/metabolism; Phosphorylation; Piperazines/pharmacology; Protein Kinase C/metabolism; Proto-Oncogene Proteins c-abl/physiology; Pyrimidines/pharmacology; RNA/chemistry; Receptors, Antigen, T-Cell/physiology; Signal Transduction; Thymus Gland/cytology; Thymus Gland/metabolism; Thymus Gland/pathology; Transcription, Genetic; Tyrosine/chemistry

Significance

Annotations

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

HUMAN:LAT

GO:0045860: positive regulation of protein kinase activity

ECO:0000270:

P

Figure 1, 2BC, and Fig. 3C-E. Figure 3 in particular indicates that "proper localization and signaling through the adapter LAT are required for normal suppression of RAG gene expression".

complete
CACAO 2120

HUMAN:LAT

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LCP2

GO:0045860: positive regulation of protein kinase activity

ECO:0000270:

P

Figure 1, Fig 2BC, Fig 3CE

complete
CACAO 2118

HUMAN:LCP2

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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