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.
Highlights
Considerable evidence supports the notion that in most signal transduction systems regulated by cellular receptors some basal level of signaling occurs continuously in a ligandindependent manner, the flux through such systems may vary considerably
We postulated that the same tonic signaling pathway might regulate a gene expression program in Jurkat cells and that a similar pathway might exist in thymocytes or T cells
Our studies reveal that even without T cell receptor (TCR) engagement, the signaling pathways normally responsive to TCR stimulation are not inert
Summary
Considerable evidence supports the notion that in most signal transduction systems regulated by cellular receptors some basal level of signaling occurs continuously in a ligandindependent manner, the flux through such systems may vary considerably. The basal tone or the steady-state level of signaling in unstimulated cells is the result of an equilibrium of positive and negative regulators within a signaling pathway. This dynamic equilibrium is often revealed when the functions of negative regulators of signal transduction are impaired. Inactivation of tyrosine phosphatase function by inhibitors (e.g., by pervanadate) frequently leads to an increased level of tyrosine phosphorylation of cellular proteins, in a ligand-independent manner. The steady-state level of signaling in the unstimulated state may itself have functional consequences, for instance, to maintain certain differentiated cellular properties or functions
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
