SOCS-6 negatively regulates T cell activation through targeting p56lck to proteasomal degradation.
The T cell-specific tyrosine kinase, p56(lck), plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56(lck). SOCS-6 was identified as a protein binding to the kinase domain of p56(lck) through yeast two-hybrid screening. SOCS-6 ... bound specifically to p56(lck) (F505), which mimics the active form of p56(lck), but not to wild type p56(lck). In Jurkat T cells, SOCS-6 binding to p56(lck) was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56(lck). SOCS-6 promoted p56(lck) ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.
Mesh Terms:
Animals, Binding Sites, Humans, Immunological Synapses, Interleukin-2, Jurkat Cells, Lymphocyte Activation, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mice, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Protein Binding, Receptors, Antigen, T-Cell, Suppressor of Cytokine Signaling Proteins, T-Lymphocytes, Two-Hybrid System Techniques
Animals, Binding Sites, Humans, Immunological Synapses, Interleukin-2, Jurkat Cells, Lymphocyte Activation, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mice, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Protein Binding, Receptors, Antigen, T-Cell, Suppressor of Cytokine Signaling Proteins, T-Lymphocytes, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Mar. 05, 2010
PubMed ID: 20007709
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