In Vivo Significance of ITK-SLP-76 Interaction in Cytokine Production
| Autor: | David M. Guimond, John D. Lambris, Juris A. Grasis, Nicholas R. Cam, Krystal Herman, Paola Magotti, Constantine D. Tsoukas |
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| Rok vydání: | 2010 |
| Předmět: |
Male
T-Lymphocytes medicine.medical_treatment Molecular Sequence Data Receptors Antigen T-Cell Biology Binding Competitive Jurkat cells SH3 domain Jurkat Cells Mice medicine Animals Humans Protein Interaction Domains and Motifs Amino Acid Sequence Receptor Molecular Biology Peptide sequence Adaptor Proteins Signal Transducing T-cell receptor Signal transducing adaptor protein Articles Cell Biology Protein-Tyrosine Kinases Phosphoproteins Molecular biology Actins Peptide Fragments Mice Inbred C57BL Cytokine Cytokines Signal transduction Signal Transduction |
| Zdroj: | Molecular and Cellular Biology. 30:3596-3609 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.01657-09 |
| Popis: | In vitro data have suggested that activation of the inducible T-cell kinase (ITK) requires an interaction with the adaptor protein SLP-76. One means for this interaction involves binding of the ITK SH3 domain to the polyproline-rich (PR) region of SLP-76. However, the biological significance of this association in live cells and the consequences of its disruption have not been demonstrated. Here, we utilized a polyarginine-rich, cell-permeable peptide that represents the portion of the SLP-76 PR region that interacts with the ITK SH3 domain as a competitive inhibitor to disrupt the association between ITK and SLP-76 in live cells. We demonstrate that treatment of cells with this peptide, by either in vitro incubation or intraperitoneal injection of the peptide in mice, inhibits the T-cell receptor (TCR)-induced association between ITK and SLP-76, recruitment and transphosphorylation of ITK, actin polarization at the T-cell contact site, and expression of Th2 cytokines. The inhibition is specific, as indicated by lack of effects by the polyarginine vehicle alone or a scrambled sequence of the cargo peptide. In view of the role of ITK as a regulator of Th2 cytokine expression, the data underscore the significance of ITK as a target for pharmacological intervention. |
| Databáze: | OpenAIRE |
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