Abstract
Multi-molecular complexes nucleated by adaptor proteins play a central role in signal transduction. In T cells, one central axis consists of the assembly of several signaling proteins linked together by the adaptors linker of activated T cells (LAT), Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), and Grb2-related adaptor downstream of Shc (Gads). Each of these adaptors has been shown to be important for normal T cell development, and their proper sub-cellular localization is critical for optimal function in cell lines. We previously demonstrated in Jurkat T cells and a rat basophilic leukemic cell line that expression of a 50-amino acid polypeptide identical to the site on SLP-76 that binds to Gads blocks proper localization of SLP-76 and SLP-76-dependent signaling events. Here we extend these studies to investigate the ability of this polypeptide to inhibit TCR-induced integrin activity in Jurkat cells and to inhibit in vivo thymocyte development and primary T cell function. These data provide evidence for the in vivo function of a dominant-negative peptide based upon the biology of SLP-76 action and suggest the possibility of therapeutic potential of targeting the SLP-76/Gads interaction.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Adhesion / immunology
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Cell Differentiation / immunology*
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Cell Line, Tumor
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Cell Movement / immunology
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Cells, Cultured
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Chemokine CXCL12 / physiology
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Growth Inhibitors / chemical synthesis
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology*
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Humans
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Integrins / antagonists & inhibitors
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Integrins / physiology
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Jurkat Cells
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / physiology
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Peptides / chemical synthesis*
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Peptides / genetics*
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Peptides / physiology
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / metabolism*
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Protein Binding / immunology
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Rats
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T-Lymphocytes / cytology*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CXCL12 protein, human
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Chemokine CXCL12
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Growth Inhibitors
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Integrins
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Mona protein, mouse
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Peptide Fragments
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Peptides
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Phosphoproteins
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SLP-76 signal Transducing adaptor proteins