SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling.
Engagement of the T cell antigen receptor (TCR) leads to rapid activation of protein tyrosine kinases, which in turn phosphorylate downstream enzymes and adapter proteins. Some adapter proteins, such as SLP-76, Vav, and LAT, positively regulate TCR-mediated signal transduction, whereas others, such as Cbl, play an inhibitory role. SLAP (Src-like ... adapter protein), an adapter protein containing a Src homology 3 and a Src homology 2 domain, was isolated from a yeast interacting screen by using N-terminal Cbl as bait. N-terminal Cbl interacts with SLAP in vivo and in vitro in a tyrosine phosphorylation-independent manner. We observed that SLAP is expressed in T cells, and upon TCR activation, SLAP interacts with ZAP-70, Syk, LAT, and TCRzeta chain in Jurkat T cells. In transiently transfected COS-7 cells, SLAP forms separate complexes with ZAP-70, Syk, and LAT through its Src homology 2 domain. Overexpression of a C-terminal-truncated SLAP mutant down-regulates nuclear factor of activated T cells-AP1 activity. We have evidence that SLAP forms homodimers through its C-terminal region. Serial truncations and mutations in the C terminus of SLAP demonstrate that there is a correlation between the loss of dimerization and the inhibition of nuclear factor of activated T cells-AP1 activity. The in vivo association of SLAP with key signaling molecules and its inhibition of T cell activation suggests that SLAP plays an important role in TCR-mediated signal transduction.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Binding Sites, COS Cells, Dimerization, Enzyme Precursors, Escherichia coli, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Membrane Proteins, Phosphoproteins, Point Mutation, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Saccharomyces cerevisiae, Signal Transduction, ZAP-70 Protein-Tyrosine Kinase
Adaptor Proteins, Signal Transducing, Animals, Binding Sites, COS Cells, Dimerization, Enzyme Precursors, Escherichia coli, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Membrane Proteins, Phosphoproteins, Point Mutation, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Saccharomyces cerevisiae, Signal Transduction, ZAP-70 Protein-Tyrosine Kinase
Proc. Natl. Acad. Sci. U.S.A.
Date: Aug. 17, 1999
PubMed ID: 10449770
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