Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor signaling.
Adaptor proteins assemble multiprotein signaling complexes, enabling the transduction of intracellular signals. While many adaptor proteins positively regulate signaling in this manner, a subgroup of adaptors function as negative regulators. Here we report the identification of a hematopoiesis-specific adaptor protein that we have designated Src-like adaptor protein 2 (SLAP-2). SLAP-2 ... is most closely related to SLAP and contains a Src homology 3 (SH3) domain and an SH2 domain, as well as an amino-terminal myristoylation site that mediates SLAP-2 association with membranes. Following stimulation of primary thymocytes with anti-CD3 and anti-CD28, SLAP-2 coimmunoprecipitates with tyrosine-phosphorylated c-Cbl and an unidentified protein of approximately 72 kDa. In activated Jurkat T cells, SLAP-2 also binds an additional 70-kDa phosphoprotein, identified as ZAP-70. Binding of SLAP-2 to both p72 and ZAP-70 is dependent on its SH2 domain, while c-Cbl interacts with the carboxy-terminal region. Overexpression of wild-type SLAP-2 alone or in combination with c-Cbl in Jurkat T cells leads to inhibition of T-cell antigen receptor-induced activation of nuclear factor of activated T cells. The inhibitory effect of SLAP-2 requires the carboxy-terminal c-Cbl binding region. Expression of SLAP-2 with SYK or ZAP-70 in COS cells or Jurkat T cells causes the degradation of these kinases, and SLAP-2 overexpression in Jurkat T cells reduces the surface expression of CD3. These results suggest that the mechanism of action of SLAP-2 and the related protein SLAP is to promote c-Cbl-dependent degradation of the tyrosine kinases SYK and ZAP-70 and down-regulation of CD3 at the cell surface.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, CD28, Antigens, CD3, Base Sequence, Cell Line, Cloning, Molecular, Conserved Sequence, DNA-Binding Proteins, Down-Regulation, Enzyme Precursors, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Mice, Molecular Sequence Data, NFATC Transcription Factors, Nuclear Proteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins pp60(c-src), Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Transcription Factors, ZAP-70 Protein-Tyrosine Kinase
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, CD28, Antigens, CD3, Base Sequence, Cell Line, Cloning, Molecular, Conserved Sequence, DNA-Binding Proteins, Down-Regulation, Enzyme Precursors, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Mice, Molecular Sequence Data, NFATC Transcription Factors, Nuclear Proteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins pp60(c-src), Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Transcription Factors, ZAP-70 Protein-Tyrosine Kinase
Mol. Cell. Biol.
Date: Jun. 01, 2002
PubMed ID: 12024036
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