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Molecular Dissection of 2B4 Signaling: Implications for Signal Transduction by SLAM-Related Receptors
- Source :
- Molecular and Cellular Biology. 24:5144-5156
- Publication Year :
- 2004
- Publisher :
- Informa UK Limited, 2004.
-
Abstract
- 2B4 is a SLAM-related receptor expressed on natural killer (NK) cells and cytotoxic T cells. It can regulate killing and gamma interferon secretion by NK cells, as well as T-cell-mediated cytotoxicity. There are conflicting data regarding the mechanism of action of 2B4. In these studies, we attempted to understand better the nature and basis of 2B4 signaling. Our studies showed that engagement of 2B4 on NK cells triggered a tyrosine phosphorylation signal implicating 2B4, Vav-1, and, to a lesser extent, SHIP-1 and c-Cbl. Structure-function analyses demonstrated that this response was defined by a series of tyrosine-based motifs in the cytoplasmic region of 2B4 and was not influenced by the extracellular or transmembrane segment of 2B4. In addition, the 2B4-induced signal was absolutely dependent on coexpression of SAP, a Src homology 2 (SH2) domain-containing adaptor associating with SLAM-related receptors and mutated in X-linked lymphoproliferative disease. It was also observed that 2B4 was detectably associated with the Src-related protein tyrosine kinase FynT in an immortalized NK cell line. Mutation of arginine 78 of SAP, a residue critical for binding of SAP to FynT, eliminated 2B4-mediated protein tyrosine phosphorylation, implying that SAP promotes 2B4 signaling most probably by recruiting FynT. Finally, despite the similarities in the signaling modalities of 2B4 and its relative SLAM, the natures of the tyrosine phosphorylation signals induced by these two receptors were found to be different. These differences were not caused by variations in the extent of binding to SAP but rather were dictated by the tyrosine-based sequences in the cytoplasmic domain of the receptors. Taken together, these data lead to a better understanding of 2B4 signaling. Furthermore, they provide firm evidence that the signals transduced by the various SLAM-related receptors are unique and that the specificity of these signals is defined by the distinctive arrays of intracytoplasmic tyrosines in the receptors.
- Subjects :
- Immunoglobulins
Receptors, Cell Surface
In Vitro Techniques
Biology
Models, Biological
Receptor tyrosine kinase
Cell Line
Mice
chemistry.chemical_compound
Signaling Lymphocytic Activation Molecule Family Member 1
Antigens, CD
Signaling Lymphocytic Activation Molecule Family
Animals
Humans
Signaling Lymphocytic Activation Molecule Associated Protein
Phosphorylation
Receptors, Immunologic
Tyrosine
Receptor
Cell Growth and Development
Molecular Biology
Glycoproteins
Membrane Glycoproteins
Intracellular Signaling Peptides and Proteins
Tyrosine phosphorylation
Cell Biology
Lymphoproliferative Disorders
Protein Structure, Tertiary
Cell biology
Killer Cells, Natural
chemistry
Biochemistry
biology.protein
Signal transduction
Carrier Proteins
Tyrosine kinase
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....16e8ebdbb15e142b8b6ea4354b70f545