Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2
Copyright policy )Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2
B and T lymphocytes express receptors providing positive and negative co-stimulatory signals. We recently identified a novel co-stimulatory molecule, B and T lymphocyte attenuator (BTLA), which exerts inhibitory effects on B and T lymphocytes. The cytoplasmic domain of murine and human BTLA share three conserved tyrosine-based signaling motifs, a Grb-2 recognition consensus, and two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Phosphorylation of the cytoplasmic domain of BTLA induced the association with the protein tyrosine phosphatases SHP-1 and SHP-2. Association of SHP-1 and SHP-2 to other receptors can involve recruitment to either a single receptor ITIM or to two receptor ITIMs. Here, we analyzed the requirements of BTLA interaction with SHP-1 and SHP-2 in a series of murine and human BTLA mutants. For human BTLA, mutations of either Y257 or Y282, but not Y226, abrogated association with both SHP-1 and SHP-2. For murine BTLA, mutation of either Y274 or Y299, but not Y245, also abrogated association with both SHP-1 and SHP-2. These results indicate that for both murine and human BTLA, association with SHP-1 or SHP-2 requires both of conserved ITIM motifs and does not involve the conserved Grb-2 consensus. Thus, similar to the bisphosphoryl tyrosine-based activation motif (BTAM) by which the Grb-2 associated binder (Gab1), PDGF receptor, and PECAM-1 recruit SHP-2, BTLA also relies on dual ITIMs for its association with the phosphatases SHP-1 and SHP-2.
- Howard Hughes Medical Institute United States
- University of Mary United States
- Washington University in St. Louis United States
Cytoplasm, Binding Sites, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Amino Acid Motifs, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Sequence Homology, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Recombinant Proteins, Jurkat Cells, Mice, Mutation, Animals, Humans, Amino Acid Sequence, Protein Tyrosine Phosphatases, Receptors, Immunologic, Phosphotyrosine, Cells, Cultured, Protein Binding
Cytoplasm, Binding Sites, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Amino Acid Motifs, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Sequence Homology, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Recombinant Proteins, Jurkat Cells, Mice, Mutation, Animals, Humans, Amino Acid Sequence, Protein Tyrosine Phosphatases, Receptors, Immunologic, Phosphotyrosine, Cells, Cultured, Protein Binding
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