Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association.
Through the interaction with its ligands, CD80/B7-1 and CD86/B7-2 or B70, the human CD28 molecule plays a major functional role as a costimulator of T cells along with the CD3-TcR complex. We and others have previously reported that phosphatidylinositol 3-kinase inducibly associates with CD28. This association is mediated by the ... SH2 domains of the p85 adaptor subunit interacting with a cytoplasmic YMNM consensus motif present in CD28 at position 173-176. Disruption of this binding site by site-directed mutagenesis abolishes CD28-induced activation events in a murine T-cell hybridoma transfected with human CD28 gene. Here we show that the last 10 residues of the intracytoplasmic domain of CD28 (residues 193-202) are required for its costimulatory function. These residues are involved in interleukin-2 secretion, p85 binding, and CD28-associated phosphatidylinositol 3-kinase activity. In contrast, the CD28/CD8O interaction is unaffected by this deletion, as is the induction of other second messengers such as the rise in intracellular calcium and tyrosine phosphorylation of CD28-specific substrates. Furthermore, we also demonstrate that, within these residues, the tyrosine at position 200 is involved in p85 binding, probably together with the short proline-rich motif present between residues 190 and 194 (PYAPP).
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Amino Acid Sequence, Animals, Antigens, CD28, Binding Sites, Cytoplasm, Humans, Interleukin-2, Kinetics, Ligands, Mice, Molecular Sequence Data, Mutagenesis, Mutagenesis, Site-Directed, Phosphotransferases (Alcohol Group Acceptor), Point Mutation, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Recombinant Proteins, Second Messenger Systems, Sequence Deletion, T-Lymphocytes, Transfection, Tyrosine, src Homology Domains
1-Phosphatidylinositol 3-Kinase, Amino Acid Sequence, Animals, Antigens, CD28, Binding Sites, Cytoplasm, Humans, Interleukin-2, Kinetics, Ligands, Mice, Molecular Sequence Data, Mutagenesis, Mutagenesis, Site-Directed, Phosphotransferases (Alcohol Group Acceptor), Point Mutation, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Recombinant Proteins, Second Messenger Systems, Sequence Deletion, T-Lymphocytes, Transfection, Tyrosine, src Homology Domains
J. Biol. Chem.
Date: Apr. 19, 1996
PubMed ID: 8621607
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