Abstract
CTLA-4 is well documented in its negative regulation of T-cell proliferation. However, little is known regarding the signaling mechanisms induced by CTLA-4. CTLA-4 associates with the phosphatidylinositol 3-kinase, the phosphatase SHP-2 and the clathrin adaptor complexes AP-1 and AP-2. SHP-2 SH2 domain binding to CTLA-4 is unusual given the absence of a I/VxYxxI/V/L motif. Here, we demonstrate that the phosphorylation of CTLA-4 tyrosines (YVKM and YFIP) fails to allow for single or tandem SHP-2 SH2 domain binding. This was observed using wild-type and inactive SHP-2 as well as a construct with the isolated two SH2 domains. The phosphorylated YVKM and YFIP motifs therefore do not appear to represent novel binding motifs for SHP-2 SH2 domains. At the same time, we could confirm that SHP-2 can associate with CTLA-4 in murine T-cells indicating that the interaction between the phosphatase and CTLA-4 is an indirect event, possibly mediated by PI 3-kinase/SHP-2 binding.
Copyright 2000 Academic Press.
MeSH terms
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Abatacept
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Antigens, CD
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Antigens, Differentiation / chemistry
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism*
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Binding Sites / genetics
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COS Cells
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CTLA-4 Antigen
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Immunoconjugates*
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / chemistry
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Signal Transduction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Tyrosine / chemistry
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Tyrosine / metabolism
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src Homology Domains
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Immunoconjugates
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Intracellular Signaling Peptides and Proteins
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Tyrosine
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Abatacept
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Phosphatidylinositol 3-Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse
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SH2 Domain-Containing Protein Tyrosine Phosphatases