Abstract
The T and natural killer (NK) cell-specific gene SAP (SH2D1A) encodes a 'free SH2 domain' that binds a specific tyrosine motif in the cytoplasmic tail of SLAM (CD150) and related cell surface proteins. Mutations in SH2D1A cause the X-linked lymphoproliferative disease, a primary immunodeficiency. Here we report that a second gene encoding a free SH2 domain, EAT-2, is expressed in macrophages and B lympho cytes. The EAT-2 structure in complex with a phosphotyrosine peptide containing a sequence motif with Tyr281 of the cytoplasmic tail of CD150 is very similar to the structure of SH2D1A complexed with the same peptide. This explains the high affinity of EAT-2 for the pTyr motif in the cytoplasmic tail of CD150 but, unlike SH2D1A, EAT-2 does not bind to non-phosphorylated CD150. EAT-2 binds to the phosphorylated receptors CD84, CD150, CD229 and CD244, and acts as a natural inhibitor, which interferes with the recruitment of the tyrosine phosphatase SHP-2. We conclude that EAT-2 plays a role in controlling signal transduction through at least four receptors expressed on the surface of professional antigen-presenting cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Motifs
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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B-Lymphocytes / metabolism*
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Base Sequence
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Blood Coagulation Factors*
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COS Cells
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Glycoproteins / metabolism*
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Humans
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Immunoglobulins / metabolism*
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Intracellular Signaling Peptides and Proteins*
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Macromolecular Substances
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Macrophages / metabolism*
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Mice
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Models, Molecular*
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Molecular Sequence Data
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Protein Binding / physiology
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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 / antagonists & inhibitors
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Protein Tyrosine Phosphatases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-fyn
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Receptors, Cell Surface / metabolism
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Sequence Homology, Amino Acid
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Signal Transduction / physiology
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family Member 1
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Transcription Factors / chemistry*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Two-Hybrid System Techniques
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X-Ray Diffraction
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src Homology Domains / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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Blood Coagulation Factors
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Carrier Proteins
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Glycoproteins
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Immunoglobulins
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Proto-Oncogene Proteins
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Receptors, Cell Surface
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SH2D1A protein, human
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SH2D1B protein, human
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SLAMF1 protein, human
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Sh2d1a protein, mouse
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Sh2d1b1 protein, mouse
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Signaling Lymphocytic Activation Molecule Associated Protein
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Transcription Factors
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activated protein C receptor
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Signaling Lymphocytic Activation Molecule Family Member 1
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FYN protein, human
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Fyn protein, mouse
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Proto-Oncogene Proteins c-fyn
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PTPN11 protein, human
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PTPN6 protein, human
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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
Associated data
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GENBANK/AF256653
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PDB/1I3Z