Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes.
B cell linker protein (BLNK) is a SLP-76-related adaptor protein essential for signal transduction from the BCR. To identify components of BLNK-associated signaling pathways, we performed a phosphorylation-dependent yeast two-hybrid analysis using BLNK probes. Here we report that the serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1), which is activated upon ... antigen-receptor stimulation and which has been implicated in the regulation of MAP kinase pathways, interacts physically and functionally with BLNK in B cells and with SLP-76 in T cells. This interaction requires Tyr(379) of HPK1 and the Src homology 2 (SH2) domain of BLNK/SLP-76. Via homology modeling, we defined a consensus binding site within ligands for SLP family SH2 domains. We further demonstrate that the SH2 domain of SLP-76 participates in the regulation of AP-1 and NFAT activation in response to T cell receptor (TCR) stimulation and that HPK1 inhibits AP-1 activation in a manner partially dependent on its interaction with SLP-76. Our data are consistent with a model in which full activation of HPK1 requires its own phosphorylation on tyrosine and subsequent interaction with adaptors of the SLP family, providing a mechanistic basis for the integration of this kinase into antigen receptor signaling cascades.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Binding Sites, Carrier Proteins, Cell Line, DNA, Complementary, Databases as Topic, Enzyme Activation, Humans, Immunoblotting, Jurkat Cells, Lymphocytes, Mice, Mice, Inbred C57BL, Models, Biological, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Phosphoproteins, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Signal Transduction, T-Lymphocytes, Transcription Factor AP-1, Two-Hybrid System Techniques, Up-Regulation, src Homology Domains
Adaptor Proteins, Signal Transducing, Animals, Binding Sites, Carrier Proteins, Cell Line, DNA, Complementary, Databases as Topic, Enzyme Activation, Humans, Immunoblotting, Jurkat Cells, Lymphocytes, Mice, Mice, Inbred C57BL, Models, Biological, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Phosphoproteins, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Signal Transduction, T-Lymphocytes, Transcription Factor AP-1, Two-Hybrid System Techniques, Up-Regulation, src Homology Domains
J. Biol. Chem.
Date: Nov. 30, 2001
PubMed ID: 11487585
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