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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.

Pubmed ID: 11487585

Authors

  • Sauer K
  • Liou J
  • Singh SB
  • Yablonski D
  • Weiss A
  • Perlmutter RM

Journal

The Journal of biological chemistry

Publication Data

November 30, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA72531

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