The SH3 domain-containing adaptor HIP-55 mediates c-Jun N-terminal kinase activation in T cell receptor signaling.
HIP-55 (hematopoietic progenitor kinase 1 (HPK1)-interacting protein of 55 kDa, also called SH3P7 and mAbp1) is a novel SH3 domain-containing protein. HIP-55 binds to actin filaments both in vitro and in vivo. HIP-55 activates HPK1 and c-Jun N-terminal kinase (JNK), which are two important lymphocyte signaling molecules. Until now, the ... regulation and function of HIP-55 in T cell receptor (TCR) signaling were unknown. We found that HIP-55 was recruited to glycolipid-enriched microdomains upon TCR stimulation, which indicates that HIP-55 is regulated by TCR signaling. HIP-55 interacted with ZAP-70, a critical protein-tyrosine kinase in TCR signaling, and this interaction was induced by TCR signaling. ZAP-70 phosphorylated HIP-55 at Tyr-334 and Tyr-344 in vitro and in vivo, and the HIP-55 mutant (Y334F/Y344F) was not tyrosine-phosphorylated in stimulated T cells. To study its function in T cell activation, HIP-55-deficient Jurkat T cells were established using the RNA interference approach. In the HIP-55-deficient cells, TCR (but not UV)-stimulated JNK activation was decreased. Furthermore, the activation of HPK1, a known JNK upstream activator and HIP-55-interacting protein, was also decreased in the HIP-55-deficient cells. Our data reveal the regulation of HIP-55 during TCR signaling, and using a genetic approach, we demonstrate for the first time that HIP-55 plays a functional role in TCR signaling.
Mesh Terms:
Blotting, Western, Carrier Proteins, Cell Line, Enzyme Activation, Gene Expression Regulation, Humans, JNK Mitogen-Activated Protein Kinases, Jurkat Cells, Mitogen-Activated Protein Kinases, Phosphorylation, Plasmids, Precipitin Tests, Protein Structure, Tertiary, Protein Transport, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Transfection, Tyrosine, Ultraviolet Rays, ZAP-70 Protein-Tyrosine Kinase, src Homology Domains
Blotting, Western, Carrier Proteins, Cell Line, Enzyme Activation, Gene Expression Regulation, Humans, JNK Mitogen-Activated Protein Kinases, Jurkat Cells, Mitogen-Activated Protein Kinases, Phosphorylation, Plasmids, Precipitin Tests, Protein Structure, Tertiary, Protein Transport, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Transfection, Tyrosine, Ultraviolet Rays, ZAP-70 Protein-Tyrosine Kinase, src Homology Domains
J. Biol. Chem.
Date: Dec. 26, 2003
PubMed ID: 14557276
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