Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HPK1 is a Ste20-related serine-threonine kinase that inducibly associates with the adaptors SLP-76 and Gads after T cell receptor (TCR) signaling. Here, HPK1 deficiency resulted in enhanced TCR-induced phosphorylation of SLP-76, phospholipase C-gamma1 and the kinase Erk, more-persistent calcium flux, and increased production of cytokines and antigen-specific antibodies. Furthermore, HPK1-deficient mice were more susceptible to experimental autoimmune encephalomyelitis. Although the interaction between SLP-76 and Gads was unaffected, the inducible association of SLP-76 with 14-3-3tau (a phosphorylated serine-binding protein and negative regulator of TCR signaling) was reduced in HPK1-deficient T cells after TCR stimulation. HPK1 phosphorylated SLP-76 and induced the interaction of SLP-76 with 14-3-3tau. Our results indicate that HPK1 negatively regulates TCR signaling and T cell-mediated immune responses.
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PMID:Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses. 1711 60

TCR stimulation not only initiates positive signals for T cell activation, but also induces negative signals that down-regulate T cells. We previously reported that Sprouty1, a negative regulator of Ras-MAPK pathway of receptor tyrosine kinases, was induced by TCR signal and inhibited TCR signaling in CD4+ T cell clones. In this study, we addressed the mechanism underlying Sprouty1 inhibition of T cells. When overexpressed in Jurkat T cells, Sprouty1 inhibited TCR signal-induced IL-2 transcription, and also AP-1, NFAT, and NF-kappaB activation, which suggests that Sprouty1 acts at proximal TCR signalosome. Accordingly, we found that Sprouty1 translocated to immune synapse upon TCR engagement in both Jurkat cells and activated primary T cells and interacted with various signaling molecules in the TCR signalosome, such as linker for activation of T cells (LAT), phospholipase C-gamma1 (PLC-gamma1), c-Cbl/Cbl-b, and HPK1. Sprouty1 inhibited LAT phosphorylation, leading to decreased MAPK activation and IL-2 production. Deletion of C-terminal 54 amino acids in Sprouty1 abolished its inhibitory effect and this deletion mutant was unable to translocate to immune synapse and interact with LAT. Overall, our data suggest that Sprouty1 induced by TCR signal negatively regulates further TCR signaling by interacting with proximal signaling molecules in immune synapse, providing a novel regulatory mechanism of T cells.
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PMID:Recruitment of Sprouty1 to immune synapse regulates T cell receptor signaling. 1991 61