Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses

Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature Immunology (Impact Factor: 20). 02/2007; 8(1):84-91. DOI: 10.1038/ni1416
Source: PubMed


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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Available from: Jonathan S Boomer, Jun 24, 2014
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    • "Interestingly, we observed that Bam32-PLC-g1- Pak1 complexes compete with Bam32-PLC-g1-HPK1 complexes. Pak1 is related to HPK1, which is, in contrast to Pak1, a negative regulator of Erk activation (Shui et al., 2007). The competition between these two complexes could fine-tune Erk activation. "
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    ABSTRACT: In T cells, the adaptor Bam32 is coupled to Erk activation downstream of the TCR by an unknown mechanism. We characterized in Jurkat cells and primary T lymphocytes a pathway dependent on Bam32-PLC-γ1-Pak1 complexes, in which Pak1 kinase activates Raf-1 and Mek-1, both upstream of Erk. In the Bam32-PLC-γ1-Pak1 complex, catalytically inactive PLC-γ1 is used as a scaffold linking Bam32 to Pak1. PLC-γ1(C-SH2) directly binds S141 of Bam32, preventing LAT-mediated activation of Ras by PLC-γ1. The Bam32-PLC-γ1 interaction enhances the binding of the SH3 domain of the phospholipase with Pak1. The PLC-γ1(SH3)-Pak1 interaction activates Pak1 independently of the small GTPases Rac1/Cdc42, previously described as being the only activators of Pak1 in T cells. Direct binding of the SH3 domain of PLC-γ1 to Pak1 dissociates inactive Pak1 homodimers, a mechanism required for Pak1 activation. We have thus uncovered a LAT/Ras-independent, Bam32-nucleated pathway that activates Erk signaling in T cells.
    Molecular cell 09/2012; 48(2). DOI:10.1016/j.molcel.2012.08.011 · 14.02 Impact Factor
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    • "Aged (40 w) HPK1−/− mice showed reductions of surface IgM density in transitional B-cells (Figure 5D) which leads to a significant increase in the transitional 3/IgMlow fraction (Figure 5E), a phenotype that in an attenuated form reflects the B-cell development observable in anti-HELtg/HELtg mice [33]. The findings of Shui et al. [31] additionally stated a stronger overall increase in specific immunoglobulin levels after T-cell dependent protein antigen administration in HPK1−/− mice, which was suggested to be the result of cognate T-cell hyperreactivity. An alternative explanation of the described B-cell hyperreactivities could be a cell intrinsic defect in limiting Rap1-dependent integrin activation known to be of critical importance in refining antigenic activation thresholds. "
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    ABSTRACT: Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-related serine/threonine kinase activated by a range of environmental stimuli including genotoxic stress, growth factors, inflammatory cytokines and antigen receptor triggering. Being inducibly recruited to membrane-proximal signalling scaffolds to regulate NFAT, AP-1 and NFkappaB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined. By using two loss of function models, we show that HPK1 displays a novel function in regulating B-cell integrin activity. Wehi 231 lymphoma cells lacking HPK1 after shRNA mediated knockdown exhibit increased basic activation levels of Ras-related protein 1 (Rap1), accompanied by a severe lymphocyte function-associated antigen-1 (LFA-1) dependent homotypic aggregation and increased adhesion to intercellular adhesion molecule 1 (ICAM-1). The observed phenotype of enhanced integrin activity is caused downstream of Src, by a signalling module independent of PI3K and PLC, involving HPK1, SKAP55 homologue (SKAP-HOM) and Rap1-GTP-interacting adaptor molecule (RIAM). This alters actin dynamics and renders focal adhesion kinase (FAK) constitutively phosphorylated. Bone marrow and splenic B-cell development of HPK1(-/-) mice are largely unaffected, except age-related tendencies for increased splenic cellularity and BCR downregulation. In addition, naïve splenic knockout B-cells appear hyperresponsive to a range of stimuli applied ex vivo as recently demonstrated by others for T-cells. We therefore conclude that HPK1 exhibits a dual function in B-cells by negatively regulating integrin activity and controlling cellular activation, which makes it an interesting candidate to study in pathological settings like autoimmunity and cancer.
    PLoS ONE 09/2010; 5(9). DOI:10.1371/journal.pone.0012468 · 3.23 Impact Factor
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    • "HPK-1 has a complex relationship with SLP- 76. It can phosphorylate SLP-76; however, this ultimately leads to decreased SLP-76 and PLC- g1 phosphorylation and IL-2 production (Di Bartolo et al. 2007; Shui et al. 2007). SHIP-1 is a lipid phosphatase that mediates Fc receptor-dependent negative signaling (Daeron and Lesourne 2006). "
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    ABSTRACT: The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.
    Cold Spring Harbor perspectives in biology 08/2010; 2(8):a005512. DOI:10.1101/cshperspect.a005512 · 8.68 Impact Factor
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