Article

Lymphocyte calcium signaling from membrane to nucleus.

Program in Immunology, Stanford University, Stanford, California 94305, USA.
Nature Immunology (Impact Factor: 24.97). 02/2006; 7(1):25-32. DOI: 10.1038/ni1295
Source: PubMed

ABSTRACT Ca(2+) signals control a variety of lymphocyte responses, ranging from short-term cytoskeletal modifications to long-term changes in gene expression. The identification of molecules and channels that modulate Ca(2+) entry into T and B lymphocytes has both provided details of the molecular events leading to immune responses and raised controversy. Here we review studies of the pathways that allow Ca(2+) entry, the function of Ca(2+) in the regulation of cell polarity and motility and the principles by which Ca(2+)-dependent transcription regulates lymphocyte function.

0 Followers
 · 
102 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Upon B-cell antigen receptor (BCR) activation, the protein tyrosine kinase Syk phosphorylates the adaptor protein SH2 domain-containing leukocyte protein of 65 kDa (SLP-65), thus coupling the BCR to diverse signalling pathways. Here, we report that SLP-65 is not only a downstream target and substrate of Syk but also a direct binding-partner and activator of this kinase. This positive feedback is mediated by the binding of the SH2 domain of SLP-65 to an autophosphorylated tyrosine of Syk. The mutant B cells that cannot form the Syk/SLP-65 complex are defective in BCR-induced extracellular signal-regulated kinase, nuclear factor kappa B and nuclear factor of activated T cells, but not Akt activation, and are blocked in B-cell development. Furthermore, we show that formation of the Syk/SLP-65 complex is required for sustained Ca(2+) responses in activated B cells. We suggest that after activation and internalization of the BCR, Syk remains active as part of a membrane-bound Syk/SLP-65 complex controlling sustained signalling and calcium influx.
    The EMBO Journal 06/2008; 27(9):1333-44. DOI:10.1038/emboj.2008.62 · 10.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenic mycobacteria survive within macrophages by avoiding lysosomal delivery, instead residing in mycobacterial phagosomes. Upon infection, the leukocyte-specific protein coronin 1 is actively recruited to mycobacterial phagosomes, where it blocks lysosomal delivery by an unknown mechanism. Analysis of macrophages from coronin 1-deficient mice showed that coronin 1 is dispensable for F-actin-dependent processes such as phagocytosis, motility, and membrane ruffling. However, upon mycobacterial infection, coronin 1 was required for activation of the Ca(2+)-dependent phosphatase calcineurin, thereby blocking lysosomal delivery of mycobacteria. In the absence of coronin 1, calcineurin activity did not occur, resulting in lysosomal delivery and killing of mycobacteria. Furthermore, blocking calcineurin activation with cyclosporin A or FK506 led to lysosomal delivery and intracellular mycobacterial killing. These results demonstrate a role for coronin 1 in activating Ca(2+) dependent signaling processes in macrophages and reveal a function for calcineurin in the regulation of phagosome-lysosome fusion upon mycobacterial infection.
    Cell 08/2007; 130(1):37-50. DOI:10.1016/j.cell.2007.04.043 · 33.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphocyte signaling and activation leads to the influx of extracellular Ca(2+) via the activation of Ca(2+) release activated Ca(2+) (CRAC) channels in the plasma membrane. Activation of CRAC channels occurs following emptying of the endoplasmic reticulum intracellular Ca(2+) stores. One model to explain the coupling of store-emptying to CRAC activation is the secretion-like conformational coupling model. This model proposes that store depletion increases junctions between the endoplasmic reticulum and the plasma membrane in a manner that could be regulated by the cortical actin cytoskeleton. Here, we show that stabilization or depolymerization of the actin cytoskeleton failed to affect CRAC activation. We therefore conclude that rearrangement of the actin cytoskeleton is dispensable for store-operated Ca(2+) entry in T-cells.
    FEBS Letters 08/2007; 581(18):3557-62. DOI:10.1016/j.febslet.2007.06.068 · 3.34 Impact Factor

Preview

Download
2 Downloads
Available from