The adaptor protein EBP50 is important for localization of the protein kinase A–Ezrin complex in T-cells and the immunomodulating effect of cAMP

2009 ◽  
Vol 425 (2) ◽  
pp. 381-388 ◽  
Author(s):  
Anne Jorunn Stokka ◽  
Randi Mosenden ◽  
Anja Ruppelt ◽  
Birgitte Lygren ◽  
Kjetil Taskén
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
T Cell Activation ◽  
Interleukin 2 ◽  
Adaptor Protein ◽  
Membrane Microdomains ◽  
Type I ◽  
Kinase A

We recently reported that the dual-specificity AKAP (A-kinaseanchoring protein) Ezrin targets type I PKA (protein kinase A) to the vicinity of the TCR (T-cell receptor) in T-cells and, together with PAG (phosphoprotein associated with glycosphingolipid-enriched membrane microdomains) and EBP50 [ERM (Ezrin/Radixin/Moesin)-binding phosphoprotein 50], forms a scaffold that positions PKA close to its substrate, Csk (C-terminal Src kinase). This complex is important for controlling the activation state of T-cells. Ezrin binds the adaptor protein EBP50, which again contacts PAG. In the present study, we show that Ezrin and EBP50 interact with high affinity (KD=58±7 nM). A peptide corresponding to the EB (Ezrin-binding) region in EBP50 (EBP50pep) was used to further characterize the binding kinetics and compete the Ezrin–EBP50 interaction by various methods in vitro. Importantly, loading T-cells with EBP50pep delocalized Ezrin, but not EBP50. Furthermore, disruption of this complex interfered with cAMP modulation of T-cell activation, which is seen as a reversal of cAMP-mediated inhibition of IL-2 (interleukin 2) production, demonstrating an important role of EBP50 in this complex. In summary, both the biochemical and functional data indicate that targeting the Ezrin–EBP interaction could be a novel and potent strategy for immunomodulation.

scholarly journals Inhibition of T Cell Activation by Cyclic Adenosine 5′-Monophosphate Requires Lipid Raft Targeting of Protein Kinase A Type I by the A-Kinase Anchoring Protein Ezrin

2007 ◽  
Vol 179 (8) ◽  
pp. 5159-5168 ◽  
Author(s):  
Anja Ruppelt ◽  
Randi Mosenden ◽  
Mikaela Grönholm ◽  
Einar M. Aandahl ◽  
Derek Tobin ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
T Cell Activation ◽  
Lipid Raft ◽  
Cell Activation ◽  
Type I ◽  
Anchoring Protein ◽  
Kinase A

scholarly journals Impaired Secretion of IL-10 by T Cells from Patients with Common Variable Immunodeficiency–Involvement of Protein Kinase A Type I

2003 ◽  
Vol 170 (11) ◽  
pp. 5772-5777 ◽  
Author(s):  
Are Martin Holm ◽  
Pål Aukrust ◽  
Einar Martin Aandahl ◽  
Fredrik Müller ◽  
Kjetil Taskén ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Common Variable Immunodeficiency ◽  
Type I ◽  
Common Variable ◽  
Kinase A

scholarly journals T cell receptor induced intracellular redistribution of type I protein kinase A

Immunology ◽  
2004 ◽  
Vol 113 (4) ◽  
pp. 453-459 ◽  
Author(s):  
Wenhong Zhou ◽  
Leoncio Vergara ◽  
Rolf Konig
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Type I ◽  
Kinase A

scholarly journals The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells

2009 ◽  
Vol 185 (3) ◽  
pp. 521-534 ◽  
Author(s):  
Yoshihisa Kaizuka ◽  
Adam D. Douglass ◽  
Santosh Vardhana ◽  
Michael L. Dustin ◽  
Ronald D. Vale
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Signaling Molecules ◽  
Membrane Microdomains ◽  
Receptor Interaction

The interaction between a T cell and an antigen-presenting cell (APC) can trigger a signaling response that leads to T cell activation. Prior studies have shown that ligation of the T cell receptor (TCR) triggers a signaling cascade that proceeds through the coalescence of TCR and various signaling molecules (e.g., the kinase Lck and adaptor protein LAT [linker for T cell activation]) into microdomains on the plasma membrane. In this study, we investigated another ligand–receptor interaction (CD58–CD2) that facilities T cell activation using a model system consisting of Jurkat T cells interacting with a planar lipid bilayer that mimics an APC. We show that the binding of CD58 to CD2, in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-ζ chain, Lck, and LAT) into microdomains. When simultaneously activated, TCR and CD2 initially colocalize in small microdomains but then partition into separate zones; this spatial segregation may enable the two receptors to enhance signaling synergistically. Our results show that two structurally distinct receptors both induce a rapid spatial reorganization of molecules in the plasma membrane, suggesting a model for how local increases in the concentration of signaling molecules can trigger T cell signaling.

Additive effects of IL-2 and protein kinase A type I antagonist on function of T cells from HIV-infected patients on HAART

AIDS ◽  
1999 ◽  
Vol 13 (17) ◽  
pp. 109-114 ◽  
Author(s):  
Einar Martin Aandahl ◽  
Pål Aukrust ◽  
Fredrik Müller ◽  
Vidar Hansson ◽  
Kjetil Taskén ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Type I ◽  
Additive Effects ◽  
Kinase A

scholarly journals Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains (Pag), a Novel Ubiquitously Expressed Transmembrane Adaptor Protein, Binds the Protein Tyrosine Kinase Csk and Is Involved in Regulation of T Cell Activation

2000 ◽  
Vol 191 (9) ◽  
pp. 1591-1604 ◽  
Author(s):  
Tomás̆ Brdic̆ka ◽  
Dagmar Pavlis̆tová ◽  
Albrecht Leo ◽  
Eddy Bruyns ◽  
Vladimír Kor̆ínek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Adaptor Protein ◽  
Jurkat Cells ◽  
Negative Regulator ◽  
Membrane Microdomains ◽  
Quiescent State

According to a recently proposed hypothesis, initiation of signal transduction via immunoreceptors depends on interactions of the engaged immunoreceptor with glycosphingolipid-enriched membrane microdomains (GEMs). In this study, we describe a novel GEM-associated transmembrane adaptor protein, termed phosphoprotein associated with GEMs (PAG). PAG comprises a short extracellular domain of 16 amino acids and a 397-amino acid cytoplasmic tail containing ten tyrosine residues that are likely phosphorylated by Src family kinases. In lymphoid cell lines and in resting peripheral blood α/β T cells, PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood α/β T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates. Moreover, overexpression of PAG in Jurkat cells downregulates T cell receptor–mediated activation of the transcription factor nuclear factor of activated T cells. These findings collectively suggest that in the absence of external stimuli, the PAG–Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state.

Abstract 156: Deletion of the Lymphocyte Adaptor Protein LNK Promotes Aortic Dissection

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Fanny Laroumanie ◽  
Mohamed A Saleh ◽  
William McMaster ◽  
Annet Kirabo ◽  
Meenakshi S Madhur
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aortic Dissection ◽  
T Cell Activation ◽  
Ex Vivo ◽  
Adaptor Protein ◽  
T Cell Subsets ◽  
Cytokine Signaling ◽  
Type I ◽  
Ang Ii

Background: The immune response plays a key role in the development of aortic dissection. In particular, interferon gamma (IFNγ), produced by the T cell subsets, Th1 (CD4 + ) and Tc1 (CD8 + ), is elevated in human aortic dissection samples. Interestingly, a polymorphism in the gene SH2B3 that encodes LNK has been associated with several cardiovascular diseases in humans. LNK is an intracellular adaptor protein that has been shown to negatively regulate T cell activation and cytokine signaling. We hypothesized that LNK deficiency promotes aortic dissection through enhanced Th1/Tc1 responses. Methods: Angiotensin II (Ang II; 1000 ng/kg/min) was infused for 14 days into LNK -/- or WT mice in the absence or presence of an initial intraperitoneal injection of saline equal to 10% of their body weight. Kaplan-Meier survival curves were generated and flow cytometry, RT-PCR, histology were used to assess aortic inflammation and remodeling. Naïve CD4 + T cells from WT and LNK -/- mice were polarized ex vivo with Th1 polarizing cytokines and expression of IFNγ and T-bet were evaluated. Results: LNK -/- mice infused with Ang II exhibited an accelerated rate of aortic dissection or rupture compared to WT mice and this was exacerbated by saline injection prior to Ang II infusion (Figure). LNK -/- mice treated with salt plus Ang II exhibited increased aortic inflammation compared to WT mice. Aortic expression of IFNγ, T-bet and MMP9 were increased, while the expression of the procollagens type I and III were reduced in LNK -/- mice compared to WT mice. Ex vivo, naïve CD4 + T cells from LNK -/- mice expressed more T-bet and IFNγ compared to corresponding naïve T cells from WT mice when cultured under Th1 polarizing conditions. Conclusion: Loss of LNK enhances the Th1/Tc1 responses and promotes adverse aortic remodeling leading to development of aortic dissection and rupture. Targeting LNK and the Th1/Tc1 cell subsets could be a potential therapeutic strategy for the management of aortic dissection.

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