Interaction of the Cytoplasmic Tail of CTLA-4 (CD152) with a Clathrin-Associated Protein Is Negatively Regulated by Tyrosine Phosphorylation

Bradshaw, Jeffrey D.; Lü, Ping; Leytze, Gina; Rodgers, Julie; Schieven, Gary L.; Bennett, Kelly L.; Linsley, Peter S.; Kurtz, Stephen E.

doi:10.1021/bi971762i

Cited by 110 publications

(109 citation statements)

References 31 publications

(62 reference statements)

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“…7). The phosphorylation-dependent control of CEACAM1 expression at the cell surface closely parallels that of the well-characterized inhibitory receptor CTLA-4, which is also mediated by AP-2 (45,46). The intracellular storage of these coinhibitory receptors presumably facilitates an early sensitivity to TCR-dependent activating signals, with subsequent diminution as CEACAM1 is delivered to the cell surface.…”

Section: Discussionmentioning

confidence: 73%

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

Lee

Ostrowski

Gray-Owen

2008

The Journal of Immunology

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Neisseria gonorrhoeae colony opacity-associated (Opa) proteins bind to human carcinoembryonic antigen cellular adhesion molecules (CEACAM) found on host cells including T lymphocytes. Opa binding to CEACAM1 suppresses the activation of CD4+ T cells in response to a variety of stimuli. In this study, we use primary human CD4+ T cells isolated from peripheral blood to define the molecular events occurring subsequent to Opa-CEACAM1 binding. We establish that, in contrast to other cell types, T cells do not engulf N. gonorrhoeae upon CEACAM1 binding. Instead, the bacteria recruit CEACAM1 from intracellular stores and maintain it on the T cell surface. Upon TCR ligation, the co-engaged CEACAM1 becomes phosphorylated on tyrosine residues within the ITIMs apparent in the cytoplasmic domain. This allows the recruitment and subsequent activation of the src homology domain 2-containing tyrosine phosphatases SHP-1 and SHP-2 at the site of bacterial attachment, which prevents the normal tyrosine phosphorylation of the CD3ζ-chain and ZAP-70 kinase in response to TCR engagement. Combined, this dynamic response allows the bacteria to effectively harness the coinhibitory function of CEACAM1 to suppress the adaptive immune response at its earliest step.

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Section: Discussionmentioning

confidence: 73%

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

Lee

Ostrowski

Gray-Owen

2008

The Journal of Immunology

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“…Therefore, if CTLA-4 is delivered to the cell surface at an accelerated rate in lupus T cells, its expression may remain elevated despite an increased rate of CTLA-4 internalisation. Surface expression of CTLA-4 is also governed by a motif within the cytoplasmic tail which when phosphorylated prevents its association with clathrin-associated AP-2 and hinders internalisation [48]. It is well established that proximal intracellular signalling is dysfunctional in lupus T cells and this may contribute to alterations in the kinetics of CTLA-4 recycling [49].…”

Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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“…Consistent with this hypothesis, tyrosine 1472 on NR2B is part of a consensus motif (YppØ) for AP-2 binding, a protein that mediates endocytosis via clathrin-coated pits (60). Studies in immune cells have demonstrated that T cell receptors preferentially interact with AP-2 when a tyrosine residue in the cytoplasmic domain of the receptor is nonphosphorylated (1,61). Roche et al (58) have shown that NMDAR internalization in dissociated hippocampal neurons is clathrin-mediated.…”

Section: Figmentioning

confidence: 91%

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

Alvestad¹,

Grosshans²,

Coultrap³

et al. 2003

Journal of Biological Chemistry

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NMDA1 receptors are ionotropic glutamate receptors that mediate calcium and sodium entry into neurons. In the CA1 region of the hippocampus, activation of these receptors is known to be required for induction of long term potentiation (LTP), a cellular process proposed by many as a possible mechanism of memory formation. Aberrant NMDA receptor function can result in cell death and may have implications in pathophysiologic disorders such as Parkinson's disease and epilepsy as well as age-related dementias like Alzheimer's disease (7-11). NMDA receptors are heteromeric assemblies of NR1 and NR2 subunits. The NR1 family is composed of a single gene, which can be alternatively spliced to generate eight theoretical splice variants (12). The NR2 family includes four genes, each encoding a unique subunit: NR2A, NR2B, NR2C, and NR2D (13). A third gene family, NR3, has been discovered, but the function of these subunits is not well understood. Whereas the NR1 subunit is required for a functional channel, differential incorporation of NR2 subunits regulates receptor function. The NR2 subunits, particularly NR2A and NR2B, have been shown to influence the sensitivity of NMDA receptors to ethanol block in cultured neurons as wells as transfected HEK293 cells and oocytes (14 -17). More recent studies have indicated that NR1 subunits may also play a key role in mediating the effects of ethanol on channel activity (18 -20).Ethanol is known to have widespread effects on the central nervous system. Ethanol inhibits transmission at the NMDAR subtype of glutamatergic excitatory synapses and enhances inhibitory GABAergic synaptic transmission. In addition, we and others have demonstrated that ethanol blocks LTP in the hippocampus (6,(21)(22)(23). Given that NMDA receptors are both required for induction of LTP and inhibited by ethanol, it is likely that inhibition of LTP by ethanol in the hippocampus is due, at least in part, to inhibition of NMDA receptors. The molecular mechanisms of this inhibition however, remain unknown.One hypothesis that we favor is that ethanol may inhibit the NMDAR by reducing its phosphorylation. Indeed, ethanol has been shown to enhance protein-tyrosine phosphatase activity and also inhibit receptor tyrosine kinase activity (24, 25). Moreover, previous studies suggest that Fyn, a member of the Src family of tyrosine kinases, may be a key player in regulating the sensitivity of NMDARs to ethanol in the hippocampus (26 -28

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Interaction of the Cytoplasmic Tail of CTLA-4 (CD152) with a Clathrin-Associated Protein Is Negatively Regulated by Tyrosine Phosphorylation

Cited by 110 publications

References 31 publications

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

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