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PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells.

ABSTRACT: BACKGROUND: PAG/Cbp represents a ubiquitous mechanism for regulating Src family kinases by recruiting Csk to the plasma membrane, thereby controlling cellular activation. Since Src kinases are known oncogenes, we used RNA interference in primary human T cells to test whether the loss of PAG resulted in lymphocyte transformation. RESULTS: PAG-depletion enhanced Src kinase activity and augmented proximal T-cell receptor signaling; exactly the phenotype expected for loss of this negative regulator. Surprisingly, rather than becoming hyper-proliferative, PAG-suppressed T cells became unresponsive. This was mediated by a Fyn-dependent hyper-phosphorylation of the inhibitory receptor CTLA-4, which recruited the protein tyrosine phosphatase Shp-1 to lipid rafts. Co-suppression of CTLA-4 abrogates this inhibition and restores proliferation to T cells. CONCLUSION: We have identified a fail-safe mechanism as well as a novel contribution of CTLA-4 to setting the activation threshold in T cells.

SUBMITTER: Smida M 

PROVIDER: S-EPMC3763844 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells.

Smida Michal M   Cammann Clemens C   Gurbiel Slavyana S   Kerstin Nadja N   Lingel Holger H   Lindquist Sabine S   Simeoni Luca L   Brunner-Weinzierl Monika C MC   Suchanek Miloslav M   Schraven Burkhart B   Lindquist Jonathan A JA  

Cell communication and signaling : CCS 20130419 1

<h4>Background</h4>PAG/Cbp represents a ubiquitous mechanism for regulating Src family kinases by recruiting Csk to the plasma membrane, thereby controlling cellular activation. Since Src kinases are known oncogenes, we used RNA interference in primary human T cells to test whether the loss of PAG resulted in lymphocyte transformation.<h4>Results</h4>PAG-depletion enhanced Src kinase activity and augmented proximal T-cell receptor signaling; exactly the phenotype expected for loss of this negati  ...[more]