Spatiotemporal control of cyclic AMP immunomodulation through the PKA-Csk inhibitory pathway is achieved by anchoring to an Ezrin-EBP50-PAG scaffold in effector T cells |
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| Authors: | Isabelle Cornez |
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| Affiliation: | The Biotechnology Centre of Oslo, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, P.O. Box 1125, Blindern, N-0317 Oslo, Norway |
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| Abstract: | A variety of immunoregulatory signals to effector T cells from monocytes, macrophages and regulatory T cells act through cyclic adenosine monophosphate. In the effector T cell, the protein kinase A (PKA) type I isoenzyme localizes to lipid rafts during T cell activation and modulates directly the proximal events that take place after engagement of the T cell receptor. The most proximal target for PKA phosphorylation is C-terminal Src kinase (Csk), which initiates a negative signal pathway that fine-tunes the T cell activation process. The A kinase anchoring protein Ezrin colocalizes PKA and Csk by forming a supramolecular signaling complex consisting of PKA, Ezrin, Ezrin/radixin/moesin (ERM) binding protein of 50 kDa (EBP50), phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (GEMs) (PAG) and Csk. |
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| Keywords: | AC, adenylyl cyclase AKAP, A kinase anchoring protein APC, antigen presenting cell cAMP, cyclic adenosine monophosphate Cbp, Csk binding protein Csk, C-terminal Src kinase EBP50, Ezrin/radixin/moesin (ERM) binding protein of 50 kDa Gads, Grb-related adaptor downstream of Shc GEFs, guanine nucleotide exchange factors GPCR, G protein-coupled receptor Grb2, growth factor receptor bound protein-2 ITAMs, immunoreceptor tyrosine-based activation motifs LAT, linker for activation of T cells NFAT, nuclear factor of activated T cells NF-κB, nuclear factor κB PAG, phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (GEMs) PDE, phosphodiesterase PI3K, phosphatidylinositol 3 kinase PKA, protein kinase A PKC, protein kinase C PLCγ1, phospholipase Cγ1 PTKs, protein tyrosine kinases PTPs, protein tyrosine phosphatases SH2, Src homology 2 SLP-76, SH2 domain-containing leukocyte protein of 76 kDa TCR, T cell receptor |
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