Negative regulation of T-cell receptor activation by the cAMP-PKA-Csk signalling pathway in T-cell lipid rafts.
Spatial organization of signal proteins in specialized cholesterol and glycosphingolipid-enriched microdomains (lipid rafts) provide specificity in lymphocyte signalling. Src kinases associate with lipid rafts on the basis of their dual acylation in the N-terminus and initiate T cell signalling. The immunomodulatory signal enzyme protein kinase A (PKA) is a serine/threonine kinase that controls a number of processes important for immune activation by phosphorylation of substrates that alters protein-protein interactions or changes the enzymatic activity of target proteins in T cells. PKA substrates involved in immune activation include transcription factors, members of the MAP kinase pathway, phospholipases and the Src kinase Csk. The 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 and major target for PKA phosphorylation is the C-terminal Src kinase Csk which initiates a negative signal pathway that fine-tunes the T cell activation process.
Tasken
Kjetil
K
Biotechnology Centre of Oslo, University of Oslo, N-0317 Oslo, Norway. kjetil.tasken@biotek.uio.no
Ruppelt
Anja
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D019061:src-Family Kinases
D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4