TABLE CONTENTS 1. Abstract 2. Introduction 3. Lipid rafts as signaling platforms 4. Initiation of the T-cell signaling cascade 5. Suppression of Src-family PTKs by Csk 6. Spatiotemporal regulation of Csk releases Lck from inhibition and allows T cell activation to occur 7. Regulation of proximal T-cell signaling by PKA type I 8. Regulation of Csk activity, a molecular mechanism for the inhibitory effect of cAMP on immune functions 9. Uncoupling from cAMP immunomodulation by recruitment of a

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... phodiesterase that degrades cAMP 10. Summary and Perspectives 11. Acknowledgments 12. References ABSTRACT 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.