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Protein kinase A intersects SRC signaling in membrane microdomains.

Regulation of Src kinase activity is tightly coupled to the phosphorylation status of the C-terminal regulatory tyrosine Tyr(527), which, when phosphorylated by Csk, represses Src. Here, we demonstrate that activation of Csk through a prostaglandin E(2)-cAMP-protein kinase A (PKA) pathway inhibits Src. This inhibitory pathway is operative in detergent-resistant membrane fractions where cAMP-elevating agents activate Csk, resulting in a concomitant decrease in Src activity. The inhibitory effect on Src depends on a detergent-resistant membrane-anchored Csk and co-localization of all components of the inhibitory pathway in membrane microdomains. Furthermore, epidermal growth factor-induced activation of Src and phosphorylation of the Src substrates Cbl and focal adhesion kinase are inhibited by activation of the cAMP-PKA-Csk pathway. We propose a novel mechanism whereby G protein-coupled receptors inhibit Src signaling by activation of Csk in a cAMP-PKA-dependent manner.

Pubmed ID: 12606547


  • Abrahamsen H
  • Vang T
  • Task√©n K


The Journal of biological chemistry

Publication Data

May 9, 2003

Associated Grants


Mesh Terms

  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Humans
  • Jurkat Cells
  • Membrane Microdomains
  • Phosphorylation
  • Protein-Tyrosine Kinases
  • Signal Transduction
  • src Homology Domains
  • src-Family Kinases