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Updated: Oct 2, 2026

Development and Application of Rapamycin-regulated Tyrosine Phosphatases
06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

PKA phosphorylation of Src mediates cAMP's inhibition of cell growth via Rap1

John M Schmitt1, Philip J S Stork

  • 1Vollum Institute and Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, OR 97201, USA.

Molecular Cell
|January 24, 2002
PubMed

Insights

Cyclic AMP (cAMP) inhibits fibroblast cell growth by activating protein kinase A (PKA), which then activates Src tyrosine kinase. This pathway regulates cell proliferation and ERK signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Cyclic AMP (cAMP) is a crucial second messenger that regulates various cellular processes.
  • cAMP antagonizes growth factor signaling pathways, including extracellular signal-regulated kinases (ERKs), and inhibits cell growth in fibroblasts.
  • The precise molecular mechanisms underlying cAMP's antiproliferative effects are not fully elucidated.

Purpose of the Study:

  • To investigate the role of protein kinase A (PKA) and the small G protein Rap1 in cAMP-mediated inhibition of ERK activation and cell growth.
  • To identify the specific signaling molecules and pathways involved in PKA's activation of Rap1.
  • To elucidate the function of Src tyrosine kinase in the cAMP signaling pathway.

Main Methods:

  • Fibroblast cell culture and stimulation.
  • Western blotting to detect protein phosphorylation and activation.
  • In vitro kinase assays.
  • Rap1 activation assays.
  • Cell proliferation assays.

Main Results:

  • PKA activation of Rap1 is mediated by a signaling complex including C3G, Crk-L, Cbl, and Src.
  • Src tyrosine kinase is essential for cAMP-induced activation of Rap1 and subsequent inhibition of ERKs and cell growth.
  • PKA directly phosphorylates Src at serine 17, which is critical for Src activation and the downstream signaling cascade.
  • This phosphorylation event is required for cAMP's inhibitory effects on ERK signaling and cell proliferation.

Conclusions:

  • Src tyrosine kinase plays an antiproliferative role in the physiological regulation of cell growth by cAMP.
  • The PKA-Src signaling axis represents a key pathway through which cAMP exerts its inhibitory effects on cell proliferation.
  • Understanding this pathway provides insights into potential therapeutic targets for diseases involving aberrant cell growth.

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