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Direct modulation of the protein kinase A catalytic subunit α by growth factor receptor tyrosine kinases

George B Caldwell1, Alan K Howe, Christian K Nickl

  • 1Department of Medical Laboratory and Radiation Sciences, The University of Vermont, Burlington, Vermont 05405, USA.

Journal of Cellular Biochemistry
|August 26, 2011
PubMed

Insights

Growth factor receptors directly regulate protein kinase A (PKA) activity through tyrosine phosphorylation of its catalytic subunit. This novel signaling pathway enhances PKA enzymatic function, impacting cell growth and migration.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Protein kinase A (PKA) regulates cell proliferation and migration, processes downstream of growth factor receptor tyrosine kinases (RTKs).
  • The precise signaling mechanisms connecting PKA and RTKs have been largely unknown.

Purpose of the Study:

  • To investigate the direct interaction between RTKs and PKA.
  • To identify the post-translational modifications involved in RTK-mediated regulation of PKA.

Main Methods:

  • In vitro kinase assays using epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors.
  • Mass spectrometry to identify phosphorylation sites on PKA catalytic subunit (PKA-C).
  • Site-directed mutagenesis (Y330F) to assess the role of tyrosine 330 phosphorylation.
  • Enzyme kinetics (K(m) determination) to measure PKA activity.
  • Cellular assays in response to EGF, PDGF, and fibroblast growth factor 2 (FGF2).

Main Results:

  • RTKs (EGFR and PDGFR) directly tyrosine phosphorylate PKA-C.
  • Tyrosine 330 (Y330) on PKA-C was identified as a key receptor-mediated phosphorylation site.
  • Phosphorylation at Y330 significantly decreased the K(m) for a peptide substrate, indicating increased PKA enzymatic activity.
  • Tyrosine-phosphorylated PKA-C was detected in cells stimulated with growth factors and in migrating fibroblasts.

Conclusions:

  • RTKs directly modulate PKA-C function via tyrosine phosphorylation at Y330.
  • This identifies a novel mechanism of PKA regulation, linking RTK signaling to PKA activity.
  • The findings reveal a direct functional interaction between RTKs and PKA, impacting cellular processes like migration.

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