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Related Experiment Videos

Galpha and Gbeta gamma require distinct Src-dependent pathways to activate Rap1 and Ras.

John M Schmitt1, Philip J S Stork

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

The Journal of Biological Chemistry
|September 11, 2002
PubMed
Summary

Src tyrosine kinase mediates beta-adrenergic receptor signaling to extracellular signal-regulated kinases (ERKs). This study reveals Src directly activates Rap1 via PKA phosphorylation, distinct from Ras activation, clarifying distinct beta-adrenergic signaling pathways.

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Area of Science:

  • Cellular signaling pathways
  • Receptor-mediated signal transduction
  • Protein kinase function

Background:

  • The beta-adrenergic receptor agonist isoproterenol activates extracellular signal-regulated kinases (ERKs).
  • Src tyrosine kinase is essential for this ERK activation.
  • Ras and Rap1 small G proteins are implicated in isoproterenol signaling to ERKs.

Purpose of the Study:

  • To investigate the role of Src in the activation of Ras and Rap1 by isoproterenol.
  • To elucidate the distinct mechanisms by which beta-adrenergic receptors signal through Src to downstream effectors.
  • To determine if PKA directly phosphorylates Src in response to beta-adrenergic stimulation.

Main Methods:

  • Utilized HEK293 cells and isoproterenol stimulation.

Related Experiment Videos

  • Employed Src mutants (SrcS17A and SrcS17D) to assess PKA-dependent phosphorylation.
  • Investigated the activation of Rap1, Ras, ERKs, and AKT, and their associations (e.g., Rap1/B-Raf).

    • Main Results:

    • Isoproterenol-induced activation of both Rap1 and Ras requires Src.
    • Rap1 activation, Rap1/B-Raf association, and ERK activation are PKA-dependent and blocked by SrcS17A.
    • Ras and AKT activation are Gbetagamma-dependent, PKA-independent, and unaffected by SrcS17A.

    Conclusions:

    • Rap1 activation by isoproterenol is mediated by direct PKA-dependent phosphorylation of Src.
    • Ras activation occurs via a separate, Gbetagamma-dependent pathway.
    • Beta(2)-adrenergic receptor signaling diverges through Src via distinct mechanisms to activate Rap1/ERK and Ras/AKT pathways.