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Galphaq-dependent activation of mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase cascade

J Yamauchi1, H Itoh, H Shinoura

  • 1Department of Cell Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma-shi, Nara 630-0101, Japan.

Biochemical and Biophysical Research Communications
|November 9, 2001
PubMed

Insights

G-protein-coupled receptors activate c-Jun N-terminal kinase (JNK) via Gq alpha subunits, not Gbetagamma. This pathway involves MKK4, c-Src, and Rho GTPases, offering new insights into cellular signaling.

Area of Science:

  • Cellular signaling pathways
  • G-protein-coupled receptor (GPCR) research
  • Molecular biology

Background:

  • G-protein-coupled receptors (GPCRs) are crucial cell surface receptors involved in numerous physiological processes.
  • Typically, GPCRs activate c-Jun N-terminal kinase (JNK) through G protein betagamma (Gbetagamma) subunits, often involving Rho family small GTPases.
  • The specific mechanisms of JNK activation by different GPCRs, particularly Gq-coupled receptors, require further elucidation.

Purpose of the Study:

  • To investigate the specific G protein subunits mediating JNK activation by the alpha1B-adrenergic receptor, a prototypic Gq-coupled receptor.
  • To identify the downstream signaling molecules involved in this JNK activation pathway.
  • To determine the role of c-Src and Rho family small GTPases in alpha1B-adrenergic receptor-mediated JNK activation.

Main Methods:

  • Transient transfection of human embryonic kidney cells to express the alpha1B-adrenergic receptor and associated G proteins.
  • Utilizing specific inhibitors and genetic manipulations to dissect the signaling pathway.
  • Assessing JNK activation using kinase assays.
  • Studying signaling in native hamster smooth muscle cells expressing the alpha1B-adrenergic receptor.

Main Results:

  • JNK activation by the alpha1B-adrenergic receptor was mediated by the Gq alpha subunit (Galphaq), not Gbetagamma.
  • Mitogen-activated protein kinase kinase 4 (MKK4), but not MKK7, was selectively required for JNK activation.
  • Activation of MKK4 by the alpha1B-adrenergic receptor/Galphaq complex necessitated the involvement of c-Src and Rho family small GTPases.
  • Similar signaling was observed in native hamster smooth muscle cells.

Conclusions:

  • The alpha1B-adrenergic receptor/Galphaq complex activates JNK through a pathway involving MKK4.
  • This activation is dependent on the synergistic action of c-Src family tyrosine kinases and Rho family small GTPases.
  • These findings reveal a distinct mechanism of JNK regulation by Gq-coupled GPCRs in mammalian cells.

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