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How does arrestin assemble MAPKs into a signaling complex?

Xiufeng Song1, Sergio Coffa1, Haian Fu1

  • 1Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232 and the Department of Pharmacology, Emory University, Atlanta, Georgia 30322.

The Journal of Biological Chemistry
|November 13, 2008
PubMed

Insights

Arrestins act as scaffolds for mitogen-activated protein kinase (MAPK) pathways. Arrestin3 specifically activates JNK3, revealing new insights into arrestin-mediated MAPK signaling.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Biochemistry

Background:

  • Arrestins bind activated G protein-coupled receptors, redirecting signaling.
  • Arrestins also function as scaffolds for mitogen-activated protein kinase (MAPK) pathways.
  • The specific roles of different arrestin isoforms in MAPK activation are not fully understood.

Purpose of the Study:

  • To investigate the interaction of arrestins with components of the ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2 MAPK cascades.
  • To determine the functional specificity of arrestins in mediating MAPK activation.
  • To elucidate the molecular mechanisms underlying arrestin-mediated MAPK signaling.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • In vitro kinase assays to measure MAPK activation.
  • Site-directed mutagenesis to identify binding elements.

Main Results:

  • All four vertebrate arrestins interact with JNK3, MKK4, and ASK1.
  • Only arrestin3 facilitates JNK3 activation, independent of receptor binding.
  • Key arrestin-binding elements were identified in JNK3 and ASK1.
  • Both arrestin2 and arrestin3 domains interact with all six tested kinases.

Conclusions:

  • Arrestin's functional specificity in MAPK activation is not solely determined by differential kinase binding.
  • Free arrestin3 can directly promote JNK3 phosphorylation.
  • Arrestin domains interact with multiple kinases, suggesting a scaffold function in organizing MAPK signaling modules.

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