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Receptor tyrosine kinase activation induces free fatty acid 4 receptor phosphorylation, β-arrestin interaction, and

Sócrates Villegas-Comonfort1, Alejandro Guzmán-Silva1, M Teresa Romero-Ávila1

  • 1Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ap. Postal 70-248, Ciudad de México, 04510, Mexico.

European Journal of Pharmacology
|May 13, 2019
PubMed

Insights

Growth factors like insulin activate Free Fatty Acid Receptor 4 (FFA4) phosphorylation and internalization, revealing cross-talk between receptor tyrosine kinases and FFA4 signaling pathways.

Area of Science:

  • Endocrinology and Metabolism
  • Cell Signaling
  • G Protein-Coupled Receptors

Background:

  • Free Fatty Acid Receptor 4 (FFA4), also known as GPR120, is a G protein-coupled receptor sensing long-chain fatty acids.
  • FFA4 plays a role in metabolism and its dysfunction is linked to endocrine disturbances.
  • FFA4 is known to undergo phosphorylation and internalization upon agonist stimulation and protein kinase C activation.

Purpose of the Study:

  • To investigate the modulation of FFA4 by the activation of receptor tyrosine kinases (RTKs).
  • To elucidate the signaling pathways, including protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K), involved in RTK-mediated FFA4 regulation.
  • To assess the functional consequences of RTK activation on FFA4 signaling and trafficking.

Main Methods:

  • Stimulation of cells with various growth factors, including insulin, epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and platelet-derived growth factor (PDGF).
  • Assessment of FFA4 phosphorylation using Western blotting and measurement of intracellular calcium signaling.
  • Analysis of receptor internalization and β-arrestin co-immunoprecipitation.
  • Inhibition studies using specific blockers for PKC and PI3K.

Main Results:

  • Growth factors significantly increased FFA4 phosphorylation in a time- and concentration-dependent manner.
  • This phosphorylation was sensitive to inhibitors of PKC and PI3K, indicating their involvement.
  • FFA4 phosphorylation did not affect agonist-induced calcium signaling but decreased ERK1/2 phosphorylation.
  • Insulin, IGF-I, and EGF induced FFA4 internalization, an effect blocked by PKC and PI3K inhibitors.
  • Growth factor treatment led to FFA4-β-arrestin co-immunoprecipitation.

Conclusions:

  • Evidence of functional cross-talk between receptor tyrosine kinases and FFA4 was demonstrated.
  • PKC and PI3K play crucial roles in mediating the effects of RTK activation on FFA4.
  • RTK signaling influences FFA4 phosphorylation, trafficking, and downstream signaling events, impacting cellular responses.
Keywords:
FFA4GPR120Receptor internalizationReceptor phosphorylationReceptor tyrosine kinase

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