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Regulation of ERK2 activity by dynamic S-acylation

Saara-Anne Azizi1, Tian Qiu2, Noah E Brookes2

  • 1Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.

Cell Reports
|September 16, 2023
PubMed

Insights

Extracellular signal-regulated kinases (ERK1/2) gain a new regulatory layer through S-acylation, a reversible lipid modification. This lipidation impacts ERK1/2 signaling and is linked to metabolic syndrome, offering new therapeutic targets.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Extracellular signal-regulated kinases (ERK1/2) are crucial regulators of cellular processes within the mitogen-activated protein kinase pathway.
  • Understanding the post-translational modifications governing ERK1/2 activity is essential for deciphering complex cell signaling networks.

Purpose of the Study:

  • To investigate the novel regulatory mechanism of ERK1/2 through S-acylation.
  • To explore the functional consequences of ERK1/2 S-acylation on signaling pathways and cellular responses.
  • To establish a link between ERK1/2 lipidation and metabolic syndrome.

Main Methods:

  • Identification and characterization of S-acylation sites on ERK1/2 (C271/C254).
  • Analysis of ERK1/2 S-acylation dynamics in response to epidermal growth factor (EGF) signaling.
  • Investigation of the role of protein acyl transferases (PATs) and acyl protein thioesterases (APTs) in regulating ERK1/2 S-acylation.
  • Assessment of the impact of inhibiting S-acylation machinery on EGF-triggered transcriptional programs.
  • Correlation analysis of ERK1/2 lipidation levels with writer/eraser expression in a mouse model of metabolic syndrome.

Main Results:

  • ERK1/2 proteins are subject to S-acylation at cysteine residues C271/C254.
  • ERK1/2 S-acylation levels are dynamically regulated by EGF signaling, mirroring phosphorylation patterns.
  • Acylation-deficient ERK2 exhibits altered phosphorylation dynamics.
  • Inhibition of S-acylation "writers" (PATs) or "erasers" (APTs) modifies ERK1/2's transcriptional response to EGF.
  • In metabolic syndrome models, ERK1/2 lipidation correlates with altered expression of its modifying enzymes, linking lipidation to organismal health.

Conclusions:

  • S-acylation represents a novel, dynamic post-translational modification controlling ERK1/2 activity and signaling.
  • The interplay between S-acylation and phosphorylation fine-tunes cellular responses to growth factor stimulation.
  • Dysregulation of ERK1/2 S-acylation is implicated in metabolic syndrome, highlighting its potential as a therapeutic target.
Keywords:
CP: Molecular biologychemical biologykinase signalinglipidation

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