A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

Biochem Biophys Res Commun. 2016 May 20;474(1):193-198. doi: 10.1016/j.bbrc.2016.04.100. Epub 2016 Apr 21.

Abstract

The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf-MEK-ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2.

Keywords: CalDAG-GEFI; ERK1/2 signaling; GEF; Negative-feedback loop; Phosphorylation; RasGRP2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Enzyme Activation
  • Feedback, Physiological / physiology*
  • Gene Expression Regulation, Enzymologic / physiology*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Phosphorylation

Substances

  • Guanine Nucleotide Exchange Factors
  • RASGRP2 protein, human
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1