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Calcium-mediated interactions regulate the subcellular localization of extracellular signal-regulated kinases

Dana Chuderland1, Goldie Marmor, Alla Shainskaya

  • 1Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.

The Journal of Biological Chemistry
|February 13, 2008
PubMed

Insights

Calcium levels regulate the cellular localization of extracellular signal-regulated kinases (ERKs). Increased calcium delays ERK nuclear translocation, impacting signaling specificity and substrate interactions.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Calcium Homeostasis

Background:

  • Extracellular signal-regulated kinases (ERKs) are crucial for cellular signaling.
  • ERK subcellular localization influences signal specificity and is potentially regulated by protein interactions.
  • Calcium ions play a significant role in various cellular processes, including signaling pathway modulation.

Purpose of the Study:

  • To investigate the role of calcium in regulating ERK2 subcellular localization and protein interactions.
  • To elucidate the mechanism by which calcium affects ERK translocation and its spatiotemporal regulation.
  • To understand how calcium-mediated localization impacts ERK signaling specificity.

Main Methods:

  • Protein-protein interaction assays to identify ERK2-binding partners under varying calcium concentrations.
  • Cellular localization studies using calcium chelators and elevated calcium levels.
  • In vitro translocation assays to assess the effect of calcium on nuclear import.
  • Stimulation assays using lysophosphatidic acid (LPA) and epidermal growth factor (EGF).

Main Results:

  • Inactive ERK2 interacts with numerous proteins via its cytosolic retention sequence/common docking domain; phospho-ERK2 interacts with fewer substrates.
  • Calcium concentration significantly alters the repertoire of ERK2-interacting proteins.
  • Calcium chelators enhance ERK nuclear translocation, while elevated calcium levels inhibit it.
  • High calcium concentrations impede ERK translocation by interfering with nuclear pore transport, likely via increased binding to nuclear pore proteins.
  • Calcium-dependent delay in ERK translocation was observed upon lysophosphatidic acid stimulation compared to EGF stimulation.

Conclusions:

  • Calcium ions act as critical regulators of ERK subcellular localization.
  • Calcium modulates ERK protein-protein interactions, influencing their release from cytoplasmic anchors.
  • Calcium-dependent regulation of ERK translocation affects their spatiotemporal distribution, impacting signaling specificity and compartmentalization with substrates.

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