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GSK-3beta directly phosphorylates and activates MARK2/PAR-1

Shinichi Kosuga1, Etsu Tashiro, Toshifumi Kajioka

  • 1Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.

The Journal of Biological Chemistry
|November 1, 2005
PubMed

Insights

Glycogen synthase kinase-3beta (GSK-3beta) activates MARK2, a kinase that phosphorylates tau protein at Ser-262. This GSK-3beta-MARK2 pathway is crucial for tau phosphorylation in Alzheimer disease (AD) pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Alzheimer disease (AD) is characterized by hyperphosphorylated tau protein aggregates.
  • Serine-262 (Ser-262) is a major abnormal phosphorylation site on tau in AD brains.
  • The activation mechanism of MicroRNA-262 (MARK2), a kinase targeting Ser-262, remains unclear.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase-3beta (GSK-3beta) in the activation of MARK2.
  • To elucidate the pathway responsible for tau phosphorylation at Ser-262 in Alzheimer disease.

Main Methods:

  • Cell-based assays using lithium chloride (LiCl) to inhibit GSK-3beta.
  • In vitro kinase assays with recombinant GSK-3beta and MARK2.
  • Small interfering RNA (siRNA) mediated down-regulation of GSK-3beta and MARK2.

Main Results:

  • GSK-3beta directly phosphorylates MARK2 at Ser-212, a site within its activation loop.
  • Inhibition or down-regulation of GSK-3beta or MARK2 significantly reduced tau phosphorylation at Ser-262.
  • GSK-3beta activates MARK2, which then phosphorylates tau at Ser-262.

Conclusions:

  • Tau phosphorylation at Ser-262 in Alzheimer disease is primarily mediated by a pathway involving GSK-3beta activation of MARK2.
  • This GSK-3beta-MARK2 pathway represents a potential therapeutic target for Alzheimer disease.

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