2. Academic Validation
  3. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1

Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1

  • Mol Cell. 2006 Mar 17;21(6):749-60. doi: 10.1016/j.molcel.2006.02.009.
Ulrich Maurer 1,  Céline Charvet,  Allan S Wagman,  Emmanuel Dejardin,  Douglas R Green
Affiliations

Affiliation

  • 1 Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121, USA. ulrich.maurer@mol-med.uni-freiburg.de
PMID: 16543145 DOI: 10.1016/j.molcel.2006.02.009
Abstract

We investigated the role of glycogen synthase kinase-3 (GSK-3), which is inactivated by Akt, for its role in the regulation of Apoptosis. Upon IL-3 withdrawal, protein levels of Mcl-1 decreased but were sustained by pharmacological inhibition of GSK-3, which prevented cytochrome c release and Apoptosis. Mcl-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of Mcl-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by Akt or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of Mcl-1. A phosphorylation-site mutant (Mcl-1(S159A)), expressed in IL-3-dependent cells, showed enhanced stability upon IL-3 withdrawal and conferred increased protection from Apoptosis compared to wild-type Mcl-1. The results demonstrate that the control of Mcl-1 stability by GSK-3 is an important mechanism for the regulation of Apoptosis by growth factors, PI3K, and Akt.

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