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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
07:09

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Published on: January 7, 2019

Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis

Caroline Morel1, Scott M Carlson, Forest M White

  • 1Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Molecular and Cellular Biology
|May 13, 2009
PubMed

Insights

Stress-induced Mcl-1 protein degradation requires coordinated c-Jun N-terminal protein kinase (JNK) and glycogen synthase kinase 3 (GSK3) activity. JNK phosphorylation of Mcl-1 is essential for subsequent GSK3 phosphorylation and degradation, integrating survival and apoptotic signals.

Area of Science:

  • Cell biology
  • Molecular biology
  • Biochemistry

Background:

  • Mcl-1 is a crucial regulator of cell survival within the Bcl-2 protein family.
  • Cellular stress triggers Mcl-1 mRNA translation inhibition and protein degradation.
  • Glycogen synthase kinase 3 (GSK3) mediates Mcl-1 degradation via a phosphodegron pathway.

Purpose of the Study:

  • To elucidate the signaling pathway regulating stress-induced Mcl-1 degradation.
  • To investigate the role of c-Jun N-terminal protein kinase (JNK) in Mcl-1 regulation.
  • To define Mcl-1's function as a signal integration point.

Main Methods:

  • Phosphorylation assays to determine kinase activity.
  • Proteasomal degradation studies.
  • Western blotting to analyze protein levels and phosphorylation states.

Main Results:

  • Prior phosphorylation of Mcl-1 by JNK is essential for GSK3 phosphorylation.
  • Stress-induced Mcl-1 degradation necessitates the combined action of JNK and GSK3.
  • Mcl-1 integrates signals from JNK (proapoptotic) and AKT (prosurvival) pathways.

Conclusions:

  • Mcl-1 degradation is a coordinated process involving sequential phosphorylation by JNK and GSK3.
  • Mcl-1 acts as a molecular hub, integrating opposing cellular survival and death signals.
  • Understanding this pathway offers insights into therapeutic strategies targeting cell survival and apoptosis.

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