Mixed lineage kinase-3 stabilizes and functionally cooperates with TRIBBLES-3 to compromise mitochondrial integrity in cytokine-induced death of pancreatic beta cells

J Biol Chem. 2010 Jul 16;285(29):22426-36. doi: 10.1074/jbc.M110.123786. Epub 2010 Apr 26.


Mixed lineage kinases (MLKs) have been implicated in cytokine signaling as well as in cell death pathways. Our studies show that MLK3 is activated in leukocyte-infiltrated islets of non-obese diabetic mice and that MLK3 activation compromises mitochondrial integrity and induces apoptosis of beta cells. Using an ex vivo model of islet-splenocyte co-culture, we show that MLK3 mediates its effects via the pseudokinase TRB3, a mammalian homolog of Drosophila Tribbles. TRB3 expression strongly coincided with conformational change and mitochondrial translocation of BAX. Mechanistically, MLK3 directly interacted with and stabilized TRB3, resulting in inhibition of Akt, a strong suppressor of BAX translocation and mitochondrial membrane permeabilization. Accordingly, attenuation of MLK3 or TRB3 expression each prevented cytokine-induced BAX conformational change and attenuated the progression to apoptosis. We conclude that MLKs compromise mitochondrial integrity and suppress cellular survival mechanisms via TRB3-dependent inhibition of Akt.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Coculture Techniques
  • Cytokines / pharmacology*
  • Enzyme Activation / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / pathology*
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Stability / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Repressor Proteins / metabolism*
  • bcl-2-Associated X Protein / chemistry
  • bcl-2-Associated X Protein / metabolism


  • Cell Cycle Proteins
  • Cytokines
  • Repressor Proteins
  • TRB3 protein, mouse
  • bcl-2-Associated X Protein
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • mitogen-activated protein kinase kinase kinase 11