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Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival.

Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates c-jun N-terminal kinase (JNK) and can induce cell death in neurons. By contrast, the activation of phosphatidylinositol 3-kinase and AKT/protein kinase B (PKB) acts to suppress neuronal apoptosis. Here, we report a functional interaction between MLK3 and AKT1/PKBalpha. Endogenous MLK3 and AKT1 interact in HepG2 cells, and this interaction is regulated by insulin. The interaction domain maps to the C-terminal half of MLK3 (amino acids 511-847), and this region also contains a putative AKT phosphorylation consensus sequence. Endogenous JNK, MKK7, and MLK3 kinase activities in HepG2 cells are significantly attenuated by insulin treatment, whereas the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin reversed the effect. Finally, MLK3-mediated JNK activation is inhibited by AKT1. AKT phosphorylates MLK3 on serine 674 both in vitro and in vivo. Furthermore, the expression of activated AKT1 inhibits MLK3-mediated cell death in a manner dependent on serine 674 phosphorylation. Thus, these data provide the first direct link between MLK3-mediated cell death and its regulation by a cell survival signaling protein, AKT1.

Pubmed ID: 12458207


  • Barthwal MK
  • Sathyanarayana P
  • Kundu CN
  • Rana B
  • Pradeep A
  • Sharma C
  • Woodgett JR
  • Rana A


The Journal of biological chemistry

Publication Data

February 7, 2003

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM55853

Mesh Terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Cell Survival
  • DNA Primers
  • HeLa Cells
  • Humans
  • MAP Kinase Kinase Kinases
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt