Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest

Biochem Biophys Res Commun. 2002 Sep 13;297(1):105-10. doi: 10.1016/s0006-291x(02)02123-x.


The leucine-zipper (LZ) and sterile-alpha motif (SAM) kinase (ZAK) belongs to the MAP kinase kinase kinase (MAP3K) when upon over-expression in mammalian cells activates the JNK/SAPK pathway. The mechanisms by which ZAK activity is regulated are not well understood. Co-expression of dominant-negative MKK7 but not MKK4 and ZAK significantly attenuates JNK/SAPK activation. This result suggests that ZAK activates JNK/SAPK mediated by downstream target, MKK7. Expression of ZAK but not kinase-dead ZAK in 10T1/2 cells results in the disruption of actin stress fibers and morphological changes. Therefore, ZAK activity may be involved in actin organization regulation. Expression of wild-type ZAK increases the cell population in the G(2)/M phase of the cell cycle, which may indicate G(2) arrest. Western blot analysis shows that the decreased cyclin E level correlated strongly with the low proliferative capacity of ZAK-expressed cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Cell Cycle / physiology
  • Cell Cycle Proteins / biosynthesis
  • Cell Size / physiology
  • Enzyme Activation
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4*
  • MAP Kinase Kinase 7
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein Kinases / physiology
  • Tumor Cells, Cultured


  • Actins
  • Cell Cycle Proteins
  • Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K20 protein, human
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 7
  • MAP2K4 protein, human
  • MAP2K7 protein, human
  • Mitogen-Activated Protein Kinase Kinases