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MLK4β functions as a negative regulator of MAPK signaling and cell invasion

W F Abi Saab1, M S Brown, D N Chadee

  • 1Department of Biological Sciences, University of Toledo, Toledo, OH, USA.

Oncogenesis
|April 5, 2013
PubMed

Insights

Mixed lineage kinase 4 beta (MLK4β) suppresses mitogen-activated protein kinase (MAPK) signaling pathways. This novel suppressor inhibits MLK3 activation, blocking cancer cell invasion and matrix metalloproteinase-9 activity.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cancer research

Background:

  • Mixed lineage kinases (MLKs) are typically activators of mitogen-activated protein kinase (MAPK) signaling.
  • MAP3Ks regulate diverse cellular processes through MAPK pathways.

Purpose of the Study:

  • To investigate the role of MLK4β in MAPK signaling.
  • To determine if MLK4β acts as a suppressor of MLK3 activation and cancer cell invasion.

Main Methods:

  • Investigated MLK4β's effect on MAPK and MAP2K activities.
  • Examined MLK4β interaction with MLK3 in HCT116 cells.
  • Assessed MLK4β's impact on matrix metalloproteinase-9 (MMP-9) activity and cell invasion in SKOV3 cells.

Main Results:

  • MLK4β negatively regulates p38, c-Jun N-terminal kinase, extracellular signal-regulated kinase, MEK3, and MEK6.
  • MLK4β inhibits sorbitol- and TNF-induced p38 activation.
  • MLK4β interacts with MLK3 and inhibits MLK3 activation.
  • MLK4β suppresses MMP-9 gelatinase activity and invasion in ovarian cancer cells.

Conclusions:

  • MLK4β is a novel suppressor of MLK3 activation.
  • MLK4β negatively regulates MAPK signaling pathways.
  • MLK4β inhibits cancer cell invasion by suppressing MLK3 and MMP-9 activity.

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