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MEKK2 kinase association with 14-3-3 protein regulates activation of c-Jun N-terminal kinase

Adi E Matitau1, Timothy V Gabor, R Montgomery Gill

  • 1From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.

The Journal of Biological Chemistry
|August 22, 2013
PubMed

Insights

MAP/ERK kinase kinase-2 (MEKK2) phosphorylation at Thr-283 regulates its activity by affecting 14-3-3 binding and downstream pathway signaling. This finding is crucial for understanding stress and mitogenic signal integration.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • MEKK2 (MAP/ERK kinase kinase-2) is a key kinase in the MEKK/STE11 family.
  • It integrates stress and mitogenic signals, activating NF-κB, JNK1/2, p38, and ERK5 pathways.

Purpose of the Study:

  • To investigate the regulatory mechanism of MEKK2 activity.
  • To elucidate the role of phosphorylation and 14-3-3 binding in MEKK2 regulation.

Main Methods:

  • Phosphorylation site analysis of MEKK2.
  • Investigation of MEKK2 association with 14-3-3 adapters.
  • Functional analysis of MEKK2 activity in MEKK2(-/-) cells expressing wild-type and mutant MEKK2.

Main Results:

  • MEKK2 phosphorylation at Thr-283 reduces its activity by decreasing activation loop phosphorylation at Ser-519.
  • 14-3-3 binding to MEKK2 inhibits trans-autophosphorylation at Ser-519.
  • MEKK2 T283A mutation enhances JNK activity and IL-6 expression but reduces ERK activation and proliferation.

Conclusions:

  • Thr-283 phosphorylation is a critical regulatory mechanism for MEKK2 activation.
  • MEKK2 activity is modulated by phosphorylation-dependent 14-3-3 binding.
  • This regulation impacts stress signaling, inflammation, and cell proliferation.
Keywords:
Cell ProliferationGene ExpressionJun N-terminal Kinase (JNK)MAP Kinases (MAPKs)MEKK2Signal Transduction

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