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The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines

Nikolaos Charlaftis1, Tesha Suddason1, Xuefeng Wu2

  • 1Department of Medicine, Imperial College London, London, UK.

The EMBO Journal
|September 28, 2014
PubMed

Insights

The MEKK1 PHD motif is crucial for regulating p38 and JNK activation in response to TGF-β and EGF signaling. This motif controls TAB1 ubiquitination, impacting cell differentiation and tumor development.

Area of Science:

  • Cellular signaling pathways
  • Molecular mechanisms of kinase regulation
  • Ubiquitination and post-translational modifications

Background:

  • Mitogen-activated protein kinase kinases (MAP3Ks) are key regulators of cellular signaling.
  • MEKK1, a specific MAP3K, possesses a unique PHD motif whose function remains largely unexplored.
  • Understanding the role of the MEKK1 PHD motif is essential for deciphering its contribution to cellular processes and disease.

Purpose of the Study:

  • To investigate the functional significance of the PHD motif in MEKK1.
  • To elucidate the molecular mechanisms by which the MEKK1 PHD motif regulates downstream signaling pathways.
  • To determine the role of MEKK1 and its PHD motif in cellular differentiation and tumorigenesis.

Main Methods:

  • Generation of a knockin mouse model (Map3k1(m)(PHD)) with an inactivated MEKK1 PHD motif.
  • Utilized ES cells from the knockin model for signaling pathway analysis.
  • Employed protein microarray profiling to identify PHD substrates.
  • Investigated ubiquitination patterns of MEKK1 and TAB1 using biochemical assays.
  • Analyzed the impact of PHD motif inactivation on cellular differentiation and tumor development in vivo.

Main Results:

  • The MEKK1 PHD motif is essential for activating p38 and JNK signaling in response to TGF-β, EGF, and microtubule disruption, but not hyperosmotic stress.
  • TAB1 was identified as a substrate of the MEKK1 PHD motif.
  • Inactivation of the MEKK1 PHD motif led to defective non-canonical ubiquitination of MEKK1 and TAB1.
  • The MEKK1 PHD mediates Lys63-linked polyubiquitination of TAB1, regulating TAK1 and MAPK activation.
  • MEKK1 PHD and TAB1 are critical for ES-cell differentiation and tumorigenesis, with Map3k1(m)(/+) mice showing developmental defects.

Conclusions:

  • The MEKK1 PHD motif plays a critical role in regulating specific MAPK signaling pathways through TAB1 ubiquitination.
  • This regulatory mechanism is vital for embryonic stem cell differentiation and tumor suppression.
  • Dysfunction of the MEKK1 PHD motif contributes to aberrant development and signaling in various tissues.
Keywords:
differentiationsignallingstem celltumourigenesisubiquitin

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