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Syk-mediated tyrosine phosphorylation of mule promotes TNF-induced JNK activation and cell death

C K Lee1, Y Yang2, C Chen1

  • 1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Oncogene
|July 28, 2015
PubMed

Insights

Tumor Necrosis Factor (TNF) activates Mule by triggering its phosphorylation, causing dissociation from its inhibitor ARF. This process is crucial for TNF-induced JNK activation and cell death.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Immunology

Background:

  • Tumor Necrosis Factor (TNF) triggers JNK activation and cell death pathways.
  • Miz1 transcription factor regulates TNF-induced JNK activation by suppressing TRAF2 ubiquitination.
  • Mule/ARF-BP1 mediates Miz1 degradation upon TNF stimulation, but its activation mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which TNF activates Mule.
  • To identify the upstream regulators of Mule in the TNF signaling pathway.
  • To understand the role of Mule activation in TNF-induced JNK signaling and cell death.

Main Methods:

  • Cellular assays to study protein-protein interactions and phosphorylation.
  • Western blotting to detect protein ubiquitination and degradation.
  • RNA interference (RNAi) to silence Spleen Tyrosine Kinase (Syk).

Main Results:

  • TNF stimulation induces tyrosine phosphorylation of Mule, leading to its dissociation from the inhibitor ARF.
  • Activated Mule exhibits E3 ligase activity, promoting Miz1 degradation.
  • Inhibition of Mule phosphorylation by silencing Syk prevents Mule-ARF dissociation and downstream JNK activation and cell death.

Conclusions:

  • TNF activates Mule via ARF dissociation, mediated by tyrosine phosphorylation.
  • Syk is a key upstream kinase regulating Mule activity in TNF signaling.
  • This study reveals a critical regulatory step in the TNF-induced JNK activation and cell death pathway.

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