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

C. K. Lee, Y. Yang, C. Chen, J. Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The transcription factor Miz1 negatively regulates TNF-induced JNK activation and cell death by suppressing TRAF2 K63-polyubiquitination; upon TNF stimulation, the suppression is relieved by Mule/ARF-BP1-mediated Miz1 ubiquitination and subsequent degradation. It is not known how Mule is activated by TNF. Here we report that TNF activates Mule by inducing the dissociation of Mule from its inhibitor ARF. ARF binds to and thereby inhibits the E3 ligase activity of Mule in the steady state. TNF induces tyrosine phosphorylation of Mule, which subsequently dissociates from ARF and becomes activated. Inhibition of Mule phosphorylation by silencing of the Spleen Tyrosine Kinase (Syk) prevents its dissociation from ARF, thereby inhibiting Mule E3 ligase activity and TNF-induced JNK activation and cell death. Our data provides a missing link in TNF signaling pathway that leads to JNK activation and cell death.

Original languageEnglish (US)
Pages (from-to)1988-1995
Number of pages8
JournalOncogene
Volume35
Issue number15
DOIs
StatePublished - Apr 14 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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