Role of WW Domain-Containing oxidoreductase WWOX in driving T cell acute lymphoblastic leukemia maturation

Shenq Shyang Huang, Wan Pei Su, Hsin Pin Lin, Hsiang Ling Kuo, Hsiao Ling Wei, Nan Shan Chang

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Whether tumor suppressor WWOX (WW domain-containing oxidoreductase) stimulates immune cell maturation is largely unknown. Here, we determined that Tyr-33-phosphorylated WWOX physically binds non-phosphorylated ERK and IκBα in immature acute lymphoblastic leukemia MOLT-4 T cells and in the naïve mouse spleen. The IκBαERK• WWOX complex was shown to localize, in part, in the mitochondria. WWOX prevents Iκ Bα from proteasomal degradation. Upon stimulating MOLT-4 with ionophore A23187/phorbol myristate acetate, endogenous Iκ Bα and ERK undergo rapid phosphorylation in <5 min, and subsequently WWOX is Tyr-33 and Tyr-287 de-phosphorylated and Ser-14 phosphorylated. Three hours later, Iκ Bα starts to degrade, and ERK returns to basal or non-phosphorylation, and this lasts for the next 12 h. Finally, expression of CD3 and CD8 occurs in MOLT-4 along with reappearance of the Iκ Bα ERK• WWOX complex near 24 h. Inhibition of ERK phosphorylation by U0126 or IκBα degradation by MG132 prevents MOLT-4 maturation. By time-lapse FRET microscopy, Iκ Bα•ERK•WWOX complex exhibits an increased binding strength by 1-2-fold after exposure to ionophore A23187/phorbol myristate acetate for 15-24 h. Meanwhile, a portion of ERK and WWOX relocates to the nucleus, suggesting their role in the induction of CD3 and CD8 expression in MOLT-4.

Original languageEnglish
Pages (from-to)17319-17331
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number33
DOIs
Publication statusPublished - 2016 Aug 12

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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