Role of WW Domain-containing Oxidoreductase WWOX in Driving T Cell Acute Lymphoblastic Leukemia Maturation.

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 I?B? in immature acute lymphoblastic leukemia MOLT-4 T cells and in the naïve mouse spleen. The I?B?·ERK·WWOX complex was shown to localize, in part, in the mitochondria. WWOX prevents I?B? from proteasomal degradation. Upon stimulating MOLT-4 with ionophore A23187/phorbol myristate acetate, endogenous I?B? 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, I?B? 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 I?B?·ERK·WWOX complex near 24 h. Inhibition of ERK phosphorylation by U0126 or I?B? degradation by MG132 prevents MOLT-4 maturation. By time-lapse FRET microscopy, I?B?·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.

SUBMITTER: Huang SS 

PROVIDER: S-EPMC5016130 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature