STAT3-Stathmin Interactions Control Microtubule Dynamics in Migrating T-cells

Navin K Verma,Jennifer Dourlat,Anthony M Davies,Aideen Long,Wang-Qing Liu,Christiane Garbay,Dermot Kelleher,Yuri Volkov

doi:10.1074/jbc.m807761200

Abstract

T-cell migration is a complex highly coordinated process that involves cell adhesion to the high endothelial venules or to the extracellular matrix by surface receptor/ligand interactions, cytoskeletal rearrangements, and phosphorylation-dependent signaling cascades. The mechanism(s) that regulates T-cell migration is of considerable relevance for understanding the pathogenesis of various diseases, such as chronic inflammatory diseases and cancer metastasis. This study was designed to identify potential involvement of STAT3, a latent transcription factor, in mediating integrin-induced T-cell migration. Using our previously characterized in vitro model for lymphocyte migration, we demonstrate that STAT3 is activated and translocated to the nucleus during the process of active motility of Hut78 T-lymphoma cells triggered via LFA-1. Blocking STAT3 signaling by multiple approaches inhibited LFA-1-induced T-cell locomotion via destabilization of microtubules and post-translational modification of tubulin. Here, we show that STAT3 physically interacts with stathmin to regulate microtubule dynamics in migrating T-cells. These observations strongly indicate that STAT3 is critically important for T-cell migration and associated signaling events.

Highlights

Adhesive force to promote and stabilize T-cell and antigen-presenting cell conjugate formation
Following lymphocyte function-associated antigen-1 (LFA-1) cross-linking via immobilized anti-LFA-1, cytoplasmic STAT3 translocated into the nucleus within 10 min (Fig. 1A)
To further explore the effect of STAT3 inhibition on post-translational modification of tubulin in migrating T-cells, we examined the total expression of ␣-tubulin, acetylated ␣-tubulin, and tyrosinated ␣-tubulin by Western immunoblotting and with densitometric quantitation normalized for glyceraldehyde-3-phosphate dehydrogenase expression (Fig. 5)

Summary

Introduction

Adhesive force to promote and stabilize T-cell and antigen-presenting cell conjugate formation. Upon LFA-1 cross-linking, STAT3 is activated by tyrosine phosphorylation that translocates to the nucleus and interacts with stathmin to regulate MT dynamics in migrating T-cells. T-cell Motility Induced by LFA-1 Cross-linking Involves Activation of STAT3—In resting Hut78 cells, STAT3 was present mainly in the cytoplasm (Fig. 1A).

Results

Conclusion