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

Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2009; 284(18):12349-62. DOI: 10.1074/jbc.M807761200
Source: PubMed

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.

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Available from: Navin K Verma, Aug 20, 2015
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    • "Several studies in different cellular systems indicate that stathmin might be involved in cell migration (Ozon et al., 2002; Baldassarre et al., 2005; Verma et al., 2009), including the adult mammalian brain (Jin et al., 2004). We observed a reduction in the number of DCX-and BrdU-positive cells after long survival in the GCL [Fig. "
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    ABSTRACT: The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MT), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell-division, migration, growth and differentiation. Although there are several examples of microtubule stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of microtubule destabilizing proteins. Stathmin is such a MT destabilizing protein largely restricted to the CNS and, in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone (SGZ) of the mouse hippocampus. After mapping carefully stathmin expression in the adult Dentate Gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki-67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA-NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore our data suggest migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early post-mitotic neurons. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014.
    Developmental Neurobiology 12/2014; 74(12). DOI:10.1002/dneu.22200 · 4.19 Impact Factor
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    • "Beside this canonical function some non-canonical functions are emerging for STAT3 which are independent of tyrosine phosphorylation. It has been shown that STAT3 binds to the COOH-terminal tubulin-interacting domain of the microtubule-destabilising protein stathmin leading to stabilisation of the microtubule network (Ng et al., 2006) which directly affects cell migration (Gao and Bromberg, 2006; Verma et al., 2009). The function of STAT3 as a regulator of oxidative phosphorylation within mitochondria is another challenging observation. "
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    ABSTRACT: The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway directly links ligand-binding to a membrane-bound receptor with the activation of a transcription factor. This signalling module enables the cell to rapidly initiate a transcriptional response to external stimulation. The main components of this evolutionary conserved module are cytokines that specifically bind to cytokine receptors leading to the activation of receptor-associated Janus tyrosine kinases (JAKs). The receptor-bound JAKs activate STAT transcription factors through phosphorylation of a single tyrosine residue. Activated STAT dimers translocate into the nucleus to induce target gene expression. In this article we will review current opinions on the molecular mechanism and on intracellular dynamics of JAK/STAT signalling with a special focus on the cytokine receptor glycoprotein 130 (gp130) and STAT3. In particular we will concentrate on non-canonical aspects of Jak/STAT signalling including preassembled receptor complexes, preformed STAT dimers, STAT trafficking and non-canonical functions of STATs.
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    • "Our observation that CNTF restores regrowth of MTs after nocodazole treatment suggests that the second mechanism could play a central role, in particular under the specific condition in pmn mice in which a mutation of TBCE leads to reduced assembly of tubulin heterodimers. The p-STAT3 Y705 –stathmin interaction has been observed upon cytokine stimulation in several cell types, including T lymphocytes (Verma et al., 2009) and various cell lines (Ng et al., 2006). These studies showed that STAT3, when overexpressed together with stathmin, binds to its C terminus, the same region that also interacts with tubulin heterodimers (Ng et al., 2006). "
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    ABSTRACT: Axonal maintenance, plasticity, and regeneration are influenced by signals from neighboring cells, in particular Schwann cells of the peripheral nervous system. Schwann cells produce neurotrophic factors, but the mechanisms by which ciliary neurotrophic factor (CNTF) and other neurotrophic molecules modify the axonal cytoskeleton are not well understood. In this paper, we show that activated signal transducer and activator of transcription-3 (STAT3), an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, acts locally in axons of motoneurons to modify the tubulin cytoskeleton. Specifically, we show that activated STAT3 interacted with stathmin and inhibited its microtubule-destabilizing activity. Thus, ectopic CNTF-mediated activation of STAT3 restored axon elongation and maintenance in motoneurons from progressive motor neuronopathy mutant mice, a mouse model of motoneuron disease. This mechanism could also be relevant for other neurodegenerative diseases and provide a target for new therapies for axonal degeneration.
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