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


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,
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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 · 3.37 Impact Factor
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    • "Consistent with this possibility we found that pSTAT3 is associated with microtubules, the major transportation machinery in dendrites [72]. Earlier studies in non-neuronal cell models have reported interaction between STAT3 and microtubule-associated proteins, and effects of STAT3 on microtubule stabilization [73,74]. The LepRb-STAT3 pathway might thus affect dendritic growth/branching and/or neuronal migration and/or synaptic plasticity [58,70,75-77]. "
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    ABSTRACT: Leptin acts via neuronal leptin receptors to control energy balance. Hypothalamic pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP)/Neuropeptide Y (NPY)/GABA neurons produce anorexigenic and orexigenic neuropeptides and neurotransmitters, and express the long signaling form of the leptin receptor (LepRb). Despite progress in the understanding of LepRb signaling and function, the sub-cellular localization of LepRb in target neurons has not been determined, primarily due to lack of sensitive anti-LepRb antibodies. Here we applied light microscopy (LM), confocal-laser scanning microscopy (CLSM), and electron microscopy (EM) to investigate LepRb localization and signaling in mice expressing a HA-tagged LepRb selectively in POMC or AgRP/NPY/GABA neurons. We report that LepRb receptors exhibit a somato-dendritic expression pattern. We further show that LepRb activates STAT3 phosphorylation in neuronal fibers within several hypothalamic and hindbrain nuclei of wild-type mice and rats, and specifically in dendrites of arcuate POMC and AgRP/NPY/GABA neurons of Leprb (+/+) mice and in Leprb (db/db) mice expressing HA-LepRb in a neuron specific manner. We did not find evidence of LepRb localization or STAT3-signaling in axon-fibers or nerve-terminals of POMC and AgRP/NPY/GABA neurons. Three-dimensional serial EM-reconstruction of dendritic segments from POMC and AgRP/NPY/GABA neurons indicates a high density of shaft synapses. In addition, we found that the leptin activates STAT3 signaling in proximity to synapses on POMC and AgRP/NPY/GABA dendritic shafts. Taken together, these data suggest that the signaling-form of the leptin receptor exhibits a somato-dendritic expression pattern in POMC and AgRP/NPY/GABA neurons. Dendritic LepRb signaling may therefore play an important role in leptin's central effects on energy balance, possibly through modulation of synaptic activity via post-synaptic mechanisms.
    PLoS ONE 12/2013; 8(10):e77622. DOI:10.1371/journal.pone.0077622 · 3.23 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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