Exo70 interacts with the Arp2/3 complex and regulates cell migration

Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nature Cell Biology (Impact Factor: 19.68). 01/2007; 8(12):1383-8. DOI: 10.1038/ncb1505
Source: PubMed


The exocyst is a multiprotein complex essential for tethering secretory vesicles to specific domains of the plasma membrane for exocytosis. Here, we report that the exocyst component Exo70 interacts with the Arp2/3 complex, a key regulator of actin polymerization. We further show that the exocyst-Arp2/3 interaction is regulated by epidermal growth factor (EGF) signalling. Inhibition of Exo70 by RNA interference (RNAi) or antibody microinjection blocks the formation of actin-based membrane protrusions and affects various aspects of cell motility. We propose that Exo70, in addition to functioning in exocytosis, also regulates actin at the leading edges of migrating cells, therefore coordinating cytoskeleton and membrane traffic during cell migration.

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    • "This conclusion is in agreement with previous studies which show that mouse PAP localized presynaptically in DRG neurons [9] and in taste buds [39]. In addition, the colocalization between PAP and snapin in prostate cancer cells occurs in the cell lamellipodia [3], and it has been described that the lamellipodium is the site where exocytosis occurs in migrating mammalian cells [40], [41], supporting the hypothesis that colocalization of these proteins in the neuron will not happen in the cell soma. This presynaptic localization of TMPAP together with the fact that TMPAP resides in the axon hillock, where GABAergic synapses are located [23], supports the hypothesis that TMPAP is located in GABAergic synapses. "
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    ABSTRACT: Prostatic acid phosphatase (PAP), the first diagnostic marker and present therapeutic target for prostate cancer, modulates nociception at the dorsal root ganglia (DRG), but its function in the central nervous system has remained unknown. We studied expression and function of TMPAP (the transmembrane isoform of PAP) in the brain by utilizing mice deficient in TMPAP (PAP-/- mice). Here we report that TMPAP is expressed in a subpopulation of cerebral GABAergic neurons, and mice deficient in TMPAP show multiple behavioral and neurochemical features linked to hyperdopaminergic dysregulation and altered GABAergic transmission. In addition to increased anxiety, disturbed prepulse inhibition, increased synthesis of striatal dopamine, and augmented response to amphetamine, PAP-deficient mice have enlarged lateral ventricles, reduced diazepam-induced loss of righting reflex, and increased GABAergic tone in the hippocampus. TMPAP in the mouse brain is localized presynaptically, and colocalized with SNARE-associated protein snapin, a protein involved in synaptic vesicle docking and fusion, and PAP-deficient mice display altered subcellular distribution of snapin. We have previously shown TMPAP to reside in prostatic exosomes and we propose that TMPAP is involved in the control of GABAergic tone in the brain also through exocytosis, and that PAP deficiency produces a distinct neurological phenotype.
    PLoS ONE 05/2014; 9(5):e97851. DOI:10.1371/journal.pone.0097851 · 3.23 Impact Factor
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    • "The Exo70 exocyst subunit also interacts both in vitro and in vivo with the yeast and rat Arpc1/Arc40 subunit of the Arp2/3 complex, a key regulator of actin polymerization. Inhibition of the Exo70 function in rat kidney cells blocks formation of actin-based membrane protrusions and affects cell migration (Zuo et al., 2006), pointing to yet unknown capacity of Exo70 to regulate the actin organization and coordinating thus actin cytoskeleton with membrane trafficking during cell migration. Exo70 was recently shown to promote Arp2/3-driven microfilament nucleation and branching (Liu et al., 2012). "
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    ABSTRACT: Delivery and final fusion of the secretory vesicles with the relevant target membrane are hierarchically organized and reciprocally interconnected multi-step processes involving not only specific protein-protein interactions, but also specific protein-phospholipid interactions. The exocyst was discovered as a tethering complex mediating initial encounter of arriving exocytic vesicles with the plasma membrane. The exocyst complex is regulated by Rab and Rho small GTPases, resulting in docking of exocytic vesicles to the plasma membrane (PM) and finally their fusion mediated by specific SNARE complexes. In model Opisthokont cells, the exocyst was shown to directly interact with both microtubule and microfilament cytoskeleton and related motor proteins as well as with the PM via phosphatidylinositol 4, 5-bisphosphate specific binding, which directly affects cortical cytoskeleton and PM dynamics. Here we summarize the current knowledge on exocyst-cytoskeleton-PM interactions in order to open a perspective for future research in this area in plant cells.
    Frontiers in Plant Science 01/2014; 4:543. DOI:10.3389/fpls.2013.00543 · 3.95 Impact Factor
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    • "Therefore, the exocyst plays an important role in epithelial polarity. On the other hand, the exocyst, especially the Exo70 subunit, has also been shown to mediate directional cell migration (Letinic et al., 2009; Liu et al., 2009; Rosse et al., 2009; Rossé et al., 2006; Thapa et al., 2012; Zuo et al., 2006). Here, we show that Exo70-M, but not Exo70-E, interacts with, and kinetically stimulates, the Arp2/3 complex to promote branched actin network formation, which is essential for the generation of membrane protrusions such as invadopodia . "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is an important developmental process hijacked by cancer cells for their dissemination. Here, we show that Exo70, a component of the exocyst complex, undergoes isoform switching mediated by ESRP1, a pre-mRNA splicing factor that regulates EMT. Expression of the epithelial isoform of Exo70 affects the levels of key EMT transcriptional regulators such as Snail and ZEB2 and is sufficient to drive the transition to epithelial phenotypes. Differential Exo70 isoform expression in human tumors correlates with cancer progression, and increased expression of the epithelial isoform of Exo70 inhibits tumor metastasis in mice. At the molecular level, the mesenchymal-but not the epithelial-isoform of Exo70 interacts with the Arp2/3 complex and stimulates actin polymerization for tumor invasion. Our findings provide a mechanism by which the exocyst function and actin dynamics are modulated for EMT and tumor invasion.
    Developmental Cell 12/2013; 27(5):560-573. DOI:10.1016/j.devcel.2013.10.020 · 9.71 Impact Factor
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