scholarly journals Type Iγ phosphatidylinositol phosphate kinase is required for EGF-stimulated directional cell migration

2007 ◽  
Vol 178 (2) ◽  
pp. 297-308 ◽  
Author(s):  
Yue Sun ◽  
Kun Ling ◽  
Matthew P. Wagoner ◽  
Richard A. Anderson
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Egf Receptor ◽  
Adhesion Formation ◽  
Leading Edge ◽  
Directional Migration ◽  
Phosphatidylinositol Phosphate ◽  
Phospholipase Cγ1 ◽  
Directional Cell Migration ◽  
Phosphatidylinositol Phosphate Kinase

Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) modulates a plethora of cytoskeletal interactions that control the dynamics of actin assembly and, ultimately, cell migration. We show that the type Iγ phosphatidylinositol phosphate kinase 661 (PIPKIγ661), an enzyme that generates PI4,5P2, is required for growth factor but not G protein–coupled receptor–stimulated directional migration. By generating PI4,5P2 and regulating talin assembly, PIPKIγ661 modulates nascent adhesion formation at the leading edge to facilitate cell migration. The epidermal growth factor (EGF) receptor directly phosphorylates PIPKIγ661 at tyrosine 634, and this event is required for EGF-induced migration. This phosphorylation regulates the interaction between PIPKIγ661 and phospholipase Cγ1 (PLCγ1, an enzyme previously shown to be involved in the regulation of EGF-stimulated migration). Our results suggest that phosphorylation events regulating specific PIPKIγ661 interactions are required for growth factor–induced migration. These interactions in turn define the spatial and temporal generation of PI4,5P2 and derived messengers required for directional migration.

scholarly journals A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Xuan Cao ◽  
Tomonori Kaneko ◽  
Jenny S. Li ◽  
An-Dong Liu ◽  
Courtney Voss ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Rho Gtpases ◽  
Leading Edge ◽  
Small Gtpases ◽  
Pdgf Stimulation ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase ◽  
Directional Cell Migration ◽  
Phosphatase And Tensin Homologue

Abstract Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylation-mediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3–DLC1 and PTEN–PI3K complexes into the TNS3–PI3K and PTEN–DLC1 complexes. Subsequently, the TNS3–PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN–DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration.

scholarly journals α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation

2015 ◽  
Vol 112 (15) ◽  
pp. E1926-E1935 ◽  
Author(s):  
Shijun Wang ◽  
Chun-Hsien Chu ◽  
Tessandra Stewart ◽  
Carmen Ginghina ◽  
Yifei Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Migration ◽  
Neuronal Damage ◽  
Directional Migration ◽  
Chronic Neuroinflammation ◽  
Tyrosine Protein Kinase ◽  
Microglial Migration ◽  
Directional Cell Migration ◽  
Cytoskeleton Rearrangement

Malformed α-Synuclein (α-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in α-synucleinopathies, such as Parkinson’s disease. The mechanisms by which α-syn aggregates activate and recruit microglia remain unclear, however. Here we show that α-syn aggregates act as chemoattractants to direct microglia toward damaged neurons. In addition, we describe a mechanism underlying this directional migration of microglia. Specifically, chemotaxis occurs when α-syn binds to integrin CD11b, leading to H2O2 production by NADPH oxidase. H2O2 directly attracts microglia via a process in which extracellularly generated H2O2 diffuses into the cytoplasm and tyrosine protein kinase Lyn, phosphorylates the F-actin–associated protein cortactin after sensing changes in the microglial intracellular concentration of H2O2. Finally, phosphorylated cortactin mediates actin cytoskeleton rearrangement and facilitates directional cell migration. These findings have significant implications, given that α-syn–mediated microglial migration reaches beyond Parkinson’s disease.

scholarly journals Subcellular optogenetic activation of Cdc42 controls local and distal signaling to drive immune cell migration

2016 ◽  
Vol 27 (9) ◽  
pp. 1442-1450 ◽  
Author(s):  
Patrick R. O’Neill ◽  
Vani Kalyanaraman ◽  
N. Gautam
Keyword(s):  
Cell Migration ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Leading Edge ◽  
Signaling Networks ◽  
Membrane Protrusions ◽  
A Cell ◽  
Immune Cell Migration ◽  
Directional Cell Migration ◽  
Rhoa Signaling

Migratory immune cells use intracellular signaling networks to generate and orient spatially polarized responses to extracellular cues. The monomeric G protein Cdc42 is believed to play an important role in controlling the polarized responses, but it has been difficult to determine directly the consequences of localized Cdc42 activation within an immune cell. Here we used subcellular optogenetics to determine how Cdc42 activation at one side of a cell affects both cell behavior and dynamic molecular responses throughout the cell. We found that localized Cdc42 activation is sufficient to generate polarized signaling and directional cell migration. The optically activated region becomes the leading edge of the cell, with Cdc42 activating Rac and generating membrane protrusions driven by the actin cytoskeleton. Cdc42 also exerts long-range effects that cause myosin accumulation at the opposite side of the cell and actomyosin-mediated retraction of the cell rear. This process requires the RhoA-activated kinase ROCK, suggesting that Cdc42 activation at one side of a cell triggers increased RhoA signaling at the opposite side. Our results demonstrate how dynamic, subcellular perturbation of an individual signaling protein can help to determine its role in controlling polarized cellular responses.

scholarly journals Paxillin-Kinase-Linker Tyrosine Phosphorylation Regulates Directional Cell Migration

2009 ◽  
Vol 20 (22) ◽  
pp. 4706-4719 ◽  
Author(s):  
Jianxin A. Yu ◽  
Nicholas O. Deakin ◽  
Christopher E. Turner
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Wound Repair ◽  
Cell Polarization ◽  
Dependent Manner ◽  
Directed Cell Migration ◽  
Focal Adhesion Protein ◽  
Directional Cell Migration

Directed cell migration requires the coordination of growth factor and cell adhesion signaling and is of fundamental importance during embryonic development, wound repair, and pathological conditions such as tumor metastasis. Herein, we demonstrate that the ArfGAP, paxillin-kinase-linker (PKL/GIT2), is tyrosine phosphorylated in response to platelet-derived growth factor (PDGF) stimulation, in an adhesion dependent manner and is necessary for directed cell migration. Using a combination of pharmacological inhibitors, knockout cells and kinase mutants, FAK, and Src family kinases were shown to mediate PDGF-dependent PKL tyrosine phosphorylation. In fibroblasts, expression of a PKL mutant lacking the principal tyrosine phosphorylation sites resulted in loss of wound-induced cell polarization as well as directional migration. PKL phosphorylation was necessary for PDGF-stimulated PKL binding to the focal adhesion protein paxillin and expression of paxillin or PKL mutants defective in their respective binding motifs recapitulated the polarization defects. RNA interference or expression of phosphorylation mutants of PKL resulted in disregulation of PDGF-stimulated Rac1 and PAK activities, reduction of Cdc42 and Erk signaling, as well as mislocalization of βPIX. Together these studies position PKL as an integral component of growth factor and cell adhesion cross-talk signaling, controlling the development of front–rear cell polarity and directional cell migration.

scholarly journals Healing of Gastrointestinal Mucosa: Involvement of Polyamines

Physiology ◽  
1999 ◽  
Vol 14 (1) ◽  
pp. 12-17 ◽  
Author(s):  
Leonard R. Johnson ◽  
Shirley A. McCormack
Keyword(s):  
Signal Transduction ◽  
Cell Migration ◽  
Growth Factor ◽  
Egf Receptor ◽  
Receptor Function ◽  
Gastrointestinal Mucosa ◽  
Cellular Content ◽  
Mucosal Lesions ◽  
Signal Transduction Proteins ◽  
Cell Migration And Proliferation

Polyamines are involved in the processes of cell migration and proliferation that result in the repair of mucosal lesions. Depletion of polyamines dramatically alters the arrangement of the cytoskeleton, EGF receptor function, the activities of signal transduction proteins, the levels of several protooncogenes, and the expression and cellular content of at least one growth factor involved in these processes.

scholarly journals TNFAIP8 is a novel phosphoinositide-binding inhibitory regulator of Rho GTPases that promotes cancer cell migration

2021 ◽  
Author(s):  
Mei Lin ◽  
Honghong Sun ◽  
Svetlana A. Fayngerts ◽  
Peiwei Huangyang ◽  
Youhai H. Chen
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Somatic Mutations ◽  
Leading Edge ◽  
Cancer Cell Migration ◽  
Directional Migration ◽  
Phosphoinositide Signaling ◽  
Hydrophobic Cavity ◽  
Cavity Structure ◽  
Molecular Bridge

More than half of human tumors exhibit aberrantly dysregulated phosphoinositide signaling, yet how this is controlled remains not fully understood. While somatic mutations of PI3K, PTEN and Ras account for many cases of the hyperactivated lipid signals, other mechanisms for these dysfunctions in cancer are also being discovered. We report here that TNFAIP8 interacts with PtdIns(4,5)P2 and PtdIns(3,4,5)P3 and is likely to be hijacked by cancer cells to facilitate directional migration during malignant transformation. TNFAIP8 maintains the quiescent cellular state by sequestering inactive Rho GTPases in the cytosolic pool, which can be set free upon chemoattractant activation at the leading edge. Consequently, loss of TNFAIP8 results in severe defects of chemotaxis and adhesion. Thus, TNFAIP8, whose expression can be induced by inflammatory cytokines such as TNFα from tumor microenvironment, represents a molecular bridge from inflammation to cancer by linking NF-κB pathway to phosphoinositide signaling. Our study on the conserved hydrophobic cavity structure will also advise in silico drug screening and development of new TNFAIP8-based strategies to combat malignant human diseases.

scholarly journals Rear-polarized Wnt5a-receptor-actin-myosin-polarity (WRAMP) structures promote the speed and persistence of directional cell migration

2017 ◽  
Vol 28 (14) ◽  
pp. 1924-1936 ◽  
Author(s):  
Mary Katherine Connacher ◽  
Jian Wei Tay ◽  
Natalie G. Ahn
Keyword(s):  
Cell Migration ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Cell Movement ◽  
Leading Edge ◽  
Cellular Mechanism ◽  
Directional Movement ◽  
New Directions ◽  
And Function ◽  
Directional Cell Migration

In contrast to events at the cell leading edge, rear-polarized mechanisms that control directional cell migration are poorly defined. Previous work described a new intracellular complex, the Wnt5a-receptor-actomyosin polarity (WRAMP) structure, which coordinates the polarized localization of MCAM, actin, and myosin IIB in a Wnt5a-induced manner. However, the polarity and function for the WRAMP structure during cell movement were not determined. Here we characterize WRAMP structures during extended cell migration using live-cell imaging. The results demonstrate that cells undergoing prolonged migration show WRAMP structures stably polarized at the rear, where they are strongly associated with enhanced speed and persistence of directional movement. Strikingly, WRAMP structures form transiently, with cells displaying directional persistence during periods when they are present and cells changing directions randomly when they are absent. Cells appear to pause locomotion when WRAMP structures disassemble and then migrate in new directions after reassembly at a different location, which forms the new rear. We conclude that WRAMP structures represent a rear-directed cellular mechanism to control directional migration and that their ability to form dynamically within cells may control changes in direction during extended migration.

Epidermal growth factor receptor relocalization and kinase activity are necessary for directional migration of keratinocytes in DC electric fields

1999 ◽  
Vol 112 (12) ◽  
pp. 1967-1978 ◽  
Author(s):  
K.S. Fang ◽  
E. Ionides ◽  
G. Oster ◽  
R. Nuccitelli ◽  
R.R. Isseroff
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Electric Fields ◽  
Migration Rate ◽  
Kinase Activity ◽  
Directional Migration ◽  
Epidermal Growth ◽  
Egfr Kinase ◽  
Dc Electric Fields

Human keratinocytes migrate towards the negative pole in DC electric fields of physiological strength. This directional migration is promoted by epidermal growth factor (EGF). To investigate how EGF and its receptor (EGFR) regulate this directionality, we first examined the effect of protein tyrosine kinase inhibitors, including PD158780, a specific inhibitor for EGFR, on this response. At low concentrations, PD158780 inhibited keratinocyte migration directionality, but not the rate of migration; at higher concentrations, it reduced the migration rate as well. The less specific inhibitors, genistein, lavendustin A and tyrphostin B46, reduced the migration rate, but did not affect migration directionality. These data suggest that inhibition of EGFR kinase activity alone reduces directed motility, and inhibition of multiple tyrosine kinases, including EGFR, reduces the cell migration rate. EGFR redistribution also correlates with directional migration. EGFR concentrated on the cathodal face of the cell as early as 5 minutes after exposure to electric fields. PD158780 abolished EGFR localization to the cathodal face. These data suggest that EGFR kinase activity and redistribution in the plasma membrane are required for the directional migration of keratinocytes in DC electric fields. This study provides the first insights into the mechanisms of directed cell migration in electric fields.

scholarly journals Centrosome defines the rear of cells during mesenchymal migration

2017 ◽  
Vol 28 (23) ◽  
pp. 3240-3251 ◽  
Author(s):  
Jian Zhang ◽  
Yu-li Wang
Keyword(s):  
Cell Migration ◽  
Symmetry Breaking ◽  
Computer Modeling ◽  
Inhibition Mechanism ◽  
Local Enhancement ◽  
Directional Migration ◽  
Conventional View ◽  
Dead End ◽  
Directional Cell Migration ◽  
Global Inhibition

The importance of centrosome in directional cell migration has long been recognized. However, the conventional view that centrosome determines cell’s front, based on its often-observed position in front of the nucleus, has been challenged by contradictory observations. Here we show that centrosome defines the rear instead of the front, using cells plated on micropatterned adhesive strips to facilitate directional migration. We found that centrosome is always located proximal to the future rear before polarity is established through symmetry breaking or reversed as the cell reaches a dead end. In addition, using microsurgery to alter the distance of centrosomes from cells’ ends, we show that centrosomal proximity is predictive of the placement of the rear. Removal of centrosome impairs directional cell migration, whereas the removal of nucleus alone makes no difference in most cells. Computer modeling under the framework of a local-enhancement/global-inhibition mechanism further demonstrates that positioning of rear retraction, mediated by signals concentrated near the centrosome, recapitulates all the experimental observations. Our results resolve a long-standing controversy and explain how cells use centrosome and microtubules to maintain directional migration.

scholarly journals Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration

2020 ◽  
Vol 117 (25) ◽  
pp. 14270-14279
Author(s):  
Zhiwen Zhu ◽  
Yongping Chai ◽  
Huifang Hu ◽  
Wei Li ◽  
Wen-Jun Li ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Polymerization ◽  
Transmembrane Protein ◽  
Tyrosine Phosphatase ◽  
Leading Edge ◽  
Receptor Activity ◽  
Actin Assembly ◽  
Neuroblast Migration ◽  
Directional Cell Migration ◽  
Migrating Cells

Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration inCaenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1–dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.

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