Quantitative imaging of epithelial cell scattering identifies specific inhibitors of cell motility and cell-cell dissociation.

Abstract:

:The scattering of cultured epithelial cells in response to hepatocyte growth factor (HGF) is a model system that recapitulates key features of metastatic cell behavior in vitro, including disruption of cell-cell adhesions and induction of cell migration. We have developed image analysis tools that do not require fluorescence tagging and that automatically track and characterize three aspects of scattering in live cells: increase in cell motility, loss of cell-cell adhesion, and spatial dispersion of cells (the redistribution of cells during scattering). We used these tools to screen a library of drugs, and we identified several efficient inhibitors of scattering, which we classified as selective inhibitors of either motility or loss of cell-cell adhesion, or as nonselective inhibitors. We validated the inhibitors and putative targets from this screen in two unrelated model cell lines. Using pharmacological treatments and RNA interference (RNAi), we found that nonsteroidal anti-inflammatory drugs inhibited cell-cell dissociation, that indirubins inhibited cell motility, and that cyclin-dependent kinase 1 and ribosomal S6 kinase were signaling intermediates in HGF-induced cell scattering. This assay is suitable for larger-scale screenings of chemical compounds or RNAi libraries.

journal_name

Sci Signal

journal_title

Science signaling

authors

Loerke D,le Duc Q,Blonk I,Kerstens A,Spanjaard E,Machacek M,Danuser G,de Rooij J

doi

10.1126/scisignal.2002677

subject

Has Abstract

pub_date

2012-07-03 00:00:00

pages

rs5

issue

231

eissn

1945-0877

issn

1937-9145

pii

5/231/rs5

journal_volume

5

pub_type

杂志文章
  • TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells.

    abstract::TRPML1 (transient receptor potential mucolipin 1) is a Ca2+-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca2+ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking,...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aba1015

    authors: Thakore P,Pritchard HAT,Griffin CS,Yamasaki E,Drumm BT,Lane C,Sanders KM,Feng Earley Y,Earley S

    更新日期:2020-06-23 00:00:00

  • RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.

    abstract::Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2005301

    authors: Winter PS,Sarosiek KA,Lin KH,Meggendorfer M,Schnittger S,Letai A,Wood KC

    更新日期:2014-12-23 00:00:00

  • Mice lacking the intracellular cation channel TRIC-B have compromised collagen production and impaired bone mineralization.

    abstract::The trimeric intracellular cation (TRIC) channels TRIC-A and TRIC-B localize predominantly to the endoplasmic reticulum (ER) and likely support Ca(2+) release from intracellular stores by mediating cationic flux to maintain electrical neutrality. Deletion and point mutations in TRIC-B occur in families with autosomal ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aad9055

    authors: Zhao C,Ichimura A,Qian N,Iida T,Yamazaki D,Noma N,Asagiri M,Yamamoto K,Komazaki S,Sato C,Aoyama F,Sawaguchi A,Kakizawa S,Nishi M,Takeshima H

    更新日期:2016-05-17 00:00:00

  • Drosophila toll pathway: the new model.

    abstract::In Drosophila, recognition of microbe-specific molecules (such as bacterial peptidoglycans) activates serine protease cascades that converge to activate the Toll pathway. Recent data show that the serine protease Grass, which is activated downstream of pattern recognition receptors and was initially thought to be a co...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.252jc1

    authors: Ashok Y

    更新日期:2009-01-06 00:00:00

  • Acetylation goes global: the emergence of acetylation biology.

    abstract::For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucle...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.297pe76

    authors: Norris KL,Lee JY,Yao TP

    更新日期:2009-11-17 00:00:00

  • Receptor cooperation in B cells.

    abstract::TLR4-stimulated B cell activation is mediated by the tyrosine kinase Syk and depends on the B cell receptor. ...

    journal_title:Science signaling

    pub_type: 评论,杂志文章

    doi:10.1126/scisignal.aan7951

    authors: Foley JF

    更新日期:2017-05-23 00:00:00

  • Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors.

    abstract::Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs enco...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaw9252

    authors: Kennedy PR,Barthen C,Williamson DJ,Pitkeathly WTE,Hazime KS,Cumming J,Stacey KB,Hilton HG,Carrington M,Parham P,Davis DM

    更新日期:2019-12-17 00:00:00

  • Apoptosis, stem cells, and tissue regeneration.

    abstract::Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in re...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.3145re8

    authors: Bergmann A,Steller H

    更新日期:2010-10-26 00:00:00

  • How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD.

    abstract::Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.aaf7067

    authors: Hell JW

    更新日期:2016-04-26 00:00:00

  • The role of ciliary trafficking in Hedgehog receptor signaling.

    abstract::Defects in the biogenesis of or transport through primary cilia affect Hedgehog protein signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. The Hedgehog receptor Patched negatively regulates the activity and ciliary accumulation of Smoothened, a seven-transmembrane protein that is e...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaa5622

    authors: Kim J,Hsia EY,Brigui A,Plessis A,Beachy PA,Zheng X

    更新日期:2015-06-02 00:00:00

  • An introduction to MATLAB.

    abstract::This two-part lecture introduces students to the scientific computing language MATLAB. Prior computer programming experience is not required. The lectures present basic concepts of computer programming logic that tend to cause difficulties for beginners in addition to concepts that relate specifically to the MATLAB la...

    journal_title:Science signaling

    pub_type:

    doi:10.1126/scisignal.2001984

    authors: Sobie EA

    更新日期:2011-09-13 00:00:00

  • Nucleolar localization of a netrin-1 isoform enhances tumor cell proliferation.

    abstract::Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to be due to the ability of this secreted cue to stimulate survival when bound to its receptors. We showed that in contrast to full-length, secreted netrin-1, some cancer cells produced a truncated intranuclear form of netrin-1 (ΔN-netrin-...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002456

    authors: Delloye-Bourgeois C,Goldschneider D,Paradisi A,Therizols G,Belin S,Hacot S,Rosa-Calatrava M,Scoazec JY,Diaz JJ,Bernet A,Mehlen P

    更新日期:2012-08-07 00:00:00

  • Target acquired: Selective autophagy in cardiometabolic disease.

    abstract::The accumulation of damaged or excess proteins and organelles is a defining feature of metabolic disease in nearly every tissue. Thus, a central challenge in maintaining metabolic homeostasis is the identification, sequestration, and degradation of these cellular components, including protein aggregates, mitochondria,...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.aag2298

    authors: Evans TD,Sergin I,Zhang X,Razani B

    更新日期:2017-02-28 00:00:00

  • 2009: signaling breakthroughs of the year.

    abstract::Nominations for this year's signaling breakthroughs spanned physiology, therapeutics and drug development, neuroscience, and plant signaling. Among the most exciting advances in mammalian biology were therapeutic applications of research that are overturning the conventional boundaries of signaling pathways,unexpected...

    journal_title:Science signaling

    pub_type: 社论,历史文章,评审

    doi:10.1126/scisignal.3103eg1

    authors: Adler EM

    更新日期:2010-01-05 00:00:00

  • Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.

    abstract::Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aal4055

    authors: Hutson MR,Keyte AL,Hernández-Morales M,Gibbs E,Kupchinsky ZA,Argyridis I,Erwin KN,Pegram K,Kneifel M,Rosenberg PB,Matak P,Xie L,Grandl J,Davis EE,Katsanis N,Liu C,Benner EJ

    更新日期:2017-10-10 00:00:00

  • Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway.

    abstract::Understanding the complex dynamics of growth factor signaling requires both mechanistic and kinetic information. Although signaling dynamics have been studied for pathways downstream of receptor tyrosine kinases and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, they have not been inv...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004416

    authors: Vizán P,Miller DS,Gori I,Das D,Schmierer B,Hill CS

    更新日期:2013-12-10 00:00:00

  • Integration of protein abundance and structure data reveals competition in the ErbB signaling network.

    abstract::The mechanisms of context-specific differences in signal transduction, such as those that occur among different cell types, are not fully understood. One possibility is that differences in the abundance of proteins change signaling outputs because these proteins compete for binding to hub proteins at critical network ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004560

    authors: Kiel C,Verschueren E,Yang JS,Serrano L

    更新日期:2013-12-17 00:00:00

  • AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB.

    abstract::Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention facto...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaf2797

    authors: Hornick NI,Doron B,Abdelhamed S,Huan J,Harrington CA,Shen R,Cambronne XA,Chakkaramakkil Verghese S,Kurre P

    更新日期:2016-09-06 00:00:00

  • Dysregulation of microRNA biogenesis and gene silencing in cancer.

    abstract::MicroRNAs (miRNAs) are small noncoding RNAs that suppress the abundance of partially complementary mRNAs and inhibit their translation. Each miRNA can regulate hundreds of mRNAs, sometimes strongly but often weakly, to mediate a diverse array of biological functions, including proliferation, cell signaling, differenti...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.2005825

    authors: Hata A,Lieberman J

    更新日期:2015-03-17 00:00:00

  • Controlling the number of tooth rows.

    abstract::The organization and renewal capacity of teeth vary greatly among vertebrates. Mammals have only one row of teeth that are renewed at most once, whereas many nonmammalian species have multirowed dentitions and show remarkable capacity to replace their teeth throughout life. Although knowledge on the genetic basis of t...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.285pe53

    authors: Mikkola ML

    更新日期:2009-08-25 00:00:00

  • A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner.

    abstract::Natural killer group 2D (NKG2D), an activating receptor on natural killer (NK) cells and a subset of T cells, recognizes stress-inducible proteins, including MICA and ULBP2, which are present on infected or transformed cells. Whether each NKG2D ligand (NKG2DL) has a distinct biological role is not clear. Using superre...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aal3606

    authors: Bálint Š,Lopes FB,Davis DM

    更新日期:2018-04-10 00:00:00

  • Transduction of redox signaling by electrophile-protein reactions.

    abstract::Over the last 50 years, the posttranslational modification (PTM) of proteins has emerged as a central mechanism for cells to regulate metabolism, growth, differentiation, cell-cell interactions, and immune responses. By influencing protein structure and function, PTM leads to a multiplication of proteome diversity. Re...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.290re7

    authors: Rudolph TK,Freeman BA

    更新日期:2009-09-29 00:00:00

  • Quantifying crosstalk among interferon-γ, interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model.

    abstract::T helper (T(H)) cells integrate biochemical cues present in the tissue microenvironment and produce cytokines that orchestrate immune responses. Previous discoveries have revealed a qualitative understanding of how T(H) cells process this biochemical information; however, the lack of methods to quantify how well these...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002657

    authors: Klinke DJ 2nd,Cheng N,Chambers E

    更新日期:2012-04-17 00:00:00

  • Real-time dynamics of peptide ligand-dependent receptor complex formation in planta.

    abstract::The CLAVATA (CLV) and flagellin (flg) signaling pathways act through peptide ligands and closely related plasma membrane-localized receptor-like kinases (RLKs). The plant peptide CLV3 regulates stem cell homeostasis, whereas the bacterial flg22 peptide elicits defense responses. We applied multiparameter fluorescence ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aab0598

    authors: Somssich M,Ma Q,Weidtkamp-Peters S,Stahl Y,Felekyan S,Bleckmann A,Seidel CA,Simon R

    更新日期:2015-08-04 00:00:00

  • Comment on "load-induced modulation of signal transduction networks": reconciling ultrasensitivity with bifunctionality?

    abstract::Jiang et al. (Research Article, 11 October 2011, DOI: 10.1126/scisignal.2002152) used a combined experimental and computational modeling approach to study the dynamic response behavior of covalent modification cycles in the presence of downstream targets ("loads"). Despite remarkable agreement between experiments and ...

    journal_title:Science signaling

    pub_type: 评论,信件

    doi:10.1126/scisignal.2002699

    authors: Straube R

    更新日期:2012-01-03 00:00:00

  • Noncanonical NF-κB signaling is limited by classical NF-κB activity.

    abstract::Precise regulation of nuclear factor κB (NF-κB) signaling is crucial for normal immune responses, and defective NF-κB activity underlies a range of immunodeficiencies. NF-κB is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of κB kinase β (IK...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004557

    authors: Gray CM,Remouchamps C,McCorkell KA,Solt LA,Dejardin E,Orange JS,May MJ

    更新日期:2014-02-04 00:00:00

  • 4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling.

    abstract::Clinical response to chimeric antigen receptor (CAR) T cell therapy is correlated with CAR T cell persistence, especially for CAR T cells that target CD19+ hematologic malignancies. 4-1BB-costimulated CAR (BBζ) T cells exhibit longer persistence after adoptive transfer than do CD28-costimulated CAR (28ζ) T cells. 4-1B...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aay8248

    authors: Philipson BI,O'Connor RS,May MJ,June CH,Albelda SM,Milone MC

    更新日期:2020-03-31 00:00:00

  • Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling.

    abstract::Cardiomyocytes contract against a mechanical load during each heartbeat, and excessive mechanical stress leads to heart diseases. Using a cell-in-gel system that imposes an afterload during cardiomyocyte contraction, we found that nitric oxide synthase (NOS) was involved in transducing mechanical load to alter Ca(2+) ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2005046

    authors: Jian Z,Han H,Zhang T,Puglisi J,Izu LT,Shaw JA,Onofiok E,Erickson JR,Chen YJ,Horvath B,Shimkunas R,Xiao W,Li Y,Pan T,Chan J,Banyasz T,Tardiff JC,Chiamvimonvat N,Bers DM,Lam KS,Chen-Izu Y

    更新日期:2014-03-18 00:00:00

  • Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels.

    abstract::Activation of Ca2+-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca2+ signals (Ca2+ sparks) acts as a brake on pressure-induced (myogenic) vasoconstriction-a fundamental mechanism that regulates blood flow in small resistance arteries...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaf6625

    authors: Khavandi K,Baylie RA,Sugden SA,Ahmed M,Csato V,Eaton P,Hill-Eubanks DC,Bonev AD,Nelson MT,Greenstein AS

    更新日期:2016-10-11 00:00:00

  • Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple.

    abstract::Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades, and their dysregulation plays an integral role in cancer progression. Three cascades that contribute to oncogenic potential are those mediated by Wnt proteins and the receptor Frizzled (FZD), growth factor receptor ty...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aao4220

    authors: Aznar N,Ear J,Dunkel Y,Sun N,Satterfield K,He F,Kalogriopoulos NA,Lopez-Sanchez I,Ghassemian M,Sahoo D,Kufareva I,Ghosh P

    更新日期:2018-02-27 00:00:00