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Mark H. Ginsberg - One of the best experts on this subject based on the ideXlab platform.

  • the structure of an Integrin talin complex reveals the basis of inside out signal transduction
    The EMBO Journal, 2009
    Co-Authors: Nicholas J Anthis, Mark H. Ginsberg, Kate L Wegener, Chungho Kim, Benjamin T Goult, Edward D Lowe, Ioannis Vakonakis, Neil Bate, David R Critchley, Iain D Campbell
    Abstract:

    Fundamental to cell adhesion and migration, Integrins are large heterodimeric membrane proteins that uniquely mediate inside-out signal transduction, whereby adhesion to the extracellular matrix is activated from within the cell by direct binding of talin to the cytoplasmic tail of the Beta Integrin subunit. Here, we report the first structure of talin bound to an authentic full-length Beta Integrin tail. Using biophysical and whole cell measurements, we show that a specific ionic interaction between the talin F3 domain and the membrane-proximal helix of the Beta tail disrupts an Integrin alpha/Beta salt bridge that helps maintain the Integrin inactive state. Second, we identify a positively charged surface on the talin F2 domain that precisely orients talin to disrupt the heterodimeric Integrin transmembrane (TM) complex. These results show key structural features that explain the ability of talin to mediate inside-out TM signalling.

  • talin phosphorylation by cdk5 regulates smurf1 mediated talin head ubiquitylation and cell migration
    Nature Cell Biology, 2009
    Co-Authors: Cai Huang, Zenon Rajfur, Nima Yousefi, Zaozao Chen, Kenneth A Jacobson, Mark H. Ginsberg
    Abstract:

    Cell migration is a dynamic process that requires temporal and spatial regulation of Integrin activation and focal adhesion assembly/disassembly. Talin, an actin and Beta-Integrin tail-binding protein, is essential for Integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates Integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.

  • increased filamin binding to Beta Integrin cytoplasmic domains inhibits cell migration
    Nature Cell Biology, 2001
    Co-Authors: David A. Calderwood, Martin A. Schwartz, Anna Huttenlocher, William B Kiosses, David M Rose, Darren G Woodside, Mark H. Ginsberg
    Abstract:

    Multicellular animal development depends on Integrins. These adhesion receptors link to the actin cytoskeleton, transmitting biochemical signals and force during cell migration and interactions with the extracellular matrix. Many Integrin-cytoskeleton connections are formed by filamins and talin. The Beta7 Integrin tail binds strongly to filamin and supports less migration, fibronectin matrix assembly and focal adhesion formation than either the Beta1D tail, which binds strongly to talin, or the Beta1A tail, which binds modestly to both filamin and talin. To probe the role of filamin binding, we mapped the filamin-binding site of Integrin tails and identified amino acid substitutions that led to selective loss of filamin binding to the Beta7 tail and gain of filamin binding to the Beta1A tail. These changes affected cell migration and membrane protrusions but not fibronectin matrix assembly or focal adhesion formation. Thus, tight filamin binding restricts Integrin-dependent cell migration by inhibiting transient membrane protrusion and cell polarization.

Gustavo Eustaquio Alvim Britomelo - One of the best experts on this subject based on the ideXlab platform.

Bárbara E. Souza - One of the best experts on this subject based on the ideXlab platform.

  • effect of essential oil from ageratum fastigiatum on Beta Integrin cd18 expression on human lymphocytes stimulated with phorbol myristate acetate in vitro
    Natural Product Research, 2020
    Co-Authors: Bárbara E. Souza, Marcelo H. F. Ottoni, Priscila G. M. De Alvarenga, Agnes Batista Meireles, João V. W. Silveira, Valéria Gomes Almeida, Cristiane Fuzer F. Grael, Michaelle Geralda Dos Santos, Libardo Andres Gonzaleztorres, Gustavo Eustaquio Alvim Britomelo
    Abstract:

    Agareratum fastigiatum is a Brazilian medicinal plant used as anti-inflammaroty and for wound healing by the folk medicine. In vitro and in vivo studies involving A. fastigiatum essential oil (EOAF...

  • Effect of essential oil from Ageratum fastigiatum on Beta-Integrin (CD18) expression on human lymphocytes stimulated with phorbol myristate acetate in vitro
    2019
    Co-Authors: Bárbara E. Souza, Marcelo H. F. Ottoni, Priscila G. M. De Alvarenga, Agnes Batista Meireles, João V. W. Silveira, Valéria Gomes Almeida, Michaelle Dos G. Santos, Libardo Andrés González-torres, Cristiane Fuzer F. Grael, Gustavo Eustáquio Alvim Brito-melo
    Abstract:

    Agareratum fastigiatum is a Brazilian medicinal plant used as anti-inflammaroty and for wound healing by the folk medicine. In vitro and in vivo studies involving A. fastigiatum essential oil (EOAF) showed indications of anti-inflammatory activity, however, its effect on membrane Integrins involved on cell migration is still unclear. Hence, it was evaluated in the present study the effect of EOAF on CD18 frequency on human lymphocytes. By using gas chromatography/mass spectrometry it was identified 9 compounds on EOAF: α-pinene; β-pinene; β-myrcene; d-limonene; β-ocimene; sesquiterpenes; α-copaene; 4,8-β-epóxi-caryophyllene; germacrene and bicyclogermacrene. On in vitro tests, 6.25 × 10−3 and 12.5 × 10−3 µL/mL EOAF reduced CD18 frequency on phorbol-12-myristate-13-acetate (PMA)-stimulated lymphocytes. Such cells were obtained from peripheral blood of healthy volunteers, and were treated or not with EOAF. They were stained with fluorescent anti-CD18 monoclonal antibodies, after 24 hours incubation. Our data corroborates previous findings, indicating a possible anti-inflammatory activity of EOAF.

Cai Huang - One of the best experts on this subject based on the ideXlab platform.

  • talin phosphorylation by cdk5 regulates smurf1 mediated talin head ubiquitylation and cell migration
    Nature Cell Biology, 2009
    Co-Authors: Cai Huang, Zenon Rajfur, Nima Yousefi, Zaozao Chen, Kenneth A Jacobson, Mark H. Ginsberg
    Abstract:

    Cell migration is a dynamic process that requires temporal and spatial regulation of Integrin activation and focal adhesion assembly/disassembly. Talin, an actin and Beta-Integrin tail-binding protein, is essential for Integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates Integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.

Reinhard Fässler - One of the best experts on this subject based on the ideXlab platform.

  • Integrin linked kinase is an adaptor with essential functions during mouse development
    Nature, 2009
    Co-Authors: Anika Lange, Sara A Wickstrom, Madis Jakobson, Roy Zent, Kirsi Sainio, Reinhard Fässler
    Abstract:

    The development of multicellular organisms requires Integrin-mediated interactions between cells and their extracellular environment. Integrin binding to extracellular matrix catalyses assembly of multiprotein complexes, which transduce mechanical and chemical signals that regulate many aspects of cell physiology. Integrin-linked kinase (Ilk) is a multifunctional protein that binds Beta-Integrin cytoplasmic domains and regulates actin dynamics by recruiting actin binding regulatory proteins such as alpha- and Beta-parvin. Ilk has also been shown to possess serine/threonine kinase activity and to phosphorylate signalling proteins such as Akt1 and glycogen synthase kinase 3Beta (Gsk3Beta) in mammalian cells; however, these functions have been shown by genetic studies not to occur in flies and worms. Here we show that mice carrying point mutations in the proposed autophosphorylation site of the putative kinase domain and in the pleckstrin homology domain are normal. In contrast, mice with point mutations in the conserved lysine residue of the potential ATP-binding site of the kinase domain, which mediates Ilk binding to alpha-parvin, die owing to renal agenesis. Similar renal defects occur in alpha-parvin-null mice. Thus, we provide genetic evidence that the kinase activity of Ilk is dispensable for mammalian development; however, an interaction between Ilk and alpha-parvin is critical for kidney development.

  • mechanisms that regulate adaptor binding to Beta Integrin cytoplasmic tails
    Journal of Cell Science, 2009
    Co-Authors: Kyle R Legate, Reinhard Fässler
    Abstract:

    Cells recognize and respond to their extracellular environment through transmembrane receptors such as Integrins, which physically connect the extracellular matrix to the cytoskeleton. Integrins provide the basis for the assembly of intracellular signaling platforms that link to the cytoskeleton and influence nearly every aspect of cell physiology; however, Integrins possess no enzymatic or actin-binding activity of their own and thus rely on adaptor molecules, which bind to the short cytoplasmic tails of Integrins, to mediate and regulate these functions. Many adaptors compete for relatively few binding sites on Integrin tails, so regulatory mechanisms have evolved to reversibly control the spatial and temporal binding of specific adaptors. This Commentary discusses the adaptor proteins that bind directly to the tails of Beta Integrins and, using talin, tensin, filamin, 14-3-3 and Integrin-linked kinase (ILK) as examples, describes the ways in which their binding is regulated.