Cell adhesion and motility in the regulation of metastatic invasivity

Department of Biochemical Science
Viale Morgagni 50, 50019 Florence
Tel: 055-4598343 332
Fax: 055-4598905

Cell adhesion and motility in the regulation of metastatic invasivity - team members Principal investigator: Paola Chiarugi

Team members
Buricchi
Fiaschi
Giannoni
Grimaldi
Parri
Matthias

Introduction

Paola Chiarugi is Full Professor of Biochemistry of the Faculty of Medicine and Surgery at the University of Florence. She is a member of the Excellence and Research Centre for Transfer and High Formation: Studies at a Molecular and Clinical Level of Chronic, Inflammatory, Degenerative and Neoplastic Diseases at the Interuniversity Institute of Miology. She is member of F1000 Biology (1000 leading Biologists), FISV (Italian Federation of Life Sciences) and SIB (Italian Society of Biochemistry and Molecular Biology).

Chiarugi has been studying the structure-function relationship of tyrosine phosphatases for 10 years. Her studies have contributed towards the elucidation of the action mechanism of these enzymes with mutagenesis techniques and then also to the definition of their role in the control of cell proliferation, adhesion, and motility. More recently her interests have been directed towards the redox regulation of oxidant-sensitive proteins during cell proliferation, cell adhesion to extracellular matrix, and plasticity of cell motility during tumor cell invasion.

Main research themes

  • Reactive Oxygen Species as Intracellular Messengers driving cell migration and protection from anoikis:
    Reactive oxygen species (ROS) include oxygen metabolites such as superoxide anions and hydrogen peroxide, which are essential mediators of cell signaling. They are generated as by-products of normal aerobic metabolism or as second messengers in various transduction pathways. Several lines of evidence demonstrate that NADPH oxidase is specifically involved in the generation of ROS by means of soluble growth factors, while 5-Lipoxygenase (LOX) is a source of ROS during the synthesis of leukotrienes. Transient fluctuations in ROS provide important regulatory functions, and a number of defense systems have evolved to fight ROS accumulation. Unfortunately, these defense mechanisms are not always adequate for counteracting ROS production, resulting in a state of oxidative stress, implicated in a wide variety of disease processes including cancer. The balance and duration of the oxidative burst may transform an oxidative injury into a sustained hormonal message. A great deal of evidence supports the role of second messengers for ROS during anchorage dependent-cell growth and their involvement in the signals elicited by soluble growth factors (GFs) such as interleukin-1, tumor necrosis factor-alpha, insulin, platelet derived GF (PDGF) and epidermal GF (EGF). Recent findings indicate that intracellular ROS are generated following integrin engagement, and that these oxidants are necessary for integrin signaling during cell adhesion and spreading, synergizing with GF signaling.

    Our contribution to redox biology deals with the demonstration that ROS act on intracellular proteins by modulating their functions via reversible oxidation. Thiols, by virtue of their ability to be reversibly oxidized, are recognized as key targets of oxidative stress, and they therefore act as redox sensitive switches. Target proteins for ROS include protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs). We have reported the reversible oxidation among PTPs, firstly for PTP1B during EGF signaling, and secondly for Low Mw (LMW)-PTP during PDGF stimulation and integrin signaling. More recently, we and also other authors have reported reversible oxidation during growth factor signaling for SHP2 and PTEN. H2O2 can also activate protein kinases and, among these, PTKs.

    Nevertheless, PTKs activation appears to be essentially due to two mechanisms: i) a direct cysteine oxidation; ii) a concomitant inhibition of PTPs that indirectly leads to sustained activation of PTKs. In particular, we recently reported the relevance of Src redox regulation for anchorage-dependent growth. We also described how the tyrosine kinase c-Src is oxidized in response to ECM adhesion and that this leads to an enhancement of its kinase activity. The oxidation/activation is probably due to an S-S bond between Cys245 and Cys487, thus leading to the achievement of the full activation of the Src kinase during cell/ECM contact (see figure above).

    In addition, an increase in Focal Adhesion Kinase (FAK) tyrosine phosphorylation owing to oxidative stress has been described in different cell lines. We have also reported how integrin-dependent ROS burst culminates in a down-regulation of a FAK phosphatase, namely LMW-PTP. The redox regulation of FAK leads to ERK and Src phosphorylation through the inhibition of LMW-PTP, ultimately affecting focal adhesion formation and cell spreading. The model that we recently proposed descibes how the Rac-mediated ROS production during anchorage-dependent cell growth results in the inhibition of LMW-PTP and an increase in the phosphorylation/activation of its targets, p190Rho-GAP, Src and FAK. This signal leads to the down-regulation of Rho activity, accounting for Rac-induced formation of membrane ruffles during integrin-mediated cell spreading. These findings, together with those concerning FAK regulation, define a key role for the redox regulation of LMW-PTP in the redox-dependent control of actin cytoskeleton during cell adhesion and proliferation. Finally, we have reported how the redox regulation of SHP2, another PTP, influences anchorage-dependent cell growth. In particular, SHP2 is transiently oxidized during both PDGF signaling and integrin-mediated cell adhesion, in the latter case the oxidation/inhibition of SHP2 is responsible for the hyperphosphorylation of FAK (see fig. below).

    Joint integrin/RTK signaling is required for cell proliferation, survival, and migration. Several mechanisms ensure that integrin and RTK signals are properly integrated in the anchorage-dependent cell. Formation of integrin/GF-receptor complexes may lead to three kinds of signals: concerted, integrin-dependent RTK activation, and GF-dependent integrin activation. In the first case, signals triggered by GF receptors and those induced by integrin engagement might follow parallel pathways, with additive activation of converging signaling cascades. This collaboration can exploit membrane-proximal transducers, such as FAK, that act as signaling scaffolds to keep the complex together. This coordinated activity of FAK is highlighted by the observation that fibroblasts lacking FAK are refractory to PDGF and EGF-dependent migration, and this defect is overcome by the re-expression of a functional FAK. In the second case, integrin engagement can lead to adhesion-dependent, ligand-independent activation of integrin-associated GF receptors. At least for the EGF-R/alphav-integrin complex, this type of collaboration is assured by Src and involves the recruitment of the adaptor protein p120Cas.

    In contrast to untrasformed cells, GF autocriny and anchorage-independent growth are a fundamental feature of cancer cells. Indeed, cell transformation results in alterations in serum- and adhesion-dependent cell growth, loss of contact inhibition, and changes in adhesiveness and motility. It has been noted that ROS production is increased in cancer cells and these oxidants are thought to play multiple roles in tumor initiation, progression, and maintenance. In particular, excess ROS production associated with cell transformation could release co-stimulatory and deregulated signals which are normally and transiently triggered by cell/ECM interaction. Accordingly, constitutive over-expression of active oncogenic Rac-1 or Ras in non-transformed adherent cells confers these cells with the ability to grow in the absence of ECM contact.

    Oxygen radicals have been implicated in a number of conditions ranging from aging to atherosclerosis. Little is known with regard to how ROS like superoxide and hydrogen peroxide are regulated in cells and what specific aspects of cellular activity might be influenced by the physiological and pathophysiological levels of these molecules. We are attempting to use a molecular biological approach to address these issues. It is our hope that we can gain a broader and more complete understanding of how cellular ROS are regulated. In addition, we are attempting to identify the direct molecular targets of cellular oxidants. Finally, we are hopeful that this molecular understanding will lead to new insights into diseases in which oxidant stress plays a role, and help in the design of new therapeutic agents. Cancer cells can generate constitutively high levels of ROS, which are thought to promote cell proliferation, cell motility, invasion, and angiogenesis, all of which are prerequisites for tumor metastasis. We are now focusing our interest on developing redox-based drugs with a selective potential to kill cancer cells. If the redox make-up of the cancer cell is distinctly different from that of healthy cells, it might be possible to employ redox-activated agents to selectively target the cancer.

    Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctly different from their 'healthy' counterparts, and several attempts have been made to use this naturally occurring oxidative stress to selectively kill cancer cells. Within this context, we are particularly interested in redox catalysts, i.e. drugs that enhance the toxicity of ROS. Biochemical research into catalysts able to generate or interconvert ROS is still in its infancy. Nevertheless, recent progress has been made with compounds mimicking the redox behavior of SOD and GPx. Such enzyme mimics exhibit a catalytic activity similar to their parent enzyme, but show a different substrate specificity. This leads to ROS-based catalysis distinctly different from the 'normal' SOD or GPx reactions (hydrogen peroxide and hydroxyl radicals from superoxide), and in vivo it can result in cancer cell death owing to increased toxicity of ROS. Importantly, the compounds used in these studies were highly specific for cancer cells, and did not have a major effect on healthy cells, i.e. in the absence of elevated intracellular ROS concentrations. Our future plan involves the use of some of these drugs in collaboration with C. Jacob in Germany in our redox-dependent model of carcinogenesis.

  • The involvement of Eph/ephrins in plasticity of cell motility and metastasis dissemination:
    Considering the high incidence and mortality rate due to metastatic cancers, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy. In recent years, two broad mechanisms for metastasis have received significant attention: plasticity in cell motility, i.e. transition towards a different motile phenotype, and tumor microenvironment interactions. The achievement of the migratory feature is a prerequisite of metastases and a hallmark of malignant tumor progression. The change in adhesive preferences of cancer cells that mediate their reciprocal interaction with the extracellular matrix (ECM) and neighboring stromal cells is a crucial event in the acquisition of metastatic properties. Recently, several key advances have challenged the view of cancer cell motility indicating two essential milestones: first, that the gene expression-based motile phenotype is determined very early on during cancer development and second, that cancer cells display different type of cell motility among mesenchymal, collective, and amoeboid motility. One of the main features of invasive growth is the ability of metastatic cancers to shift between modes of motility, eluding simple anticancer treatments, which represents a major challenge for developing strategies aimed at blocking the spreading of cancer cells. Many mechanisms of tumor cell motility have been described, including collective, mesenchymal, and amoeboid. Collective cell motility involves the movement of whole clusters or sheets of tumor cells. Activation of c-Met receptor tyrosine kinase is often the initiating event for mesenchymal motility. This leads to the PI3K-dependent activation of Rac and Cdc42 at the leading edge of the cell, which coordinate actin polymerization. The concomitant inhibition of Rho activity at the trailing edge of the cell promotes the cell body retraction. Mechanistically, this is similar to a collective form of mesenchymal motility, with the cells at the front producing Matrix Metalloprotease (MMPs) and generating a 'path' for the following cells. This leads to activation of Rac1 at the leading edge of the cell, and the inhibition of RhoA. Ameboid motility is the most primitive form of cell migration that allows cells to glide through rather than degrade ECM barriers through a weakness of cell-ECM attachments. Unlike mesenchymal motility, cells moving through an ameboid mode show inhibition of Rac1 and strong activation of RhoA GTPases.

    It is estimated that a third of carcinomas undergoes an epithelial to mesenchymal transition (EMT) and after the transition, uses mesenchymal motility to spread. EMT is sustained by a great change in the gene-expression pattern, mainly driven by AP1 and SMAD2 transcription factors and Snail/slug transcription repressor. EMT is accompanied by a reduction or loss of E-cadherin and the re- expression of N-cadherin, which appears to enhance the motility of various tumor cell types. Recent literature has opened a dramatic perspective on pharmacological intervention on cancer spreading due to the ability of cancer cells to switch between modes of motility. The blockade of pericellular proteolysis, inhibiting mesenchymal motility, does not reduce the overall motility of breast carcinoma cells owing to a compensation mechanism leading to mesenchymal-amoeboid transition (MAT). Known mechanisms for acquiring an amoeboid motility style are the weakening and down-regulation of integrin and cadherin functions. Reducing the force of attachment to the ECM or the neighboring cells, without interfering with cell contractility, propels cell rounding and generates hydrostatic pressure, promoting remodeling of cell shape and thus causing cells to switch to amoeboid motility. In addition to MAT, collective amoeboid transition (CAT) may play a role in cancer spreading. CAT is due to a simultaneously weakening of cell-ECM and cell-cell contacts and has been described in ß1 integrin inhibition in melanoma explants. At the moment it is unclear whether collective cell migration can shift towards amoeboid directly (CAT), or via a mesenchymal migration step (see figure above).

    The synchronized movement of cells and cell layers is a necessary process involved in determining vertebrate development, while abnormal cell migration and adhesion in adult organisms are trademarks of metastatic cancer progression. Eph-like receptors and their ligands called 'ephrins' are necessary in facilitating and directing the movement of cells during various developmental processes. While barely expressed in adult tissues except for the central nervous system, Eph and ephrin expression is eminent in highly invasive breast, colon, lung and brain tumors, as well as leukemia and malignant melanomas.

    EphrinA1 effect on the motility shift towards ameboid style: ephrinA1 leads to Rho activation (A) and Rac inactivation (B), as indicated by GST-pull down assays of the small GTPases. In addition, the ligand does not alter the expression of MMPs (C, gelatin zymography), and leads to the formation of actin cortical rings giving rise to cell body retraction D, (confocal analysis of phalloidin stained ephrin-stimulated cells)

    Our laboratory has attempted to elucidate the molecular mechanism via which Eph receptors affect cell adhesion and migration during embryogenesis and oncogenesis. We have investigated the molecular cues elicited by ephrinA1 in carcinoma cells and their motile phenotype. Ephrin kinases and their ephrin ligands transduce repulsion of cells in axon guidance, migration, invasiveness, and tumor growth, exerting a negative signaling on cell proliferation and adhesion. A key role of their kinase activity has been confirmed by mutant kinase inactive receptors which shift the cellular response from repulsion to adhesion. Our studies were aimed at investigating the role of tyrosine phosphorylation of EphA2 kinase on repulsive cues. We recently demonstrated that LMW-PTP, by means of dephosphorylation of EphA2 kinase, negatively regulates the ephrinA1-mediated repulsive response, cell proliferation, cell adhesion and spreading, and the formation of retraction fibers, thereby confirming the relevance of the net level of tyrosine phosphorylation of Eph receptors. A second approach to the focus is the study of single tyrosine substitution of EphA2 on the ephrinA1-mediated repulsive response, cell adhesion, and spreading. The integration of both PTP-mediated and tyrosine mutants-mediated studies allowed us to draw a comprehensive picture of the tyrosine kinase dependent and independent responses. Our ongoing studies show evidence that ephrinA1 inhibits integrin mediated adhesion through a redox-based Rac1 signaling, thus releasing previously engaged cell-matrix constraints. We demonstrated that the release of these constraints is a key hallmark of ephrin elicited motility and invasive properties of Ephs-expressing carcinomas.

    Beside these studies we focused our interest on the second milestone of cell movement: the release of cell-ECM constraints. Again we investigated the role of ephrinA1 as a motile factor. Interactions linking the Eph receptor tyrosine kinase and ephrin ligands transduce short-range repulsive signals regulating several motile biological processes including axon pathfinding, angiogenesis, and tumor growth. These ephrin-induced effects are believed to be mediated by alterations in actin dynamics and cytoskeleton reorganization. The members of the small Rho GTPase family elicit various effects on actin structures and are probably involved in Eph receptor-induced actin modulation. In particular, some ephrin ligands lead to a decrease in integrin-mediated cell adhesion and spreading.

    We have reported that the ability of ephrinA1 to inhibit cell adhesion and spreading in prostatic carcinoma cells is strictly dependent on the decrease in the activity of the small GTPase Rac1 (see figure above). Given the recognized role of Rac-driven redox signaling for the integrin function, reported to play an essential role in focal adhesion formation and in the overall organization of actin cytoskeleton, we investigated the possible involvement of oxidants in ephrinA1/EphA2 signaling. We provided evidence that Reactive Oxygen Species are an integration point of the ephrinA1/integrin interplay. We identified a redox circuitry in which the ephrinA1-mediated inhibition of Rac1 leads to a negative regulation of integrin redox signaling affecting the activity of the tyrosine phosphatase LMW-PTP. The enzyme in turn actively dephosphorylates its substrate p190RhoGAP, finally leading to RhoA activation. Altogether our data suggest a redox-based Rac-dependent upregulation of Rho activity, concurring with the inhibitory effect elicited by ephrinA1 on integrin-mediated adhesion strength.

Research grants

  • Cofin 2002 to Paola Chiarugi: "Redox regulation of cell signaling via modulation of the phosphorylation of the proteins" 63,000 Euro
  • Cofin 2004 to Paola Chiarugi ""Oxidative stress, cancer and metastatic growth: the role of redox regulation" 91,500 Euro.
  • Ente Cassa Di Risparmio di Firenze to Paola Chiarugi 2003-2004: "The role of the reactive species of oxygen in the activation of the Src and Ras oncogens: their role in tumoral progression" 40,.000 Euro.
  • Interuniversity Biotechnology Consortium to Paola Chiarugi 2004: The role of tyrosinic phosphorylation of the a2 eprhinic receptor in the regulation of the repulsive response. . 20,000 Euro.
  • Regione Toscana, Tresor Project to Paola Chiarugi 2004-2007: New therapeutic applications of the receptor agonists for the proliferation activators of PPAR peroxisomes" 750,000 Euro
  • Ente Cassa Di Risparmio di Firenze to Paola Chiarugi E Giampietro Ramponi 2005: Cancer and metastatic growth: the role of cellular motility as a balance between cellular adhesion and repulsion. 100,000 Euro.
  • Italian Cancer Research Association 2006: The role of ephrin kinases in the regulation of cancer progression and invasiveness" 40,000 Euro.

Main collaborations

  • Martin Lackmann, Department of Biochemistry & Molecular Biology, PO Box 13D, Monash University, Victoria 3800 Australia, Clayton Victoria 3168, Australia
  • Claus Jacob, B.Sc. M.A. D.Phil.(Oxon) MRSC CChem, Head of Bioorganic Chemistry, School of Pharmacy, Building B 2.1., Room 1.13, Saarland State University, D-66041 Saarbruecken, Germany
  • C.H.J. van Eijck, Department of Surgery, Erasmus MC, Rotterdam. The Netherlands.
  • Arne Ostman, Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Giovanni Raugei, Dipartimento di Scienze Biochimiche, Universita' degli Studi di Firenze.
  • Paola Defilippi, Universita' degli Studi di Torino, Dipartimento di Genetica, Biologia e Biochimica.
  • Mario Serio, Dipartimento di Fisiopatologia Clinica Universita' degli Studi di Firenze
  • Lido Calorini, Dipartimento di Patologia ed Oncologia Sperimentali, Universita' degli Studi di Firenze.

Publications

  1. P. Chiarugi, T. Fiaschi, M. L. Taddei, D. Talini, E. Giannoni, G. Raugei and G. Ramponi ''Two vicinal cysteines confer a peculiar redox regulation to LMW-PTP in response to PDGF stimulation'' J. Biol Chem. (2001) 276:33478-87.
  2. Chiarugi P, Fiaschi T, Buricchi F, Giannoni E, Taddei ML, Talini D, Cozzi G, Zecchi-Orlandini S, Raugei G, Ramponi G. ''Low Molecular Weight Protein-tyrosine Phosphatase Is Involved in Growth Inhibition during Cell Differentiation'' J Biol Chem. (2001) 276:49156-63.
  3. Chiarugi P. ''The redox regulation of LMW-PTP during cell proliferation or growth inhibition'' IUBMB Life 2001 Jul;52(1-2):55-9.
  4. Chiarugi P, Cirri P, Taddei ML, Talini D, Doria L, Fiaschi T, Buricchi F, Giannoni E, Camici G, Raugei G, Ramponi G. ''New perspectives in PDGF receptor down-regulation: the main role of phosphotyrosine phosphatases.'' J. Cell Sci. (2002), 115: 2219-32.
  5. Chiarugi P, Cirri P, Taddei ML, Giannoni E, Fiaschi T, Buricchi F, Camici G, Raugei G, Ramponi G. ''Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation'', J Biol. Chem. (2002) 277(40):37331-8
  6. Raugei G, Ramponi G, Chiarugi P. ''Low molecular weight protein tyrosine phosphatases: small, but smart'' Cell Mol. Life Sci. (2002) 59(6):941-9.
  7. Taddei ML, Chiarugi P, Cirri P, Buricchi F, Fiaschi T, Giannoni E, Talini D, Cozzi G, Formigli L, Raugei G, Ramponi G. '' beta-Catenin Interacts with Low-Molecular-Weight Protein Tyrosine Phosphatase Leading to Cadherin-mediated Cell-Cell Adhesion Increase.'' Cancer Res (2002), 62(22):6489-99.
  8. P. Chiarugi ''Reactive oxygen species as mediators of cell adhesion'' Ital. J. Biochemistry, (2003) Mar., 52(1):28-32.
  9. Chiarugi P, Pani G, Giannoni E, Taddei L, Colavitti R, Raugei G, Symons M, Borrello S, Galeotti T, Ramponi G., "Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion", J. Cell Biol., (2003), 161(5):933-44.
  10. Giannoni E, Chiarugi P, Cozzi G, Magnelli L, Taddei ML, Fiaschi T, Buricchi F, Raugei G, Ramponi G., "LFA-1 mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity"., J Biol Chem. 2003; 278(38): 36763-76.
  11. Chiarugi P., Cirri, P., "Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction", Trends Biochem. Sci. (2003) 28(9):509-14.
  12. Fiaschi T, Chiarugi P, Buricchi F, Giannoni E, Taddei ML, Magnelli L, Cozzi G, Raugei G, Ramponi G. Down-regulation of platelet-derived growth factor receptor signaling during myogenesis. Cell Mol Life Sci. 2003 Dec;60(12):2721-35.
  13. P. Chiarugi, M. L. Taddei, N. Schiavone, L. Papucci, E. Giannoni, T. Fiaschi, S. Capaccioli, G. Raugei and G. Ramponi, LMW-PTP is a positive regulator of tumor onset and growth. Oncogene, 2004, 23(22) :3905-14.
  14. Cirri P, Taddei ML, Chiarugi P, Buricchi F, Caselli A, Paoli P, Giannoni E, Camici G, Manao G, Raugei G, Ramponi G. Insulin Inhibits PDGF-induced Cell Proliferation. Mol Biol Cell. 2005 Jan;16(1):73-83.
  15. P. Chiarugi. E. Giannoni "Anchorage dependent cell growth: tyrosine kinases and phosphatases meet redox regulation" Antioxidant and Redox Signaling. 2005 May-Jun;7(5-6):578-92.
  16. P. Chiarugi. " PTPs versus PTKs: the redox side of the coin" Free Radic. Res. 2005 Apr;39(4):353-64.
  17. P. Chiarugi, M. L. Taddei and G. Ramponi "Oxidation and tyrosine phosphorylation: synergistic or antagonistic cues in PTP regulation" Cell. Mol. Life Science2005 May;62(9):931-6.
  18. Giannoni E, Buricchi F, Raugei G, Ramponi G, Chiarugi P. Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol. 2005 Aug;25(15):6391-403
  19. Parri M, Buricchi F, Taddei ML, Giannoni E, Raugei G, Ramponi G, Chiarugi P. EphrinA1 repulsive response is regulated by an EphA2 tyrosine phosphatase. J Biol Chem. 2005 Oct 7;280(40):34008-18.
  20. Taddei ML, Chiarugi P, Cuevas C, Ramponi G, Raugei G., Oxidation and inactivation of low molecular weight protein tyrosine phosphatase by the anticancer drug Aplidin. Int J Cancer. 2005 Nov 14;
  21. Taddei ML, Parri M, Mello T, Catalano A, Levine AD, Raugei G, Ramponi G, Chiarugi P. Integrin-mediated cell adhesion and spreading engagedifferent sources of reactive oxygen species. Antioxid Redox Signal. 2007;9(4):469-81.
  22. Chiarugi P, Fiaschi T. Redox signaling in anchorage-dependent cell growth. Cell Signal. 2006 Nov 28;
  23. Chiarugi P, Buricchi F. Protein Tyrosine Phosphorylation and Reversible Oxidation: Two Cross-Talking Posttranslation Modifications. Antioxid Redox Signal. 2007;9(1):1-24.
  24. Giannoni E, Raugei G, Chiarugi P, Ramponi G. A novel redox-based switch: LMW-PTP oxidation enhances Grb2 binding and leads to ERK activation. Biochem Biophys Res Commun. 2006 Sep 22;348(2):367-73. 2006 Jul 28.
  25. Fiaschi T, Cozzi G, Raugei G, Formigli L, Ramponi G, Chiarugi P. Redox regulation of beta-actin during integrin-mediated cell adhesion. J Biol Chem. 2006 Aug 11;281(32):22983-91. 2006 Jun 5.
  26. F.Buricchi, E.Giannoni, G.Grimaldi, M.Parri, G.Raugei, G. Ramponi, P.Chiarugi Redox regulation of ephrin/integrin cross-talk. Cell Adhesion & Migration, in press.
  27. Tania Fiaschi, Francesca Buricchi, Giacomo Cozzi, Stephanie Matthias, Matteo Parri, Giovanni Raugei, Giampietro Ramponi and Paola Chiarugi. Redox-dependent and ligand-independent trans-activation of insulin receptor by Globular Adiponectin/ACRP30. Hepatology, in press.

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