title: Redox regulation of ephrin/integrin cross-talk.
abstract: Interactions linking the Eph receptor tyrosine kinase and ephrin ligands transduce short-range repulsive signals regulating several motile biological processes including axon path-finding, 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 spread. Here we show 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. Given the recognized role of Rac-driven redox signaling for 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 now provide evidence that Reactive Oxygen Species are an integration point of the ephrinA1/integrin interplay. We identify 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.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buricchi
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.forename: Giovanna
authors.initials: G
authors.lastname: Grimaldi
authors.forename: Matteo
authors.initials: M
authors.lastname: Parri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raugei
authors.forename: Giampietro
authors.initials: G
authors.lastname: Ramponi
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D036382:Ephrin-A1 / Q000235:genetics / Q000378:metabolism*; D036383:Ephrin-A2 / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C074560:ARHGAP35 protein, human; D000199:Actins; D036382:Ephrin-A1; D036383:Ephrin-A2; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D011518:Proto-Oncogene Proteins; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C066737:RHOA protein, human; C490429:ACP1 protein, human; D017027:Protein Tyrosine Phosphatases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein