title: Cellular invasion by Staphylococcus aureus reveals a functional link between focal adhesion kinase and cortactin in integrin-mediated internalisation.
abstract: Nosocomial infections by Staphylococcus aureus, a Gram-positive pathogen colonising human skin and mucosal surfaces, are an increasing health care problem. Clinical isolates almost invariably express fibronectin-binding proteins that, by indirectly linking the bacteria with host integrin alpha5beta1, can promote uptake of the microorganisms by eukaryotic cells. Integrin engagement by pathogenic fibronectin-binding S. aureus, but not by non-pathogenic S. carnosus, triggered the recruitment of focal contact-associated proteins vinculin, tensin, zyxin and FAK to the sites of bacterial attachment. Moreover, dominant-negative versions of FAK-blocked integrin-mediated internalisation and FAK-deficient cells were severely impaired in their ability to internalise S. aureus. Pathogen binding induced tyrosine phosphorylation of several host proteins associated with bacterial attachment sites, including FAK and the Src substrate cortactin. In FAK-deficient cells, local recruitment of cortactin still occurred, whereas the integrin- and Src-dependent tyrosine phosphorylation of cortactin was abolished. As siRNA-mediated gene silencing of cortactin or mutation of critical amino acid residues within cortactin interfered with uptake of S. aureus, our results reveal a novel functional connection between integrin engagement, FAK activation and Src-mediated cortactin phosphorylation. Cooperation between FAK, Src and cortactin in integrin-mediated internalisation of bacteria also suggests a molecular scenario of how engagement of integrins could be coupled to membrane endocytosis.
authors.affiliation: Zentrum für Infektionsforschung, Universität Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Agerer
authors.forename: Sigrid
authors.initials: S
authors.lastname: Lux
authors.forename: Antje
authors.initials: A
authors.lastname: Michel
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.forename: Knut
authors.initials: K
authors.lastname: Ohlsen
authors.forename: Christof R
authors.initials: CR
authors.lastname: Hauck
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004705:Endocytosis; D005353:Fibronectins / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D009154:Mutation; D010766:Phosphorylation; D013210:Staphylococcus / Q000502:physiology / Q000648:ultrastructure; D013211:Staphylococcus aureus / Q000502:physiology* / Q000648:ultrastructure; D000070876:Tensins; D014443:Tyrosine / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism; D060589:Zyxin; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; C495869:Cttn protein, mouse; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D006023:Glycoproteins; D039081:Integrin alpha5beta1; D008840:Microfilament Proteins; D000070876:Tensins; C092842:ZYX protein, human; D060589:Zyxin; D016596:Vinculin; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases