Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis.
ErbB2 is a receptor tyrosine kinase belonging to the family of epidermal growth factor (EGF) receptors which is generally involved in cell differentiation, proliferation, and tumor growth, and activated by heterodimerization with the other members of the family. We show here that type IV pilus-mediated adhesion of Neisseria meningitidis onto endothelial cells induces tyrosyl phosphorylation and massive recruitment of ErbB2 underneath the bacterial colonies. However, neither the phosphorylation status nor the cellular localization of the EGF receptors, ErbB3 or ErbB4, were affected in infected cells. ErbB2 phosphorylation induced by N. meningitidis provides docking sites for the kinase src and leads to its subsequent activation. Specific inhibition of either ErbB2 and/or src activity reduces bacterial internalization into endothelial cells without affecting bacteria-induced actin cytoskeleton reorganization or ErbB2 recruitment. Moreover, inhibition of both actin polymerization and the ErbB2/src pathway totally prevents bacterial entry. Altogether, our results provide new insight into ErbB2 function by bringing evidence of a bacteria-induced ErbB2 clustering leading to src kinase phosphorylation and activation. This pathway, in cooperation with the bacteria-induced reorganization of the actin cytoskeleton, is required for the efficient internalization of N. meningitidis into endothelial cells, an essential process enabling this pathogen to cross host cell barriers.
Hoffmann
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Laboratoire d'Immuno-Pharmacologie Moléculaire, Centre National de la Recherche Scientifique, Institut Cochin de Génétique Moléculaire, 75014 Paris, France.
Eugène
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E
Nassif
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Couraud
P O
PO
Bourdoulous
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S
D000199:Actins / Q000378:metabolism; D001422:Bacterial Adhesion; D002460:Cell Line; D051356:Cortactin; D003598:Cytoskeletal Proteins; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D010861:Fimbriae, Bacterial / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009345:Neisseria meningitidis / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism; D000099149:Ezrin
D000199:Actins; D051356:Cortactin; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017027:Protein Tyrosine Phosphatases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; D019061:src-Family Kinases; D000099149:Ezrin; C101044:RTKI cpd