A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation.
Fibronectin, a 250-kDa eukaryotic extracellular matrix protein containing an RGD motif plays crucial roles in cell-cell communication, development, tissue homeostasis, and disease development. The highly complex fibrillar fibronectin meshwork orchestrates the functions of other extracellular matrix proteins, promoting cell adhesion, migration, and intracellular signaling. Here, we demonstrate that CagL, a 26-kDa protein of the gastric pathogen and type I carcinogen Helicobacter pylori, mimics fibronectin in various cellular functions. Like fibronectin, CagL contains a RGD motif and is located on the surface of the bacterial type IV secretion pili as previously shown. CagL binds to the integrin receptor alpha(5)beta(1) and mediates the injection of virulence factors into host target cells. We show that purified CagL alone can directly trigger intracellular signaling pathways upon contact with mammalian cells and can complement the spreading defect of fibronectin(-/-) knock-out cells in vitro. During interaction with various human and mouse cell lines, CagL mimics fibronectin in triggering cell spreading, focal adhesion formation, and activation of several tyrosine kinases in an RGD-dependent manner. Among the activated factors are the nonreceptor tyrosine kinases focal adhesion kinase and Src but also the epidermal growth factor receptor and epidermal growth factor receptor family member Her3/ErbB3. Interestingly, fibronectin activates a similar range of tyrosine kinases but not Her3/ErbB3. These findings suggest that the bacterial protein CagL not only exhibits functional mimicry with fibronectin but is also capable of activating fibronectin-independent signaling events. We thus postulate that CagL may contribute directly to H. pylori pathogenesis by promoting aberrant signaling cross-talk within host cells.
University College Dublin, School of Biomolecular and Biomedical Sciences, Ardmore House, Belfield Campus, Dublin 4, Ireland.
Nicole
N
Tegtmeyer
Roland
R
Hartig
Robin M
RM
Delahay
Manfred
M
Rohde
Sabine
S
Brandt
Jens
J
Conradi
Seiichiro
S
Takahashi
Adam J
AJ
Smolka
Norbert
N
Sewald
Steffen
S
Backert
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D016480:Helicobacter pylori; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D001426:Bacterial Proteins; D005353:Fibronectins; D055767:Immobilized Proteins; D016023:Integrins; D009842:Oligopeptides; D019000:Phosphotyrosine; C047981:arginyl-glycyl-aspartic acid; D011505:Protein-Tyrosine Kinases