The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation.
The gastric pathogen Helicobacter pylori translocates the CagA protein into epithelial cells by a type IV secretion process. Translocated CagA is tyrosine phosphorylated (CagA(P-Tyr)) on specific EPIYA sequence repeats by Src family tyrosine kinases. Phos phorylation of CagA induces the dephosphorylation of as yet unidentified cellular proteins, rearrangements of the host cell actin cytoskeleton and cell scattering. We show here that CagA(P-Tyr) inhibits the catalytic activity of c-Src in vivo and in vitro. c-Src inactivation leads to tyrosine dephosphorylation of the actin binding protein cortactin. Concomitantly, cortactin is specifically redistributed to actin-rich cellular protrusions. c-Src inactivation and cortactin dephosphorylation are required for rearrangements of the actin cytoskeleton. Moreover, CagA(P-Tyr)-mediated c-Src inhibition downregulates further CagA phosphorylation through a negative feedback loop. This is the first report of a bacterial virulence factor that inhibits signalling of a eukaryotic tyrosine kinase and on a role of c-Src inactivation in host cell cytoskeletal rearrangements.
Selbach
Matthias
M
Max-Planck-Institut für Infektionsbiologie, Abt. Molekulare Biologie, Schumannstrasse 20/21, D-10117 Berlin, Germany.
Moese
Stefan
S
Hurwitz
Robert
R
Hauck
Christof R
CR
Meyer
Thomas F
TF
Backert
Steffen
S
D000199:Actins / Q000378:metabolism*; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D051356:Cortactin; D003599:Cytoskeleton / Q000378:metabolism; D025461:Feedback, Physiological; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D018613:Microscopy, Confocal; D008954:Models, Biological; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases
D000199:Actins; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C495868:CTTN protein, human; D051356:Cortactin; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases