Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA.
Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with atrophic gastritis, peptic ulcer, and gastric adenocarcinoma. The cagA gene product CagA is translocated from H. pylori into gastric epithelial cells and undergoes tyrosine phosphorylation by Src family kinases (SFKs). Tyrosine-phosphorylated CagA binds and activates SHP-2 phosphatase and the C-terminal Src kinase (Csk) while inducing an elongated cell shape termed the "hummingbird phenotype." Here we show that CagA reduces the level of focal adhesion kinase (FAK) tyrosine phosphorylation in gastric epithelial cells. The decrease in phosphorylated FAK is due to SHP-2-mediated dephosphorylation of FAK at the activating phosphorylation sites, not due to Csk-dependent inhibition of SFKs, which phosphorylate FAK. Coexpression of constitutively active FAK with CagA inhibits induction of the hummingbird phenotype, whereas expression of dominant-negative FAK elicits an elongated cell shape characteristic of the hummingbird phenotype. These results indicate that inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA. Impaired cell adhesion and increased motility by CagA may be involved in the development of gastric lesions associated with cagA-positive H. pylori infection.
Tsutsumi
Ryouhei
R
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Sapporo 060-0815, Japan.
Takahashi
Atsushi
A
Azuma
Takeshi
T
Higashi
Hideaki
H
Hatakeyama
Masanori
M
D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology / Q000382:microbiology / Q000473:pathology*; D016481:Helicobacter Infections / Q000201:enzymology*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D025941:Protein Interaction Mapping; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019061:src-Family Kinases
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C080866:cagA protein, Helicobacter pylori; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases