DOI: 10.1046/j.1365-2958.2002.02781.x. c‐Src/Lyn kinases activate <i>Helicobacter pylori</i> CagA through tyrosine phosphorylation of the EPIYA motifs

c‐Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs

10.1046/j.1365-2958.2002.02781.x

Crossref journal-article

Wiley

Molecular Microbiology (311)

Abstract

SummaryThe human pathogen Helicobacter pylori colonizes the mucous layer of the stomach. During parasitic infection, freely swimming bacteria adhere to the gastric epithelial cells and trigger intracellular signalling pathways. This process requires the translocation of the effector protein CagA into the host cell through a specialized type IV secretion system encoded in the cag pathogenicity island. Following transfer, CagA is phosphorylated on tyrosine re‐sidues by a host cell kinase. Here, we describe how the tyrosine phosphorylation of CagA is restricted to a previously identified repeated sequence called D1. This sequence is located in the C‐terminal half of the protein and contains the five‐amino‐acid motif EPIYA, which is amplified by duplications in a large fraction of clinical isolates. Tyrosine phosphorylation of CagA is essential for the activation process that leads to dramatic changes in the morphology of cells growing in culture. In addition, we observed that two members of the src kinases family, c‐Src and Lyn, account for most of the CagA‐specific kinase activity in host cell lysates. Thus, CagA translocation followed by tyrosine phosphorylation at the EPIYA motifs promotes a growth factor‐like response with intense cytoskeletal rearrangements, cell elongation effects and increased cellular motility.

Bibliography

Stein, M., Bagnoli, F., Halenbeck, R., Rappuoli, R., Fantl, W. J., & Covacci, A. (2002). câSrc/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Molecular Microbiology, 43(4), 971â980. Portico.

Authors 6

Markus Stein (first)
Fabio Bagnoli (additional)
Robert Halenbeck (additional)
Rino Rappuoli (additional)
Wendy J. Fantl (additional)
Antonello Covacci (additional)

References 36 Referenced 359

10.1084/jem.191.4.593
10.1046/j.1462-5822.2000.00043.x
10.1093/emboj/16.10.2730
10.1128/jvi.53.1.7-12.1985 / J Virol / Myristic acid, a rare fatty acid, is the lipid attached to the transforming protein of Rous sarcoma virus and its cellular homolog. by Buss J.E. (1985)
10.1073/pnas.93.25.14648 / Proc Natl Acad Sci USA / cag, a pathogenicity island of Helicobacter pylori, encodes type I‐specific and disease‐associated virulence factors. by Censini S. (1996)
10.1128/iai.65.5.1949-1952.1997 / Infect Immun / Introduction of unmarked mutations in the Helicobacter pylori vacA gene with a sucrose sensitivity marker. by Copass M. (1997)
10.1073/pnas.77.7.3783
10.1073/pnas.90.12.5791
10.1083/jcb.111.6.3097
10.1002/1097-0169(200012)47:4<307::AID-CM5>3.0.CO;2-Q / Cell Motil Cytoskeleton / Interaction of the enteropathogenic Escherichia coli protein, translocated intimin receptor (Tir), with focal adhesion proteins. by Freeman N.L. (2000)
10.1038/361730a0
10.1128/IAI.66.5.2346-2348.1998 / Infect Immun / Proteins encoded by the cag pathogenicity island of Helicobacter pylori are required for NF‐kappaB activation. by Glocker E. (1998)
10.1016/S0960-9822(00)00543-1
10.1016/0014-4827(87)90013-9
10.1073/pnas.170281997
10.1038/14087
10.1016/S0092-8674(00)80437-7
10.1046/j.1365-2958.1999.01569.x
10.1126/science.287.5457.1497
10.1126/science.290.5496.1594
10.1093/emboj/16.9.2307
10.1046/j.1365-2958.2002.02780.x
10.1083/jcb.100.2.409
10.1128/iai.59.12.4562-4569.1991 / Infect Immun / Intracellular targeting of the Yersinia YopE cytotoxin in mammalian cells induces actin microfilament disruption. by Rosqvist R. (1991)
10.1128/MCB.14.3.1680
10.1126/science.3917576
10.1073/pnas.96.25.14559 / Proc Natl Acad Sci USA / Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. by Segal E.D. (1999)
10.1046/j.1365-2958.1999.01642.x
10.1128/MCB.26.1.261-276.2006
10.1073/pnas.91.25.12253
10.1073/pnas.97.3.1263
10.1111/j.1365-2958.1995.18050867.x / Mol Microbiol / Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL‐8 in gastric epithelial cells. by Tummuru M. (1995)
10.1046/j.1365-2958.2000.01898.x
10.1016/0092-8674(79)90361-1
10.1038/379466a0
10.1128/iai.63.1.94-98.1995 / Infect Immun / Analysis of expression of CagA and VacA virulence factors in 43 strains of Helicobacter pylori reveals that clinical isolates can be divided into two major types and that CagA is not necessary for expression of the vacuolating cytotoxin. by Xiang Z. (1995)

Dates

Type	When
Created	22 years, 5 months ago (March 12, 2003, 6:42 a.m.)
Deposited	1 year, 10 months ago (Oct. 17, 2023, 5:56 a.m.)
Indexed	4 weeks, 2 days ago (Aug. 6, 2025, 8:40 a.m.)
Issued	23 years, 7 months ago (Feb. 1, 2002)
Published	23 years, 7 months ago (Feb. 1, 2002)
Published Online	23 years, 5 months ago (March 27, 2002)
Published Print	23 years, 7 months ago (Feb. 1, 2002)

Funders 0

None

BibTeX

@article{Stein_2002, title={c‐Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs}, volume={43}, ISSN={1365-2958}, url={http://dx.doi.org/10.1046/j.1365-2958.2002.02781.x}, DOI={10.1046/j.1365-2958.2002.02781.x}, number={4}, journal={Molecular Microbiology}, publisher={Wiley}, author={Stein, Markus and Bagnoli, Fabio and Halenbeck, Robert and Rappuoli, Rino and Fantl, Wendy J. and Covacci, Antonello}, year={2002}, month=feb, pages={971–980} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        6
      ]
    ],
    "date-time": "2025-08-06T12:40:51Z",
    "timestamp": 1754484051688
  },
  "reference-count": 36,
  "publisher": "Wiley",
  "issue": "4",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2002,
            3,
            27
          ]
        ],
        "date-time": "2002-03-27T00:00:00Z",
        "timestamp": 1017187200000
      },
      "content-version": "vor",
      "delay-in-days": 54,
      "URL": "http://onlinelibrary.wiley.com/termsAndConditions#vor"
    }
  ],
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        2002,
        2
      ]
    ]
  },
  "abstract": "<jats:title>Summary</jats:title><jats:p>The human pathogen <jats:italic>Helicobacter pylori</jats:italic> colonizes the mucous layer of the\n\n stomach. During parasitic infection, freely swimming bacteria adhere to the gastric\n\n epithelial cells and trigger intracellular signalling pathways. This process requires\n\n the translocation of the effector protein CagA into the host cell through a specialized\n\n type IV secretion system encoded in the <jats:italic>cag</jats:italic> pathogenicity island. Following transfer, CagA is phosphorylated on tyrosine re\u2010sidues by a host cell kinase. Here, we describe how the tyrosine phosphorylation of CagA is restricted to a previously identified repeated sequence called D1. This sequence is located in the C\u2010terminal half of the protein and contains the five\u2010amino\u2010acid motif EPIYA, which is amplified by duplications in a large fraction of clinical isolates. Tyrosine phosphorylation of CagA is essential for the activation process that leads to dramatic changes in the morphology of cells growing in culture. In addition, we observed that two members of the src kinases family, c\u2010Src and Lyn, account for most of the CagA\u2010specific kinase activity in host cell lysates. Thus, CagA translocation followed by tyrosine phosphorylation at the EPIYA motifs promotes a growth factor\u2010like response with intense cytoskeletal rearrangements, cell elongation effects and increased cellular motility.</jats:p>",
  "DOI": "10.1046/j.1365-2958.2002.02781.x",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2003,
        3,
        12
      ]
    ],
    "date-time": "2003-03-12T11:42:12Z",
    "timestamp": 1047469332000
  },
  "page": "971-980",
  "source": "Crossref",
  "is-referenced-by-count": 359,
  "title": "c\u2010Src/Lyn kinases activate <i>Helicobacter pylori</i> CagA through tyrosine phosphorylation of the EPIYA motifs",
  "prefix": "10.1111",
  "volume": "43",
  "author": [
    {
      "given": "Markus",
      "family": "Stein",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Fabio",
      "family": "Bagnoli",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Robert",
      "family": "Halenbeck",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Rino",
      "family": "Rappuoli",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Wendy J.",
      "family": "Fantl",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Antonello",
      "family": "Covacci",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "311",
  "published-online": {
    "date-parts": [
      [
        2002,
        3,
        27
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_2_6_2_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1084/jem.191.4.593"
    },
    {
      "key": "e_1_2_6_3_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1462-5822.2000.00043.x"
    },
    {
      "key": "e_1_2_6_4_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/16.10.2730"
    },
    {
      "key": "e_1_2_6_5_1",
      "doi-asserted-by": "crossref",
      "first-page": "7",
      "DOI": "10.1128/jvi.53.1.7-12.1985",
      "article-title": "Myristic acid, a rare fatty acid, is the lipid attached to the transforming protein of Rous sarcoma virus and its cellular homolog.",
      "volume": "53",
      "author": "Buss J.E.",
      "year": "1985",
      "journal-title": "J Virol"
    },
    {
      "key": "e_1_2_6_6_1",
      "doi-asserted-by": "crossref",
      "first-page": "14648",
      "DOI": "10.1073/pnas.93.25.14648",
      "article-title": "cag, a pathogenicity island of Helicobacter pylori, encodes type\n\n I\u2010specific and disease\u2010associated virulence factors.",
      "volume": "93",
      "author": "Censini S.",
      "year": "1996",
      "journal-title": "Proc Natl Acad Sci USA"
    },
    {
      "key": "e_1_2_6_7_1",
      "doi-asserted-by": "crossref",
      "first-page": "1949",
      "DOI": "10.1128/iai.65.5.1949-1952.1997",
      "article-title": "Introduction of unmarked mutations in the Helicobacter pylori vacA gene\n\n with a sucrose sensitivity marker.",
      "volume": "65",
      "author": "Copass M.",
      "year": "1997",
      "journal-title": "Infect Immun"
    },
    {
      "key": "e_1_2_6_8_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.77.7.3783"
    },
    {
      "key": "e_1_2_6_9_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.90.12.5791"
    },
    {
      "key": "e_1_2_6_10_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.111.6.3097"
    },
    {
      "key": "e_1_2_6_11_1",
      "doi-asserted-by": "crossref",
      "first-page": "307",
      "DOI": "10.1002/1097-0169(200012)47:4<307::AID-CM5>3.0.CO;2-Q",
      "article-title": "Interaction of the enteropathogenic Escherichia coli protein, translocated intimin receptor (Tir), with focal adhesion proteins.",
      "volume": "47",
      "author": "Freeman N.L.",
      "year": "2000",
      "journal-title": "Cell Motil Cytoskeleton"
    },
    {
      "key": "e_1_2_6_12_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/361730a0"
    },
    {
      "key": "e_1_2_6_13_1",
      "doi-asserted-by": "crossref",
      "first-page": "2346",
      "DOI": "10.1128/IAI.66.5.2346-2348.1998",
      "article-title": "Proteins encoded by the cag pathogenicity island of Helicobacter pylori are required for NF\u2010kappaB activation.",
      "volume": "66",
      "author": "Glocker E.",
      "year": "1998",
      "journal-title": "Infect Immun"
    },
    {
      "key": "e_1_2_6_14_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0960-9822(00)00543-1"
    },
    {
      "key": "e_1_2_6_15_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0014-4827(87)90013-9"
    },
    {
      "key": "e_1_2_6_16_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.170281997"
    },
    {
      "key": "e_1_2_6_17_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/14087"
    },
    {
      "key": "e_1_2_6_18_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(00)80437-7"
    },
    {
      "key": "e_1_2_6_19_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1365-2958.1999.01569.x"
    },
    {
      "key": "e_1_2_6_20_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.287.5457.1497"
    },
    {
      "key": "e_1_2_6_21_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.290.5496.1594"
    },
    {
      "key": "e_1_2_6_22_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/16.9.2307"
    },
    {
      "key": "e_1_2_6_23_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1365-2958.2002.02780.x"
    },
    {
      "key": "e_1_2_6_24_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.100.2.409"
    },
    {
      "key": "e_1_2_6_25_1",
      "doi-asserted-by": "crossref",
      "first-page": "4562",
      "DOI": "10.1128/iai.59.12.4562-4569.1991",
      "article-title": "Intracellular targeting of the Yersinia YopE cytotoxin in mammalian cells induces actin microfilament disruption.",
      "volume": "59",
      "author": "Rosqvist R.",
      "year": "1991",
      "journal-title": "Infect Immun"
    },
    {
      "key": "e_1_2_6_26_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.14.3.1680"
    },
    {
      "key": "e_1_2_6_27_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.3917576"
    },
    {
      "key": "e_1_2_6_28_1",
      "doi-asserted-by": "crossref",
      "first-page": "14559",
      "DOI": "10.1073/pnas.96.25.14559",
      "article-title": "Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori.",
      "volume": "96",
      "author": "Segal E.D.",
      "year": "1999",
      "journal-title": "Proc Natl Acad Sci USA"
    },
    {
      "key": "e_1_2_6_29_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1365-2958.1999.01642.x"
    },
    {
      "key": "e_1_2_6_30_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.26.1.261-276.2006"
    },
    {
      "key": "e_1_2_6_31_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.91.25.12253"
    },
    {
      "key": "e_1_2_6_32_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.97.3.1263"
    },
    {
      "key": "e_1_2_6_33_1",
      "doi-asserted-by": "crossref",
      "first-page": "867",
      "DOI": "10.1111/j.1365-2958.1995.18050867.x",
      "article-title": "Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL\u20108 in gastric epithelial cells.",
      "volume": "18",
      "author": "Tummuru M.",
      "year": "1995",
      "journal-title": "Mol Microbiol"
    },
    {
      "key": "e_1_2_6_34_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1365-2958.2000.01898.x"
    },
    {
      "key": "e_1_2_6_35_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(79)90361-1"
    },
    {
      "key": "e_1_2_6_36_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/379466a0"
    },
    {
      "key": "e_1_2_6_37_1",
      "doi-asserted-by": "crossref",
      "first-page": "94",
      "DOI": "10.1128/iai.63.1.94-98.1995",
      "article-title": "Analysis of expression of CagA and VacA virulence factors in 43 strains of Helicobacter\n\n pylori reveals that clinical isolates can be divided into two major types and that CagA is not necessary for expression of the vacuolating cytotoxin.",
      "volume": "63",
      "author": "Xiang Z.",
      "year": "1995",
      "journal-title": "Infect Immun"
    }
  ],
  "container-title": "Molecular Microbiology",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.1365-2958.2002.02781.x",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "text-mining"
    },
    {
      "URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2958.2002.02781.x",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        10,
        17
      ]
    ],
    "date-time": "2023-10-17T09:56:23Z",
    "timestamp": 1697536583000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2958.2002.02781.x"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2002,
        2
      ]
    ]
  },
  "references-count": 36,
  "journal-issue": {
    "issue": "4",
    "published-print": {
      "date-parts": [
        [
          2002,
          2
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1046/j.1365-2958.2002.02781.x"
  ],
  "URL": "http://dx.doi.org/10.1046/j.1365-2958.2002.02781.x",
  "relation": {},
  "ISSN": [
    "0950-382X",
    "1365-2958"
  ],
  "subject": [],
  "container-title-short": "Molecular Microbiology",
  "published": {
    "date-parts": [
      [
        2002,
        2
      ]
    ]
  }
}