Cortactin: A Major Cellular Target of the Gastric Carcinogen Helicobacter pylori

Sharafutdinov, Irshad; Backert, Steffen; Tegtmeyer, Nicole

doi:10.3390/cancers12010159

Cited by 16 publications

(18 citation statements)

References 116 publications

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“…* The first and second SH3 domains cooperate to form a common "super SH3 platform" and allow the binding of the proline-rich region of the partner protein [33]. GST pull-down assay 4th SH3 domain Ectodomain shedding, cell adhesion, and signaling [35] Cortactin [9] Co-immunoprecipitation, GST pull-down assay, immunofluorescence colocalization Unknown Regulation of actin cytoskeleton [36] CR16 [37] GST pull-down assay Weak interaction with the 2nd, 3rd, and 4th SH3 domains Reorganization of actin cytoskeleton [38] DNM2 [37] GST pull-down assay 3rd SH3 domain Endo-/exocytosis [37] FasL (CD178) [39] Phage display screening 3rd and 4th SH3 domains Apoptosis induction [40] GRB2 [28] Affinity purification-selected reaction monitoring mass spectrometry…”

Section: Egfr Signaling Via Tks4 and Tks5mentioning

confidence: 99%

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Kudlik

Takács

Radnai

et al. 2020

IJMS

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Scaffold proteins are typically thought of as multi-domain “bridging molecules.” They serve as crucial regulators of key signaling events by simultaneously binding multiple participants involved in specific signaling pathways. In the case of epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) binding, the activated EGFR contacts cytosolic SRC tyrosine-kinase, which then becomes activated. This process leads to the phosphorylation of SRC-substrates, including the tyrosine kinase substrates (TKS) scaffold proteins. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction, promoting cell spreading and migration. The TKS4 and the TKS5 scaffold proteins are tyrosine kinase substrates with four or five SH3 domains, respectively. Their structural features allow them to recruit and bind a variety of signaling proteins and to anchor them to the cytoplasmic surface of the cell membrane. Until recently, TKS4 and TKS5 had been recognized for their involvement in cellular motility, reactive oxygen species-dependent processes, and embryonic development, among others. However, a number of novel functions have been discovered for these molecules in recent years. In this review, we attempt to cover the diverse nature of the TKS molecules by discussing their structure, regulation by SRC kinase, relevant signaling pathways, and interaction partners, as well as their involvement in cellular processes, including migration, invasion, differentiation, and adipose tissue and bone homeostasis. We also describe related pathologies and the established mouse models.

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Section: Egfr Signaling Via Tks4 and Tks5mentioning

confidence: 99%

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Kudlik

Takács

Radnai

et al. 2020

IJMS

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“…The actin-regulatory protein cortactin, encoded by the cttn gene, is one of the factors used by H. pylori to manipulate host cell signaling [ 28 ]. Cortactin can be detected as two bands of approximately 80 and 85 kDa, called p80 and p85 when analyzed by SDS-PAGE [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Cortactin Is Required for Efficient FAK, Src and Abl Tyrosine Kinase Activation and Phosphorylation of Helicobacter pylori CagA

Knorr

Sharafutdinov

Fiedler

et al. 2021

IJMS

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Cortactin is a well-known regulatory protein of the host actin cytoskeleton and represents an attractive target of microbial pathogens like Helicobacter pylori. H. pylori manipulates cortactin’s phosphorylation status by type-IV secretion-dependent injection of its virulence protein CagA. Multiple host tyrosine kinases, like FAK, Src, and Abl, are activated during infection, but the pathway(s) involved is (are) not yet fully established. Among them, Src and Abl target CagA and stimulate tyrosine phosphorylation of the latter at its EPIYA-motifs. To investigate the role of cortactin in more detail, we generated a CRISPR/Cas9 knockout of cortactin in AGS gastric epithelial cells. Surprisingly, we found that FAK, Src, and Abl kinase activities were dramatically downregulated associated with widely diminished CagA phosphorylation in cortactin knockout cells compared to the parental control. Together, we report here a yet unrecognized cortactin-dependent signaling pathway involving FAK, Src, and Abl activation, and controlling efficient phosphorylation of injected CagA during infection. Thus, the cortactin status could serve as a potential new biomarker of gastric cancer development.

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“…Cortactin is an important actin‐binding protein, which plays an intrinsic role in actin‐cytoskeletal rearrangements and cellular motility by interacting with numerous regulatory proteins (Schnoor, Stradal, & Rottner, 2018). Thus, it is not surprising that various microbial pathogens can target cortactin to manipulate bacterial attachment, host cell invasion and intracellular motility as well as cell scattering (Selbach & Backert, 2005; Sharafutdinov et al, 2020). Here we show for the first time that cortactin is overexpressed in AGS and Caco‐2 epithelial cells upon infection with highly pathogenic H. pylori strains.…”

Section: Discussionmentioning

confidence: 99%

“…One of the major host target proteins during H. pylori infection is cortactin, a factor involved in cellular cytoskeletal rearrangements (Sharafutdinov, Backert, & Tegtmeyer, 2020). Cortactin has multiple functional domains including an N‐terminal acidic domain (NTA), a filamentous actin (F‐actin) binding region, a proline‐rich domain and a C‐terminal Src homology 3 (SH3) domain (Ammer & Weed, 2008; Cosen‐Binker & Kapus, 2006; Selbach & Backert, 2005).…”

Section: Introductionmentioning

confidence: 99%

TheHelicobacter pyloritypeIVsecretion system upregulates epithelial cortactin expression by aCagA‐ andJNK‐dependent pathway

Sharafutdinov

Backert

Tegtmeyer

2021

Cellular Microbiology

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Cortactin represents an important actin‐binding factor, which controls actin‐cytoskeletal remodelling in host cells. In this way, cortactin has been shown to exhibit crucial functions both for cell movement and tumour cell invasion. In addition, the cortactin gene cttn is amplified in various cancer types of humans. Helicobacter pylori is the causative agent of multiple gastric diseases and represents a significant risk factor for the development of gastric adenocarcinoma. It has been repeatedly shown that H. pylori manipulates cancer‐related signal transduction events in infected gastric epithelial cells such as the phosphorylation status of cortactin. In fact, H. pylori modifies the activity of cortactin's binding partners to stimulate changes in the actin‐cytoskeleton, cell adhesion and motility. Here we show that H. pylori infection of cultured AGS and Caco‐2 cells for 24–48 hr leads to the overexpression of cortactin by 2–3 fold at the protein level. We demonstrate that this activity requires the integrity of the type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI) as well as the translocated effector protein CagA. We further show that ectopic expression of CagA is sufficient to stimulate cortactin overexpression. Furthermore, phosphorylation of CagA at the EPIYA‐repeat region is not required, suggesting that this CagA activity proceeds in a phosphorylation‐independent fashion. Inhibitor studies further demonstrate that the involved signalling pathway comprises the mitogen‐activated protein kinase JNK (c‐Jun N‐terminal kinase), but not ERK1/2 or p38. Taken together, using H. pylori as a model system, this study discovered a previously unrecognised cortactin activation cascade by a microbial pathogen. We suggest that H. pylori targets cortactin to manipulate the cellular architecture and epithelial barrier functions that can impact gastric cancer development. Take Aways Helicobacter pylori infection induces overexpression of cortactin at the protein level Cortactin upregulation requires the T4SS and effector protein CagA Ectopic expression of CagA is sufficient to stimulate cortactin overexpression Overexpression of cortactin proceeds CagA phosphorylation‐independent The involved host cell signalling pathway comprises the MAP kinase JNK

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Cortactin: A Major Cellular Target of the Gastric Carcinogen Helicobacter pylori

Cited by 16 publications

References 116 publications

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Cortactin Is Required for Efficient FAK, Src and Abl Tyrosine Kinase Activation and Phosphorylation of Helicobacter pylori CagA

TheHelicobacter pyloritypeIVsecretion system upregulates epithelial cortactin expression by aCagA‐ andJNK‐dependent pathway

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