ArticleProceedings of the National Academy of Sciences of the United States of America2011
Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed.
- A tandem recruitment site in the pseudokinase scaffold PEAK3 is subject to phosphorylation-dependent regulation and cancer-associated mutations.The Journal of biological chemistry · 2026Article
- PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation.Nature communications · 2025Article
- Current understanding of PEAK family members in regulation of cellular signaling pathways and cancer therapy.Molecular and cellular biochemistry · 2025Review
- The suppression of cell motility through the reduction of FAK activity and expression of cell adhesion proteins by hAMSCs secretome in MDA-MB-231 breast cancer cells.Investigational new drugs · 2024Article
- Investigating the Protective Effects of a Citrus Flavonoid on the Retardation Morphogenesis of the Oligodendroglia-like Cell Line by Rnd2 Knockdown.Neurology international · 2023Article
- Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling.Nature communications · 2023Article
- Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3.Nature communications · 2023Article
- A phospho-tyrosine-based signaling module using SPOP, CSK, and LYN controls TLR-induced IRF activity.Science advances · 2022Article
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- The inhibition of Panc1 cancer cells invasion by hAMSCs secretome through suppression of tyrosine phosphorylation of SGK223 (at Y411 site), c-Src (at Y416, Y530 sites), AKT activity, and JAK1/Stat3 signaling.Medical oncology (Northwood, London, England) · 2022Article
- Host Genome-Wide Association Study of Infant Susceptibility toInfection and immunity · 2021Article
- EPIYA motifs ofNew microbes and new infections · 2021Article
- Diversity of 3' variable region of cagA gene in Helicobacter pylori strains isolated from Chinese population.Gut pathogens · 2021Article
- Article
- The p140Cap adaptor protein as a molecular hub to block cancer aggressiveness.Cellular and molecular life sciences : CMLS · 2021Review
- Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis.Cancers · 2020Review
- PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Searching algorithm for Type IV effector proteins (S4TE) 2.0: Improved tools for Type IV effector prediction, analysis and comparison in proteobacteria.PLoS computational biology · 2019Article
- SHEDding light on the role of Pragmin pseudo-kinases in cancer.American journal of cancer research · 2019Article
- The pseudokinases SgK269 and SgK223: A novel oncogenic alliance in human cancer.Cell adhesion & migration · 2018Review
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4 authors.
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Abstract
Several pathogenic bacteria have adopted effector proteins that, upon delivery into mammalian cells, undergo tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) or EPIYA-like sequence motif by host kinases such as Src family kinases (SFKs). This EPIYA phosphorylation triggers complex formation of bacterial effectors with SH2 domain-containing proteins that results in perturbation of host cell signaling and subsequent pathogenesis. Although the presence of such an anomalous protein interaction suggests the existence of a mammalian EPIYA-containing protein whose function is mimicked or subverted by bacterial EPIYA effectors, no molecule that uses the EPIYA motif for biological function has so far been reported in mammals. Here we show that mammalian Pragmin/SgK223 undergoes tyrosine phosphorylation at the EPIYA motif by SFKs and thereby acquires the ability to interact with the SH2 domain of the C-terminal Src kinase (Csk), a negative regulator of SFKs. The Pragmin-Csk interaction prevents translocalization of Csk from the cytoplasm to the membrane and subsequent inactivation of membrane-associated SFKs. As a result, SFK activity is sustained in cells where Pragmin is phosphorylated at the EPIYA motif. Because EPIYA phosphorylation of Pragmin is mediated by SFKs, cytoplasmic sequestration of Csk by Pragmin establishes a positive feedback regulation of SFK activation. Remarkably, the Helicobacter pylori EPIYA effector CagA binds to the Csk SH2 domain in place of Pragmin and enforces membrane recruitment of Csk and subsequent inhibition of SFKs. This work identifies Pragmin as a mammalian EPIYA effector and suggests that bacterial EPIYA effectors target Pragmin to subvert SFKs for successful infection.
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