Affinage · Toxoplasma gondii

MAPK2

putative cell-cycle-associated protein kinase MAPK · UniProt A0A125YQE4

Annotated
2026-09-10
42 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TgMAPK2 is an alveolata-specific serine/threonine mitogen-activated protein kinase that governs the transition from cell growth to cell division in Toxoplasma gondii (PMID:33173004). It is a catalytically active kinase bearing all 12 canonical MAPK subdomains and a distinctive TDY dual-phosphorylation motif, unlike the mammalian ERK2 TEY motif, and its activity is insensitive to the human ERK2 inhibitor FR180204 (PMID:22030559). TgMAPK2 is essential for parasite replication: its depletion blocks centrosome duplication and the initiation of daughter cell budding, arresting parasites after incomplete DNA replication while Golgi, mitochondria, and apicoplasts continue to grow — decoupling organelle growth from cell division; because the kinase is not detected at the centrosome, it regulates centrosome duplication from a distal site (PMID:33173004). Beyond its role in the cell cycle, TgMAPK2 together with TgMAPK1 contributes to inflammasome activation and acute virulence during murine infection (PMID:27475900). How TgMAPK2 is activated remains uncharacterized in the available corpus, and no direct substrate has been identified.

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2006 Low

    Establishing where TgMAPK2 sits in kinase evolution was the first step, showing it belongs to a distinct protozoan MAPK subfamily rather than the canonical ERK/JNK/p38 groups, and thus is unlikely to behave like a metazoan MAPK.

    Evidence Molecular cloning and phylogenetic analysis of TgMAPK2

    PMID:17160647

    Open questions at the time
    • Computational classification only, with no functional experiment on the kinase
    • Does not address whether the enzyme is catalytically active or essential
  2. 2011 Medium

    Whether TgMAPK2 is a bona fide active kinase was resolved by demonstrating recombinant catalytic activity and defining a non-canonical TDY dual-phosphorylation motif, distinguishing it biochemically from mammalian ERK2.

    Evidence Molecular cloning, sequence analysis, in vitro kinase assay with inhibitor specificity test, and ddFKBP conditional expression in T. gondii

    PMID:22030559

    Open questions at the time
    • No physiological substrate identified
    • Upstream activating kinase or mechanism unknown
    • Single lab, single study
  3. 2016 Medium

    Testing the in vivo importance of Toxoplasma MAPKs linked TgMAPK2, together with TgMAPK1, to acute virulence and inflammasome activation in the host.

    Evidence Double gene deletion of TgMAPK1 and TgMAPK2, murine infection, western blot and transcript analysis of inflammasome/cytokine markers

    PMID:27475900

    Open questions at the time
    • Double-knockout design cannot attribute the phenotype to MAPK2 alone
    • Mechanistic link between kinase activity and inflammasome signaling not defined
    • Shown only in type I RH strain
  4. 2020 High

    The core cellular function of TgMAPK2 was defined by showing it is essential for centrosome duplication and initiation of daughter cell budding, placing it at a distal regulatory node controlling entry into parasite mitosis.

    Evidence Auxin-inducible degron conditional depletion with fluorescence microscopy and cell cycle analysis of centrosome, DNA, organelle, and budding readouts

    PMID:33173004

    Open questions at the time
    • Kinase substrates that drive centrosome duplication not identified
    • Mechanism by which a non-centrosomal kinase controls centrosome duplication unknown
    • Direct link between catalytic activity and the phenotype not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The activating input and downstream substrates of TgMAPK2 remain unknown: how a kinase lacking a canonical upstream MAPK cascade is regulated, and how it triggers centrosome duplication from a distal site, are unresolved.
  • No upstream regulator identified
  • No phosphorylation substrate identified
  • Non-canonical activation mechanism uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
TGMAPK1 (CO-DELETION CONTRIBUTES TO INFLAMMASOME ACTIVATION AND VIRULENCE)

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 MAPK2 (TgMAPK2) is essential for centrosome duplication and initiation of daughter cell budding in Toxoplasma. Auxin-inducible degron-mediated depletion of MAPK2 caused failure of centrosome duplication, arrest prior to mitosis (after initiation of but incomplete DNA replication), and parasite death, while Golgi, mitochondria, and apicoplasts continued to replicate — decoupling cell growth from cell division. MAPK2 was not observed at the centrosome, indicating it regulates centrosome duplication from a distal site. Auxin-inducible degron (AID) conditional knockdown, fluorescence microscopy, cell cycle analysis mBio High 33173004
2016 Deletion of both TgMAPK1 and TgMAPK2 in type I parasites decreases acute virulence in mice, associated with low levels of IL-18, NLRP1/3, ASC, and caspase-1, and high levels of IL-10 and IFN-β transcripts, as well as increased STAT1 phosphorylation and decreased STAT3 phosphorylation, implicating both MAPKs in inflammasome activation during T. gondii infection. Gene deletion (knockout mutants), murine infection model, western blot, transcript analysis Microbes and infection Medium 27475900
2011 TgMAPK2 was molecularly cloned and characterized as a 678-amino-acid, 73.1 kDa protein with the 12 canonical MAPK subdomains and a TDY dual phosphorylation motif (distinct from mammalian ERK2's TEY motif). Recombinant TgMAPK2 was catalytically active in vitro and was not inhibited by the human ERK2 inhibitor FR180204. A partial TgMAPK2 lacking ATP-binding motifs was successfully regulated by the ligand-controlled ddFKBP destabilization domain system in T. gondii. Molecular cloning, sequence analysis, in vitro kinase activity assay, conditional expression (ddFKBP system) Cell cycle Medium 22030559
2006 TgMAPK2 was cloned and shown by phylogenetic analysis to be a member of a distinct and previously unknown protozoan MAPK subfamily (pzMAPK2), evolutionarily distant from ERK, JNK, and p38 families, and related to an ERK8-like family found across diverse eukaryotic kingdoms. Molecular cloning, phylogenetic analysis Journal of molecular evolution Low 17160647
2022 Review consolidating that TgMAPK2 is essential for centrosome duplication and parasite replication, that apicomplexan MAPKs lack a canonical upstream kinase cascade, and that their regulation must occur by a distinct (non-canonical) mechanism. MAPK2 is noted as alveolata-specific with no metazoan ortholog. Review/synthesis (referencing experimental findings from primary studies) PLoS pathogens Low 36227859

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Artemisinins: pharmacological actions beyond anti-malarial. Pharmacology & therapeutics 345 24316259
2005 p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection. Journal of immunology (Baltimore, Md. : 1950) 84 15778378
2004 Manipulation of mitogen-activated protein kinase/nuclear factor-kappaB-signaling cascades during intracellular Toxoplasma gondii infection. Immunological reviews 73 15361242
2006 Toxoplasma gondii genotype determines MyD88-dependent signaling in infected macrophages. Journal of immunology (Baltimore, Md. : 1950) 65 16888020
2004 Toxoplasma gondii interferes with lipopolysaccharide-induced mitogen-activated protein kinase activation by mechanisms distinct from endotoxin tolerance. Journal of immunology (Baltimore, Md. : 1950) 60 14978104
2004 TRAF6-dependent mitogen-activated protein kinase activation differentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii. Infection and immunity 52 15385464
2013 Biochemical and immunological characterization of Toxoplasma gondii macrophage migration inhibitory factor. The Journal of biological chemistry 47 23443656
2002 Pyridinylimidazole p38 mitogen-activated protein kinase inhibitors block intracellular Toxoplasma gondii replication. International journal for parasitology 42 12076626
2003 Activation of the cellular mitogen-activated protein kinase pathways ERK, P38 and JNK during Toxoplasma gondii invasion. Parasite (Paris, France) 36 12669350
2015 Analysis of miRNA expression profiling in mouse spleen affected by acute Toxoplasma gondii infection. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 35 26569573
2011 Toxoplasma gondii induces B7-2 expression through activation of JNK signal transduction. Infection and immunity 35 21911468
2009 Early response of mucosal epithelial cells during Toxoplasma gondii infection. Journal of immunology (Baltimore, Md. : 1950) 35 19917706
2006 Toxoplasma gondii expresses two mitogen-activated protein kinase genes that represent distinct protozoan subfamilies. Journal of molecular evolution 34 17160647
2007 Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection. Antimicrobial agents and chemotherapy 25 17923491
2020 Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division. mBio 21 33173004
2021 Expression profiles of NOD-like receptors and regulation of NLRP3 inflammasome activation in Toxoplasma gondii-infected human small intestinal epithelial cells. Parasites & vectors 16 33712075
2019 Schistosoma mansoni Coinfection Attenuates Murine Toxoplasma gondii-Induced Crohn's-Like Ileitis by Preserving the Epithelial Barrier and Downregulating the Inflammatory Response. Frontiers in immunology 14 30936867
2018 Acute Toxoplasma Gondii Infection in Cats Induced Tissue-Specific Transcriptional Response Dominated by Immune Signatures. Frontiers in immunology 14 30405608
2011 Toxoplasma gondii protects against H(2)O(2) -induced apoptosis in ARPE-19 cells through the transcriptional regulation of apoptotic elements and downregulation of the p38 MAPK pathway. Acta ophthalmologica 14 21385331
2020 VEGF Production Is Regulated by the AKT/ERK1/2 Signaling Pathway and Controls the Proliferation of Toxoplasma gondii in ARPE-19 Cells. Frontiers in cellular and infection microbiology 13 32432052
2011 Molecular cloning and characterization of mitogen-activated protein kinase 2 in Toxoplasma gondii. Cell cycle (Georgetown, Tex.) 13 22030559
2010 Protective Toxoplasma gondii-specific T-cell responses require T-cell-specific expression of protein kinase C-theta. Infection and immunity 12 20498263
2016 Toxoplasma gondii mitogen-activated protein kinases are associated with inflammasome activation in infected mice. Microbes and infection 11 27475900
2023 Toxoplasma gondii-induced neutrophil extracellular traps are relevant to glycolysis, TLR2, and TLR4 MAPK signaling pathway in goats. Parasitology research 9 38087003
2017 Immunomodulation of dual specificity phosphatase 4 during visceral leishmaniasis. Microbes and infection 9 29133249
2010 Absence of mitogen-activated protein kinase family member c-Jun N-terminal kinase-2 enhances resistance to Toxoplasma gondii. Experimental parasitology 9 20117109
2022 Tylvalosin demonstrates anti-parasitic activity and protects mice from acute toxoplasmosis. Life sciences 8 35123999
2021 Reprogramming Intestinal Epithelial Cell Polarity by Interleukin-22. Frontiers in medicine 7 33912578
2020 Adenosine A3 Receptor Mediates ERK1/2- and JNK-Dependent TNF-α Production in Toxoplasma gondii-Infected HTR8/SVneo Human Extravillous Trophoblast Cells. The Korean journal of parasitology 7 32871633
2025 Recurrent pregnancy loss: Crosstalk between immune cells, decidual cells, and cellular autophagy. Reproductive biology 6 40974690
2022 Not your Mother's MAPKs: Apicomplexan MAPK function in daughter cell budding. PLoS pathogens 6 36227859
2021 Heme Oxygenase-1 Induction in Human BeWo Trophoblast Cells Decreases Toxoplasma gondii Proliferation in Association With the Upregulation of p38 MAPK Phosphorylation and IL-6 Production. Frontiers in microbiology 6 33912151
2021 Pathogenic role of mitogen activated protein kinases in protozoan parasites. Biochimie 5 34706251
2025 AMPK and CAMKK activation participate in early events of Toxoplasma gondii-triggered NET formation in bovine polymorphonuclear neutrophils. Frontiers in veterinary science 3 40171409
2017 IL-12 and IL-23 Production in Toxoplasma gondii- or LPS-Treated Jurkat T Cells via PI3K and MAPK Signaling Pathways. The Korean journal of parasitology 3 29320816
2001 [Mitogen activated protein kinases (MAPK) and Toxoplasma gondii host cell invasion]. Annales pharmaceutiques francaises 3 11787422
2022 Glycosylation Analysis of Feline Small Intestine Following Toxoplasma gondii Infection. Animals : an open access journal from MDPI 2 36290246
2021 17β-estradiol modulates the expression of hormonal receptors on THP-1 T. gondii-infected macrophages and monocytes in an AKT and ERK-dependent manner. Molecular and biochemical parasitology 2 34822916
2026 Kinase inhibitors in organoid media influence Toxoplasma gondii growth and development. Microbiology spectrum 1 41930945
2025 Comparative transcriptomic analyses of macrophages infected with Toxoplasma gondii strains of different virulence provide molecular insights into the response of macrophage in phagocytosis and polarization to infection. Molecular immunology 1 40414092
2025 SARM regulates cell apoptosis and inflammation during Toxoplasma gondii infection through a multistep mechanism. Parasites & vectors 1 40075497
2020 Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival. Frontiers in cellular and infection microbiology 1 33014898