Affinage · Toxoplasma gondii

MAPKL1

CMGC kinase, MAPK family (ERK) MAPK-1 · UniProt S8EUF0

Annotated
2026-09-10
34 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TgMAPKL1 (TgMAPK1) is a Toxoplasma gondii serine/threonine protein kinase that belongs to a protozoan-specific MAPK-related subfamily distinct from the metazoan ERK, JNK, and p38 families (PMID:17160647). It localizes to the centrosome, where loss of function produces aberrant centrosome duplication (PMID:33173004), a phenotype distinguishable from that caused by loss of TgMAPK2, indicating the two kinases govern separate steps of centrosome duplication (PMID:33173004). Inhibition of the kinase arrests the cell cycle after DNA duplication, generating enlarged parasites with multiple daughter scaffolds and incomplete cytokinesis, establishing that TgMAPKL1 is required for completion of endodyogeny (PMID:25941623). Its catalytic activity depends on an ATP-binding pocket accessible through the gatekeeper residue Ser191, and gatekeeper or ATP-site mutations (S191A, Leu162Gln) modulate sensitivity to bumped kinase inhibitors, confirming TgMAPKL1 as a direct BKI target alongside TgCDPK1 (PMID:25941623, PMID:40407244). Enzymatic assays and structural/modeling studies demonstrate that imidazole compounds (R)-RY-1-165 and (R)-RY-1-185 bind and inhibit TgMAPKL-1 in T. gondii, identifying TgMAPKL-1 as part of the multi-target mechanism of action of this scaffold (PMID:40339062). BKI-1748, which targets both TgCDPK1 and TgMAPKL-1, confers significant protection against congenital toxoplasmosis in a pregnant sheep model when administered after IgM seroconversion, demonstrating that dual inhibition of these kinases is effective in a clinically relevant large-animal model (PMID:42125495). Because apicomplexans lack the canonical MAPK kinase cascade, TgMAPKL1 must be activated by a non-canonical mechanism that has not been characterized in the available corpus (PMID:36227859).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2002 Medium

    Before any parasite MAPK was cloned, it was unknown whether p38 inhibitors blocked T. gondii replication through the host or the parasite; this work showed the drug acts directly on a parasite-encoded kinase.

    Evidence Pharmacological inhibition with SB203580/SB202190, adenoviral dominant-negative host p38, and drug-resistant mutant tachyzoites in T. gondii

    PMID:12076626

    Open questions at the time
    • Target kinase identity inferred, not molecularly proven
    • No direct enzymatic assay of the parasite kinase
  2. 2006 Medium

    The molecular identity of the parasite MAPK was defined by cloning tgMAPK1/MAPKL1 and placing it in a protozoan-specific subfamily distinct from ERK, JNK, and p38.

    Evidence Gene cloning and phylogenetic analysis of protozoan and metazoan MAPK sequences in T. gondii

    PMID:17160647

    Open questions at the time
    • Cellular function not addressed
    • No localization or loss-of-function data
  3. 2007 Low

    Extending the pharmacology in vivo, p38-class inhibitors were shown to treat infection in mice with preliminary attribution to the parasite MAPK homologue.

    Evidence In vivo mouse infection model with pharmacological inhibition and preliminary target inference

    PMID:17923491

    Open questions at the time
    • Target identity not directly confirmed
    • No genetic validation of the kinase as the effector
  4. 2014 High

    It was unknown what step of the cell cycle the kinase controls; gatekeeper engineering plus bumped kinase inhibition pinpointed a post-DNA-duplication requirement for completing daughter cell budding.

    Evidence Gatekeeper Ser191 mutagenesis (S191A), 1NM-PP1 treatment, cell cycle and morphological analysis in T. gondii RH

    PMID:25941623

    Open questions at the time
    • Direct substrates not identified
    • Mechanism linking kinase activity to cytokinesis unresolved
  5. 2020 High

    To resolve whether the two parasite MAPK-related kinases act redundantly, conditional depletion showed MAPKL1 and MAPK2 produce distinct centrosome duplication failure phenotypes, defining separate steps.

    Evidence Auxin-inducible degron depletion with comparative fluorescence microscopy in T. gondii

    PMID:33173004

    Open questions at the time
    • Molecular basis of the step specificity not defined
    • No epistatic or biochemical relationship between MAPKL1 and MAPK2 established
  6. 2025 High

    Forward genetics and reciprocal mutagenesis confirmed MAPKL1 as a direct BKI target and showed BKIs simultaneously engage both MAPKL1 and CDPK1.

    Evidence Chemical mutagenesis/BKI-1748 selection, whole-genome sequencing, Leu162Gln knock-in, and enzymatic/structural modeling with gatekeeper substitutions in T. gondii

    PMID:40407244 PMID:40339062

    Open questions at the time
    • No high-resolution structure of the inhibited kinase
    • Native regulatory phosphorylation events unmapped
  7. 2026 Medium

    Dual inhibition of MAPKL1 and CDPK1 by BKI-1748 was shown to be therapeutically effective against congenital toxoplasmosis in a large-animal model.

    Evidence Pregnant sheep infection model with oral BKI-1748, serology, and parasite detection in offspring in T. gondii TgShSp1

    PMID:42125495

    Open questions at the time
    • Efficacy is attributed to dual kinase inhibition but not deconvoluted to MAPKL1 alone
    • Mechanistic contribution of MAPKL1 not re-tested in this model

Mechanism profile

Synthesis pass · controlled-vocabulary classification
No controlled-vocabulary terms were assigned to this entry.

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Toxoplasma gondii encodes two distinct MAPK genes (tgMAPK1 and tgMAPK2) representing novel protozoan MAPK subfamilies (pzMAPKl/pzMAPK3 and pzMAPK2); tgMAPK1 (MAPKL1) is a stress-response MAPK-related gene belonging to a protozoan-specific subfamily distinct from ERK, JNK, and p38 families, as determined by phylogenetic and cloning analysis. Gene cloning, phylogenetic analysis of protozoan and metazoan MAPK sequences Journal of molecular evolution Medium 17160647
2002 Pyridinylimidazole p38 MAPK inhibitors (SB203580, SB202190) block intracellular T. gondii replication through direct action on the parasite rather than the host cell; selective host p38 MAPK inhibition via recombinant adenovirus had little effect, drug-resistant mutant tachyzoites were generated, and treated parasites developed abnormal morphology indicating defective division, implicating a parasite-encoded MAPK homologue (later identified as TgMAPKL-1) as the drug target. Pharmacological inhibition, adenoviral dominant-negative host kinase, generation of drug-resistant mutants, morphological analysis International journal for parasitology Medium 12076626
2007 Pyridinylimidazole p38 MAPK inhibitors treat T. gondii infection in vivo and preliminary studies implicate a T. gondii MAPK homologue (TgMAPKL-1) as the target of drug action, consistent with the parasite encoding an endogenous MAPK whose inhibition is anti-parasitic. In vivo mouse infection model, pharmacological inhibition, preliminary target identification Antimicrobial agents and chemotherapy Low 17923491
2014 A mutation in the gatekeeper residue Ser191 of TgMAPKL-1 (S191A) confers sensitivity to the bumped kinase inhibitor 1NM-PP1, which was originally selected as a resistance mutation. Inhibition of TgMAPKL-1 by 1NM-PP1 blocks cell cycle progression after DNA duplication, causing enlarged parasites with multiple daughter cell scaffolds and incomplete cytokinesis, demonstrating that TgMAPKL-1 is required for completion of endodyogeny. Site-directed mutagenesis of gatekeeper residue, bumped kinase inhibitor treatment, cell cycle analysis, morphological analysis International journal for parasitology. Drugs and drug resistance High 25941623
2020 MAPKL1 depletion causes a distinct centrosome duplication failure phenotype in T. gondii; the failure in centrosome duplication caused by loss of MAPKL1 is distinguishable from the centrosome duplication phenotype caused by loss of MAPK2, indicating MAPKL1 and MAPK2 regulate distinct steps of centrosome duplication. Auxin-inducible degron (AID) system for conditional protein depletion, fluorescence microscopy, comparative phenotypic analysis mBio High 33173004
2025 A forward genetic screen using chemical mutagenesis and BKI-1748 selection identified single nucleotide changes in the ATP-binding site of TgMAPKL1 (including Leu162Gln) conferring 2–6-fold resistance; introducing this mutation into wild-type parasites confirmed MAPKL1 as a direct target of BKI-1748. Combining TgMAPKL1 and TgCDPK1 resistance mutations produced up to 157-fold resistance, demonstrating that BKIs act on both kinases simultaneously. Forward genetic screen, whole-genome sequencing, site-directed mutagenesis (Leu162Gln knock-in), pharmacological resistance assays ACS infectious diseases High 40407244
2025 Enzymatic assays and structural/modeling studies demonstrate that imidazole compounds (R)-RY-1-165 and (R)-RY-1-185 bind and inhibit TgMAPKL-1 in T. gondii, alongside TgPKG, TgCDPK1, and TgCDPK4, identifying TgMAPKL-1 as part of the multi-target mechanism of action of this scaffold. Enzymatic assays, structural modeling, mutant parasite studies (gatekeeper substitutions) ACS infectious diseases Medium 40339062
2022 Review consolidating that apicomplexan MAPKL1 has been implicated in centrosome duplication regulation in Toxoplasma, and that canonical MAPK kinase cascade regulation is absent in apicomplexans, meaning MAPKL1 must be regulated by a distinct, non-canonical mechanism. Review/synthesis of prior experimental findings PLoS pathogens Low 36227859
2026 BKI-1748, which targets both TgCDPK1 and TgMAPKL-1, confers significant protection against congenital toxoplasmosis in a pregnant sheep model when administered after IgM seroconversion, demonstrating that dual inhibition of these kinases is effective in a clinically relevant large-animal model. In vivo sheep infection model, oral BKI-1748 treatment, serology, parasite detection in offspring Frontiers in cellular and infection microbiology Medium 42125495

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Artemisinins: pharmacological actions beyond anti-malarial. Pharmacology & therapeutics 345 24316259
2011 Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps. Infection and immunity 220 22104111
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
2008 Infection with Toxoplasma gondii results in dysregulation of the host cell cycle. Cellular microbiology 70 18182087
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
2021 Protein kinases in Toxoplasma gondii. International journal for parasitology 35 33581139
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
2018 Exosomes derived from Toxoplasma gondii stimulate an inflammatory response through JNK signaling pathway. Nanomedicine (London, England) 34 29542367
2006 Toxoplasma gondii expresses two mitogen-activated protein kinase genes that represent distinct protozoan subfamilies. Journal of molecular evolution 34 17160647
2015 Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells. PloS one 31 26528819
2009 Intracellular parasitism with Toxoplasma gondii stimulates mammalian-target-of-rapamycin-dependent host cell growth despite impaired signalling to S6K1 and 4E-BP1. Cellular microbiology 31 19302577
2020 Toxoplasma gondii Triggers Neutrophil Extracellular Traps Release in Dogs. Frontiers in cellular and infection microbiology 30 33102243
2009 Externally triggered egress is the major fate of Toxoplasma gondii during acute infection. Journal of immunology (Baltimore, Md. : 1950) 29 19846885
2007 Mouse neutrophils require JNK2 MAPK for Toxoplasma gondii-induced IL-12p40 and CCL2/MCP-1 release. Journal of immunology (Baltimore, Md. : 1950) 26 17785791
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
2010 Toxoplasma gondii infection positively modulates the macrophages migratory molecular complex by increasing matrix metalloproteinases, CD44 and alpha v beta 3 integrin. Veterinary parasitology 24 20080350
2006 Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii. Journal of cell science 24 17074836
2020 Silver Nanoparticle-Induced Apoptosis in ARPE-19 Cells Is Inhibited by Toxoplasma gondii Pre-Infection Through Suppression of NOX4-Dependent ROS Generation. International journal of nanomedicine 22 32547023
2014 A single mutation in the gatekeeper residue in TgMAPKL-1 restores the inhibitory effect of a bumped kinase inhibitor on the cell cycle. International journal for parasitology. Drugs and drug resistance 22 25941623
2020 Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division. mBio 21 33173004
2025 Bumped Kinase Inhibitors Inhibit both Toxoplasma gondii MAPKL1 and CDPK1. ACS infectious diseases 7 40407244
2022 Not your Mother's MAPKs: Apicomplexan MAPK function in daughter cell budding. PLoS pathogens 6 36227859
2021 Pathogenic role of mitogen activated protein kinases in protozoan parasites. Biochimie 5 34706251
2022 Glycosylation Analysis of Feline Small Intestine Following Toxoplasma gondii Infection. Animals : an open access journal from MDPI 2 36290246
2026 BKI-1748 confers a high level of protection against ovine congenital toxoplasmosis when administered after IgM seroconversion. Frontiers in cellular and infection microbiology 0 42125495
2025 Versatile Imidazole Scaffold with Potent Activity against Multiple Apicomplexan Parasites. ACS infectious diseases 0 40339062