{"gene":"MAK","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1990,"finding":"MAK (male germ cell-associated kinase) encodes a novel serine/threonine protein kinase whose predicted product contains protein kinase consensus motifs in its amino-terminal region and is approximately 40% identical to the cdc2-CDC28 gene family. Its transcripts are expressed almost exclusively in testicular germ cells entering and after meiosis.","method":"cDNA cloning, sequence analysis, Northern blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA cloning with sequence analysis and tissue expression profiling; single lab, foundational characterization","pmids":["2183027"],"is_preprint":false},{"year":1992,"finding":"MAK mRNA is specifically localized in late pachytene (stage X) and diplotene (stage XI) spermatocytes, and faintly in dividing spermatocytes (stage XII) and early round spermatids, indicating expression is concentrated around meiotic cell division.","method":"Non-radioactive in situ hybridization on frozen mouse testis sections","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in situ localization experiment, single lab, single method","pmids":["1473268"],"is_preprint":false},{"year":1993,"finding":"MAK protein products (66- and 60-kDa) are most abundant in late pachytene spermatocytes, localized mostly in the cytoplasm as a soluble form, and are associated with a 210-kDa cellular phosphoprotein that MAK phosphorylates on serine and threonine residues both in vitro (immunoprecipitate kinase assay) and in vivo.","method":"Immunoprecipitation, in vitro kinase assay, subcellular fractionation, [35S]methionine labeling, 32Pi in vivo labeling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with immunoprecipitates demonstrating phosphorylation of 210-kDa substrate on Ser/Thr, corroborated by in vivo 32Pi labeling; multiple orthogonal methods in single lab","pmids":["8321219"],"is_preprint":false},{"year":2002,"finding":"MAK is dispensable for spermatogenesis and male fertility in mice; Mak-null mice develop normally with intact spermatogenesis, though litter sizes and sperm motility in vitro are mildly reduced.","method":"Gene targeting to generate Mak−/− mice; fertility assays, histological analysis of spermatogenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with specific phenotypic readout, single lab but rigorous genetic loss-of-function study","pmids":["11971961"],"is_preprint":false},{"year":2006,"finding":"MAK and its related kinase MRK/ICK require dual phosphorylation in a TDY activation-loop motif: an unidentified threonine kinase (CCRK for MRK) phosphorylates T157, and tyrosine autophosphorylation also occurs. CCRK is the activating T157 kinase for MRK (not CDK7/cyclin H/MAT1). Protein phosphatase 5 (PP5) interacts with MRK and dephosphorylates it at T157, acting as the opposing phosphatase. MRK preferentially phosphorylates R-P-X-S/T-P consensus sites (most stringent requirement: Arg at P-3). MRK phosphorylates the antiapoptotic protein Scythe at T1080 in vitro, validated by site-directed mutagenesis and mass spectrometry.","method":"In vitro kinase assay, combinatorial peptide library screening, site-directed mutagenesis, mass spectrometry, co-immunoprecipitation, in situ phosphatase assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, mass spectrometry, and peptide library screening; multiple orthogonal methods; directly relevant to MAK family activation mechanism","pmids":["16954377"],"is_preprint":false},{"year":2010,"finding":"Mak negatively regulates ciliary length in retinal photoreceptors. Mak localizes to connecting cilia and outer-segment axonemes. In Mak-null mice, photoreceptors exhibit elongated cilia, accumulation of IFT88 and IFT57, expansion of Kif3a and acetylated α-tubulin signals in cilia, and abnormal rhodopsin accumulation in cell bodies at P14, followed by progressive degeneration. Overexpression of RP1 (a microtubule-associated protein in outer-segment axonemes) induces ciliary elongation, and co-expression of Mak rescues this elongation. The RP1 N-terminal portion is phosphorylated by Mak in vitro.","method":"Mak-null mouse generation, immunohistochemistry, immunofluorescence, in vitro kinase assay, overexpression rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — loss-of-function mouse with specific ciliary phenotype, in vitro kinase assay showing RP1 phosphorylation, rescue experiment; multiple orthogonal methods","pmids":["21148103"],"is_preprint":false},{"year":2011,"finding":"MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors in human donor tissue. An Alu insertion in exon 9 of MAK causes loss of the exon 9+12 retinal transcript isoform, which normally predominates in retinal precursors differentiated from iPSCs. The developmental switch from the exon-9-lacking to the exon-9/12-bearing transcript does not occur in patient-derived cells.","method":"Immunohistochemistry of human donor tissue, iPSC differentiation to retinal precursors, RT-PCR isoform analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunohistochemistry for subcellular localization combined with iPSC functional isoform analysis; single lab","pmids":["21825139"],"is_preprint":false},{"year":2011,"finding":"Missense mutations in MAK that alter conserved kinase residues result in loss of kinase activity as demonstrated by in vitro kinase assay, establishing that kinase activity is critical for MAK function in humans.","method":"In vitro kinase assay on patient-derived missense mutant MAK proteins","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay demonstrating loss of activity with disease mutations; single lab, single method","pmids":["21835304"],"is_preprint":false},{"year":2019,"finding":"In C. elegans, DYF-5/MAK (ortholog of mammalian MAK) acts downstream of DYF-18/CCRK in a kinase cascade to regulate ciliary length and branching morphology. Loss of dyf-5/MAK results in dramatically elongated, unbranched AWA cilia. Axonemal microtubules in dyf-18/CCRK mutants are decorated by EBP-2 end-binding protein along their lengths and show increased tubulin load and reduced tubulin turnover, indicating that CCRK-MAK activity tunes cilia length and shape by modulating axonemal microtubule stability.","method":"Genetic epistasis (double mutants), live imaging of IFT motor proteins, EBP-2 end-binding protein dynamics, microtubule-destabilizing tubulin mutations, IFT protein mutations as suppressors","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with suppressor analysis and multiple orthogonal imaging methods; directly establishes pathway position and mechanism","pmids":["30955935"],"is_preprint":false},{"year":2021,"finding":"The ciliary kinase DYF-5/MAK phosphorylates multiple sites within the tubulin-binding module of IFT-74, reducing the tubulin-binding affinity of the IFT-74/81 module approximately sixfold. Ablation or constitutive activation of IFT-74 phosphorylation abnormally elongates or shortens sensory cilia in C. elegans, respectively, establishing that MAK-dependent phosphorylation of IFT-74 regulates ciliary tubulin unloading at the tip.","method":"In vitro phosphorylation assay, binding affinity measurements, C. elegans genetics with phospho-ablating and phospho-mimetic IFT-74 mutants, ciliary length phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of kinase-substrate phosphorylation with affinity quantification, corroborated by in vivo genetic phenotypes with gain- and loss-of-phosphorylation alleles","pmids":["35969738"],"is_preprint":false},{"year":2021,"finding":"Gene delivery of retinal MAK transgene to patient iPSC-derived photoreceptor precursor cells and mak-knockdown zebrafish restores the ability to regulate primary cilia length, confirming that MAK kinase function is necessary and sufficient for ciliary length control in photoreceptors.","method":"Viral gene augmentation in patient iPSC-derived cells, mak knockdown zebrafish model, cilia length assay, rt-PCR and western blotting for transgene expression","journal":"Gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment in patient-derived cells and animal model with defined ciliary phenotype; single lab","pmids":["34518651"],"is_preprint":false},{"year":2022,"finding":"PCARE contains an evolutionarily conserved binding site for the photoreceptor kinase MAK (RP62). The MAK-binding motif within PCARE is required for PCARE's proper localization and function at the ciliary tip membrane expansion in photoreceptors.","method":"Domain deletion mutagenesis, ciliary localization assays, co-expression with WASF3 for membrane expansion measurement","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutagenesis with functional ciliary localization readout; establishes MAK-binding motif in PCARE but does not directly demonstrate MAK-PCARE interaction in vitro; single lab","pmids":["35253837"],"is_preprint":false},{"year":2024,"finding":"MAK is a ciliary tip-localized IFT regulator that cooperatively acts with the related kinase ICK. Simultaneous disruption of Mak and Ick in mice results in loss of photoreceptor ciliary axonemes and severe retinal degeneration, a more severe phenotype than either single knockout. CCRK kinase acts as an upstream activator of both Mak and Ick in retinal photoreceptor cells. Gene delivery of Ick and pharmacological inhibition of FGF receptors (negative regulators of Ick) ameliorate retinal degeneration in Mak-null mice.","method":"Conditional double knockout (Mak/Ick), histology, gene delivery rescue, pharmacological FGF receptor inhibition, genetic epistasis","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — double knockout epistasis with defined photoreceptor phenotype, upstream kinase (CCRK) pathway placement, rescue experiments; multiple orthogonal approaches","pmids":["39293864"],"is_preprint":false},{"year":2025,"finding":"Chlamydomonas MAK (CrMAK), related to mammalian ICK/MAK, localizes to cilia via its C-terminal tail and is enriched at the ciliary tip during active ciliary assembly. CrMAK is constitutively active during ciliary assembly, acts downstream of the LF1/LF3/LF2 (CCRK homologue) ciliary length-regulatory complex, and phosphorylates FAP256/CEP104 (a microtubule plus-end tracking protein). Loss of CrMAK or its kinase activity leads to aciliated cells; dephosphorylation of FAP256/CEP104 impairs ciliary assembly.","method":"Genetic loss-of-function, live cell imaging of CrMAK-GFP fusion, in vitro kinase assay showing FAP256/CEP104 phosphorylation, kinase-dead mutants, dephosphorylation experiments, epistasis with LF complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with substrate identification, kinase-dead mutagenesis, live localization imaging, and genetic epistasis placing MAK downstream of CCRK/LF complex; multiple orthogonal methods","pmids":["41231942"],"is_preprint":false}],"current_model":"MAK (male germ cell-associated kinase) is a serine/threonine kinase activated by CCRK-mediated phosphorylation of its TDY activation-loop motif, which localizes to the ciliary tip of photoreceptors and sensory neurons, where it negatively regulates ciliary length by phosphorylating IFT-74 to reduce tubulin-binding affinity and promote tubulin unloading, phosphorylating RP1 to limit axonemal elongation, and phosphorylating FAP256/CEP104 to control axonemal microtubule assembly; loss of MAK causes ciliary elongation, IFT protein accumulation, mislocalized rhodopsin, and progressive photoreceptor degeneration, and MAK cooperates with the related kinase ICK downstream of CCRK in an essential IFT-regulatory axis required for photoreceptor survival."},"narrative":{"mechanistic_narrative":"MAK (male germ cell-associated kinase) is a CDC2/CDC28-related serine/threonine protein kinase that functions as a ciliary length regulator in photoreceptors and other sensory cells [PMID:2183027, PMID:21148103]. Its catalytic activation requires dual phosphorylation of a TDY activation-loop motif, with CCRK serving as the upstream activating kinase that phosphorylates the activation-loop threonine, while protein phosphatase 5 provides opposing dephosphorylation; MAK family kinases recognize an R-P-X-S/T-P consensus with a stringent Arg at the P-3 position [PMID:16954377]. Within sensory cilia, MAK localizes to the connecting cilium and outer-segment axoneme/ciliary tip, where it negatively regulates axonemal length by phosphorylating substrates that govern microtubule and IFT dynamics: it phosphorylates the axonemal microtubule-associated protein RP1 to limit elongation [PMID:21148103], phosphorylates multiple sites in the tubulin-binding module of IFT-74 to reduce tubulin-binding affinity and promote tubulin unloading at the ciliary tip [PMID:35969738], and phosphorylates the microtubule plus-end tracking protein FAP256/CEP104 to control axonemal assembly [PMID:41231942]. Loss of MAK produces elongated cilia, accumulation of IFT proteins (IFT88, IFT57) and acetylated tubulin, mislocalized rhodopsin, and progressive photoreceptor degeneration [PMID:21148103]. MAK acts in a conserved CCRK-headed kinase axis together with the related kinase ICK, and combined loss of MAK and ICK causes loss of photoreceptor axonemes and severe retinal degeneration that is partially rescued by ICK gene delivery or FGF receptor inhibition [PMID:30955935, PMID:39293864]. In humans, loss-of-function MAK mutations—including an Alu insertion disrupting the retina-specific exon-9/12 transcript isoform and kinase-inactivating missense changes—cause inherited photoreceptor degeneration, and restoring MAK expression rescues ciliary length control [PMID:21825139, PMID:21835304, PMID:34518651].","teleology":[{"year":1990,"claim":"Established MAK as a distinct serine/threonine kinase, defining the molecular identity and tissue context that any later mechanism would have to explain.","evidence":"cDNA cloning, sequence analysis, and Northern blot in mouse testis","pmids":["2183027"],"confidence":"Medium","gaps":["No substrates or activation mechanism identified","Restricted to expression profiling, no functional assay","Apparent germ-cell restriction later proven incomplete given retinal roles"]},{"year":1992,"claim":"Refined MAK expression to specific meiotic spermatocyte stages, suggesting a role tied to meiotic cell division.","evidence":"Non-radioactive in situ hybridization on mouse testis sections","pmids":["1473268"],"confidence":"Medium","gaps":["Localizes mRNA but not protein function","No causal link to meiotic events"]},{"year":1993,"claim":"Demonstrated MAK is a functional kinase by showing it phosphorylates a 210-kDa cellular phosphoprotein on Ser/Thr in vitro and in vivo, establishing catalytic activity against a cellular substrate.","evidence":"Immunoprecipitate kinase assay, subcellular fractionation, in vivo 32Pi labeling","pmids":["8321219"],"confidence":"High","gaps":["Identity of the 210-kDa substrate never determined","Cytoplasmic soluble localization not connected to a pathway"]},{"year":2002,"claim":"Knockout showed MAK is dispensable for spermatogenesis, redirecting the search for its essential physiological role away from male fertility.","evidence":"Mak-null mouse generation with fertility and histological analysis","pmids":["11971961"],"confidence":"High","gaps":["Did not reveal where MAK is essential","Mild motility/litter phenotype mechanistically unexplained"]},{"year":2006,"claim":"Defined the activation mechanism of the MAK family: CCRK-dependent TDY activation-loop phosphorylation, PP5 as the opposing phosphatase, and an R-P-X-S/T-P substrate consensus, providing the biochemical framework for MAK regulation.","evidence":"In vitro kinase assays, peptide library screening, mass spectrometry, co-IP, and phosphatase assays on MAK/MRK(ICK)","pmids":["16954377"],"confidence":"High","gaps":["Much of the detailed work was on the related MRK/ICK rather than MAK itself","Physiological substrates not yet identified"]},{"year":2010,"claim":"Identified ciliary length control as MAK's essential function, linking its kinase activity to RP1 phosphorylation, IFT regulation, and photoreceptor survival.","evidence":"Mak-null mouse immunohistochemistry, in vitro RP1 phosphorylation, and overexpression rescue of ciliary elongation","pmids":["21148103"],"confidence":"High","gaps":["Direct phospho-sites on RP1 not mapped in vivo","Mechanism by which IFT proteins accumulate not resolved"]},{"year":2011,"claim":"Connected MAK to human inherited retinal degeneration, showing both disrupted retina-specific isoform expression and loss of kinase activity in patient mutations established kinase function as disease-critical.","evidence":"Human donor tissue immunohistochemistry, iPSC retinal differentiation isoform analysis, and in vitro kinase assays on patient missense mutants","pmids":["21825139","21835304"],"confidence":"Medium","gaps":["In vitro kinase loss not directly tied to ciliary phenotype in same study","Functional consequence of isoform switch on cilia not shown"]},{"year":2019,"claim":"Placed MAK genetically downstream of CCRK in a conserved ciliary kinase cascade controlling axonemal microtubule stability, length, and branching.","evidence":"C. elegans genetic epistasis, IFT and EBP-2 live imaging, and suppressor analysis in dyf-5/MAK and dyf-18/CCRK mutants","pmids":["30955935"],"confidence":"High","gaps":["Direct kinase substrates within the axoneme not identified in this study","Mechanism connecting microtubule turnover to length not molecularly resolved"]},{"year":2021,"claim":"Identified IFT-74 as a direct MAK substrate and showed phosphorylation of its tubulin-binding module reduces tubulin affinity, providing a molecular mechanism for tubulin unloading at the ciliary tip.","evidence":"In vitro phosphorylation and binding-affinity measurements with phospho-ablating/mimetic IFT-74 alleles in C. elegans","pmids":["35969738"],"confidence":"High","gaps":["Whether the same phospho-regulation operates on mammalian IFT-74 not shown","Spatial control of phosphorylation at the tip not resolved"]},{"year":2021,"claim":"Demonstrated MAK function is necessary and sufficient for photoreceptor ciliary length control, supporting gene augmentation as a corrective strategy.","evidence":"Viral MAK gene augmentation in patient iPSC-derived photoreceptor precursors and mak-knockdown zebrafish with cilia length assays","pmids":["34518651"],"confidence":"Medium","gaps":["Durability and substrate-level rescue not assessed","Single-lab rescue without independent replication"]},{"year":2022,"claim":"Identified a conserved MAK-binding motif in PCARE required for proper ciliary-tip localization, linking MAK to ciliary membrane expansion machinery.","evidence":"Domain deletion mutagenesis and ciliary localization/membrane-expansion assays with WASF3 co-expression","pmids":["35253837"],"confidence":"Medium","gaps":["Direct MAK-PCARE physical interaction not demonstrated in vitro","Whether PCARE is a MAK substrate unknown"]},{"year":2024,"claim":"Established MAK and ICK as cooperative, partially redundant CCRK-controlled regulators of photoreceptor axonemes, defining an essential IFT-regulatory axis for photoreceptor survival.","evidence":"Conditional Mak/Ick double knockout, genetic epistasis, ICK gene delivery, and FGF receptor inhibition rescue in mice","pmids":["39293864"],"confidence":"High","gaps":["Distinct versus shared substrates of MAK and ICK not defined","Mechanism of FGFR-mediated ICK regulation incomplete"]},{"year":2025,"claim":"Identified FAP256/CEP104 as a MAK substrate and placed MAK downstream of the CCRK-homologous LF complex, showing kinase activity is required for ciliary assembly.","evidence":"Chlamydomonas loss-of-function, CrMAK-GFP live imaging, in vitro kinase assay on FAP256/CEP104, kinase-dead mutants, and LF-complex epistasis","pmids":["41231942"],"confidence":"High","gaps":["Whether mammalian MAK phosphorylates CEP104 not shown","How FAP256/CEP104 phosphorylation mechanistically promotes assembly not resolved"]},{"year":null,"claim":"How MAK integrates its multiple ciliary substrates (RP1, IFT-74, FAP256/CEP104, PCARE) into coordinated length and assembly control, and the identity of its original germ-cell 210-kDa substrate, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the distinct substrates spatially and temporally","Germ-cell substrate and meiotic role uncharacterized","Mammalian counterparts of invertebrate/algal substrate findings not directly confirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,5,9,13]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,9,13]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5,8,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,8,9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,12]}],"complexes":[],"partners":["CCRK","ICK","RP1","IFT74","CEP104","PCARE","PP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20794","full_name":"Serine/threonine-protein kinase MAK","aliases":["Male germ cell-associated kinase"],"length_aa":623,"mass_kda":70.6,"function":"Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors (By similarity). Phosphorylates FZR1 in a cell cycle-dependent manner. Plays a role in the transcriptional coactivation of AR. Could play an important function in spermatogenesis. May play a role in chromosomal stability in prostate cancer cells","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Midbody; Cell projection, cilium, photoreceptor outer segment; Photoreceptor inner segment","url":"https://www.uniprot.org/uniprotkb/P20794/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAK","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAK","total_profiled":1310},"omim":[{"mim_id":"620969","title":"ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVb; CDAN4B","url":"https://www.omim.org/entry/620969"},{"mim_id":"620825","title":"IMMUNODEFICIENCY 119; IMD119","url":"https://www.omim.org/entry/620825"},{"mim_id":"620271","title":"TRANSMEMBRANE PROTEIN 41B; TMEM41B","url":"https://www.omim.org/entry/620271"},{"mim_id":"619823","title":"ACIDIC NUCLEAR PHOSPHOPROTEIN 32 FAMILY, MEMBER B; ANP32B","url":"https://www.omim.org/entry/619823"},{"mim_id":"618774","title":"CEBALID SYNDROME; CEBALID","url":"https://www.omim.org/entry/618774"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Connecting piece","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"retina","ntpm":110.1}],"url":"https://www.proteinatlas.org/search/MAK"},"hgnc":{"alias_symbol":["dJ417M14.2","RP62"],"prev_symbol":[]},"alphafold":{"accession":"P20794","domains":[{"cath_id":"3.30.200.20","chopping":"3-81","consensus_level":"high","plddt":89.1409,"start":3,"end":81},{"cath_id":"1.10.510.10","chopping":"84-289","consensus_level":"high","plddt":90.412,"start":84,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20794","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20794-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20794-F1-predicted_aligned_error_v6.png","plddt_mean":62.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAK","jax_strain_url":"https://www.jax.org/strain/search?query=MAK"},"sequence":{"accession":"P20794","fasta_url":"https://rest.uniprot.org/uniprotkb/P20794.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20794/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20794"}},"corpus_meta":[{"pmid":"21825139","id":"PMC_21825139","title":"Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21825139","citation_count":178,"is_preprint":false},{"pmid":"21148103","id":"PMC_21148103","title":"Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21148103","citation_count":117,"is_preprint":false},{"pmid":"2183027","id":"PMC_2183027","title":"A novel mammalian protein kinase gene (mak) is highly expressed in testicular germ cells at and after meiosis.","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2183027","citation_count":113,"is_preprint":false},{"pmid":"21835304","id":"PMC_21835304","title":"Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21835304","citation_count":89,"is_preprint":false},{"pmid":"2443001","id":"PMC_2443001","title":"Comparison of keratin monoclonal antibodies MAK-6, AE1:AE3, and CAM-5.2.","date":"1987","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2443001","citation_count":79,"is_preprint":false},{"pmid":"16954377","id":"PMC_16954377","title":"Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16954377","citation_count":71,"is_preprint":false},{"pmid":"24028079","id":"PMC_24028079","title":"HAM-2 and HAM-3 are central for the assembly of the Neurospora STRIPAK complex at the nuclear envelope and regulate nuclear accumulation of the MAP kinase MAK-1 in a MAK-2-dependent manner.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24028079","citation_count":66,"is_preprint":false},{"pmid":"22879952","id":"PMC_22879952","title":"WSC-1 and HAM-7 are MAK-1 MAP kinase pathway sensors required for cell wall integrity and hyphal fusion in Neurospora crassa.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22879952","citation_count":56,"is_preprint":false},{"pmid":"387719","id":"PMC_387719","title":"Mak mutants of yeast: mapping and characterization.","date":"1979","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/387719","citation_count":55,"is_preprint":false},{"pmid":"25411845","id":"PMC_25411845","title":"Fungal communication requires the MAK-2 pathway elements STE-20 and RAS-2, the NRC-1 adapter STE-50 and the MAP kinase scaffold HAM-5.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25411845","citation_count":54,"is_preprint":false},{"pmid":"8321219","id":"PMC_8321219","title":"Testis-specific mak protein kinase is expressed specifically in the meiotic phase in spermatogenesis and is associated with a 210-kilodalton cellular phosphoprotein.","date":"1993","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8321219","citation_count":53,"is_preprint":false},{"pmid":"28336525","id":"PMC_28336525","title":"Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28336525","citation_count":44,"is_preprint":false},{"pmid":"23125351","id":"PMC_23125351","title":"Circadian activation of the mitogen-activated protein kinase MAK-1 facilitates rhythms in clock-controlled genes in Neurospora crassa.","date":"2012","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/23125351","citation_count":41,"is_preprint":false},{"pmid":"11971961","id":"PMC_11971961","title":"A testicular germ cell-associated serine-threonine kinase, MAK, is dispensable for sperm formation.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11971961","citation_count":40,"is_preprint":false},{"pmid":"22110072","id":"PMC_22110072","title":"Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/22110072","citation_count":37,"is_preprint":false},{"pmid":"30955935","id":"PMC_30955935","title":"A CCRK and a MAK Kinase Modulate Cilia Branching and Length via Regulation of Axonemal Microtubule Dynamics in Caenorhabditis elegans.","date":"2019","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/30955935","citation_count":36,"is_preprint":false},{"pmid":"12609043","id":"PMC_12609043","title":"A Mak-like kinase is a repressor of GAMYB in barley aleurone.","date":"2003","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12609043","citation_count":33,"is_preprint":false},{"pmid":"10210333","id":"PMC_10210333","title":"Generation of phagocytic MAK and MAC-DC for therapeutic use: characterization and in vitro functional properties.","date":"1999","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10210333","citation_count":29,"is_preprint":false},{"pmid":"2410417","id":"PMC_2410417","title":"Androgen regulation of MAK mRNAs in mouse kidney.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2410417","citation_count":25,"is_preprint":false},{"pmid":"17299141","id":"PMC_17299141","title":"Expression of MAK-V/Hunk in renal distal tubules and its possible involvement in proliferative suppression.","date":"2007","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17299141","citation_count":23,"is_preprint":false},{"pmid":"35969738","id":"PMC_35969738","title":"DYF-5/MAK-dependent phosphorylation promotes ciliary tubulin unloading.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35969738","citation_count":21,"is_preprint":false},{"pmid":"23733042","id":"PMC_23733042","title":"Transcriptional profiling of Neurospora crassa Δmak-2 reveals that mitogen-activated protein kinase MAK-2 participates in the phosphate signaling pathway.","date":"2013","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/23733042","citation_count":21,"is_preprint":false},{"pmid":"1473268","id":"PMC_1473268","title":"In situ localization of male germ cell-associated kinase (mak) mRNA in adult mouse testis: specific expression in germ cells at stages around meiotic cell division.","date":"1992","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/1473268","citation_count":19,"is_preprint":false},{"pmid":"25978425","id":"PMC_25978425","title":"Identification and Characterization of MicroRNAs in Ginkgo biloba var. epiphylla Mak.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25978425","citation_count":17,"is_preprint":false},{"pmid":"25881306","id":"PMC_25881306","title":"Hunk/Mak-v is a negative regulator of intestinal cell proliferation.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25881306","citation_count":17,"is_preprint":false},{"pmid":"24244486","id":"PMC_24244486","title":"Distinct expression patterns of ICK/MAK/MOK protein kinases in the intestine implicate functional diversity.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24244486","citation_count":16,"is_preprint":false},{"pmid":"25385675","id":"PMC_25385675","title":"Retinitis pigmentosa caused by mutations in the ciliary MAK gene is relatively mild and is not associated with apparent extra-ocular features.","date":"2014","source":"Acta ophthalmologica","url":"https://pubmed.ncbi.nlm.nih.gov/25385675","citation_count":16,"is_preprint":false},{"pmid":"11129044","id":"PMC_11129044","title":"The MAK-V protein kinase regulates endocytosis in mouse.","date":"2000","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/11129044","citation_count":15,"is_preprint":false},{"pmid":"26558903","id":"PMC_26558903","title":"Efficient In Silico Identification of a Common Insertion in the MAK Gene which Causes Retinitis Pigmentosa.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26558903","citation_count":12,"is_preprint":false},{"pmid":"37399380","id":"PMC_37399380","title":"MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37399380","citation_count":9,"is_preprint":false},{"pmid":"27268441","id":"PMC_27268441","title":"Involvement of MAK-1 and MAK-2 MAP kinases in cell wall integrity in Neurospora crassa.","date":"2016","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27268441","citation_count":9,"is_preprint":false},{"pmid":"31433998","id":"PMC_31433998","title":"Classification or non-classification of substances with positive tumor findings in animal studies: Guidance by the German MAK commission.","date":"2019","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/31433998","citation_count":9,"is_preprint":false},{"pmid":"26894652","id":"PMC_26894652","title":"Intraretinal cystoid spaces in a patient with retinitis pigmentosa due to mutation in the MAK gene.","date":"2016","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26894652","citation_count":9,"is_preprint":false},{"pmid":"16481519","id":"PMC_16481519","title":"Cloning and sequence analysis of the 22-kDa antigen genes of Orientia tsutsugamushi strains Kato, TA763, AFSC 7, 18-032460, TH1814, and MAK 119.","date":"2005","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16481519","citation_count":9,"is_preprint":false},{"pmid":"7002907","id":"PMC_7002907","title":"Isolation and characterization of temperature-sensitive mak mutants of Saccharomyces cerevisiae.","date":"1980","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/7002907","citation_count":9,"is_preprint":false},{"pmid":"17559639","id":"PMC_17559639","title":"MAK-4 and -5 supplemented diet inhibits liver carcinogenesis in mice.","date":"2007","source":"BMC complementary and alternative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17559639","citation_count":8,"is_preprint":false},{"pmid":"8286591","id":"PMC_8286591","title":"Retinol differentially regulates male germ cell-associated kinase (mak) messenger ribonucleic acid expression during spermatogenesis.","date":"1993","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/8286591","citation_count":7,"is_preprint":false},{"pmid":"34518651","id":"PMC_34518651","title":"Development and biological characterization of a clinical gene transfer vector for the treatment of MAK-associated retinitis pigmentosa.","date":"2021","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34518651","citation_count":6,"is_preprint":false},{"pmid":"34899653","id":"PMC_34899653","title":"Coordinated Regulation of Protoperithecium Development by MAP Kinases MAK-1 and MAK-2 in Neurospora crassa.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34899653","citation_count":6,"is_preprint":false},{"pmid":"14759768","id":"PMC_14759768","title":"Subcellular localization of MAK-V/Hunk protein kinase expressed in COS-1 cells.","date":"2004","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/14759768","citation_count":6,"is_preprint":false},{"pmid":"9395676","id":"PMC_9395676","title":"The antioxidant and antiatherogenic effects of MAK-4 in WHHL rabbits.","date":"1996","source":"Journal of alternative and complementary medicine (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9395676","citation_count":6,"is_preprint":false},{"pmid":"37744127","id":"PMC_37744127","title":"The GUL-1 Protein Binds Multiple RNAs Involved in Cell Wall Remodeling and Affects the MAK-1 Pathway in Neurospora crassa.","date":"2021","source":"Frontiers in fungal biology","url":"https://pubmed.ncbi.nlm.nih.gov/37744127","citation_count":6,"is_preprint":false},{"pmid":"39293864","id":"PMC_39293864","title":"Ccrk-Mak/Ick signaling is a ciliary transport regulator essential for retinal photoreceptor survival.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39293864","citation_count":5,"is_preprint":false},{"pmid":"29103961","id":"PMC_29103961","title":"High-resolution Imaging in Male Germ Cell-Associated Kinase (MAK)-related Retinal Degeneration.","date":"2017","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/29103961","citation_count":5,"is_preprint":false},{"pmid":"38139394","id":"PMC_38139394","title":"Discovery and Characterization of MaK: A Novel Knottin Antimicrobial Peptide from Monochamus alternatus.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38139394","citation_count":5,"is_preprint":false},{"pmid":"22745772","id":"PMC_22745772","title":"Identification of Nedd4 E3 ubiquitin ligase as a binding partner and regulator of MAK-V protein kinase.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22745772","citation_count":5,"is_preprint":false},{"pmid":"1873360","id":"PMC_1873360","title":"Therapy of recurrent high-grade gliomas with surgery, autologous mitogen-activated IL-2-stimulated (MAK) killer lymphocytes, and rIL-2: II. Correlation of survival with MAK cell tumor necrosis factor production in vitro.","date":"1991","source":"Lymphokine and cytokine research","url":"https://pubmed.ncbi.nlm.nih.gov/1873360","citation_count":5,"is_preprint":false},{"pmid":"35253837","id":"PMC_35253837","title":"PCARE requires coiled coil, RP62 kinase-binding and EVH1 domain-binding motifs for ciliary expansion.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35253837","citation_count":4,"is_preprint":false},{"pmid":"21568852","id":"PMC_21568852","title":"Interaction between MAK-V protein kinase and synaptopodin.","date":"2011","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/21568852","citation_count":4,"is_preprint":false},{"pmid":"10393282","id":"PMC_10393282","title":"The lack of binding of methyl-n-amyl ketone (MAK) to rat liver DNA as demonstrated by direct binding measurements, and 32P-postlabeling techniques.","date":"1999","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/10393282","citation_count":4,"is_preprint":false},{"pmid":"29781741","id":"PMC_29781741","title":"Slowly progressive retinitis pigmentosa caused by two novel mutations in the MAK gene.","date":"2018","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29781741","citation_count":4,"is_preprint":false},{"pmid":"26368644","id":"PMC_26368644","title":"The Necessity of Developing New Criteria for Carcinogen Classification of Fibers by the Mak Commission.","date":"2000","source":"Inhalation toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/26368644","citation_count":4,"is_preprint":false},{"pmid":"31608171","id":"PMC_31608171","title":"Plastome of mycoheterotrophic Burmannia itoana Mak. (Burmanniaceae) exhibits extensive degradation and distinct rearrangements.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/31608171","citation_count":4,"is_preprint":false},{"pmid":"18393762","id":"PMC_18393762","title":"Membrane localization of the MAK-V protein kinase.","date":"2008","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/18393762","citation_count":3,"is_preprint":false},{"pmid":"15234748","id":"PMC_15234748","title":"MAK-5 treatment enhances the nerve growth factor-mediated neurite outgrowth in PC12 cells.","date":"2004","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15234748","citation_count":3,"is_preprint":false},{"pmid":"21798301","id":"PMC_21798301","title":"Classification of skin sensitizing substances: a comparison between approaches used by the DFG-MAK Commission and the European Union legislation.","date":"2011","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/21798301","citation_count":3,"is_preprint":false},{"pmid":"35460761","id":"PMC_35460761","title":"MAPK/MAK/MRK overlapping kinase mediated apoptosis through caspase signaling pathway from Cristaria plicata.","date":"2022","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35460761","citation_count":2,"is_preprint":false},{"pmid":"40578471","id":"PMC_40578471","title":"Ellipsoid Zone Loss as an Outcome Measure in MAK-Associated Retinitis Pigmentosa.","date":"2025","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/40578471","citation_count":2,"is_preprint":false},{"pmid":"36042901","id":"PMC_36042901","title":"Downregulation of mapk/mak/mrk overlapping kinase 1 in peripheral blood mononuclear cells of pediatric patients with type 1 diabetes mellitus.","date":"2022","source":"Journal of medical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36042901","citation_count":2,"is_preprint":false},{"pmid":"11141185","id":"PMC_11141185","title":"Characterization of a Mak subgroup Cdc2-like protein kinase from sugar beet (Beta vulgaris L.).","date":"2000","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/11141185","citation_count":2,"is_preprint":false},{"pmid":"41586737","id":"PMC_41586737","title":"N,N',N''-Tris(β-hydroxyethyl)hexahydro-1,3,5-triazine: MAK Value Documentation, addendum - Translation of the German version from 2023.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41586737","citation_count":2,"is_preprint":false},{"pmid":"41584500","id":"PMC_41584500","title":"N,N',N''-Tris(β-hydroxypropyl)hexahydro-1,3,5-triazine: MAK Value Documentation - Translation of the German version from 2023.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41584500","citation_count":1,"is_preprint":false},{"pmid":"33335286","id":"PMC_33335286","title":"From the T-cell receptor to cancer therapy: an interview with Tak W. Mak.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33335286","citation_count":1,"is_preprint":false},{"pmid":"11780494","id":"PMC_11780494","title":"[Experimental study on the influence of Gynostemma pentaphyllam Mak upon point mutation of Ha-ras oncogene in blocking leukoplakia from canceration].","date":"2000","source":"Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/11780494","citation_count":1,"is_preprint":false},{"pmid":"29066688","id":"PMC_29066688","title":"[Survival Benefit by Combined Administration of Cyclophosphamide, Lentinula edodes Mycelia Extract(LEM), and Ganoderma lucidum Mycelia Extract(MAK)in S1018B10 Tumor-Bearing Mice].","date":"2017","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/29066688","citation_count":1,"is_preprint":false},{"pmid":"41231942","id":"PMC_41231942","title":"Chlamydomonas protein kinase MAK phosphorylates FAP256/CEP104 and regulates axonemal microtubule assembly.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41231942","citation_count":0,"is_preprint":false},{"pmid":"42164643","id":"PMC_42164643","title":"1,2-Dimethylhydrazine: MAK Value Documentation, addendum - Translation of the German version from 2021.","date":"2024","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/42164643","citation_count":0,"is_preprint":false},{"pmid":"42164639","id":"PMC_42164639","title":"Toluene: MAK Value Documentation, addendum - Translation of the German version from 2021.","date":"2024","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/42164639","citation_count":0,"is_preprint":false},{"pmid":"42164646","id":"PMC_42164646","title":"Monomethylhydrazine: MAK Value Documentation, addendum - Translation of the German version from 2021.","date":"2024","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/42164646","citation_count":0,"is_preprint":false},{"pmid":"41584501","id":"PMC_41584501","title":"Tetramethylol acetylenediurea: MAK Value Documentation - Translation of the German version from 2023.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41584501","citation_count":0,"is_preprint":false},{"pmid":"41971562","id":"PMC_41971562","title":"Synthetic amorphous silica: MAK Value Documentation, addendum - Translation of the German version from 2023.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41971562","citation_count":0,"is_preprint":false},{"pmid":"42164652","id":"PMC_42164652","title":"1,1-Dimethylhydrazine: MAK Value Documentation, addendum - Translation of the German version from 2021.","date":"2024","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/42164652","citation_count":0,"is_preprint":false},{"pmid":"15773550","id":"PMC_15773550","title":"[Molecular cloning and characterization of the mouse mak-v/Hunk gene promoter].","date":"2005","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/15773550","citation_count":0,"is_preprint":false},{"pmid":"42164637","id":"PMC_42164637","title":"Triphenylphosphine: MAK Value Documentation, addendum - Translation of the German version from 2022.","date":"2024","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/42164637","citation_count":0,"is_preprint":false},{"pmid":"42126134","id":"PMC_42126134","title":"MAK-2 Kinase Is Required for Extended Longevity and Enhanced Stress Resistance Resulting From Mild Impairment of Mitochondrial Function in isp-1 Mutants.","date":"2026","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/42126134","citation_count":0,"is_preprint":false},{"pmid":"41973600","id":"PMC_41973600","title":"Chloroform: MAK Value Documentation, addendum - Translation of the German version from 2022.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41973600","citation_count":0,"is_preprint":false},{"pmid":"41575991","id":"PMC_41575991","title":"Formononetin ameliorates SP-induced urticaria in mice via suppressing TAK1/MAK signaling pathway.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41575991","citation_count":0,"is_preprint":false},{"pmid":"41657991","id":"PMC_41657991","title":"Single-cell RNA-seq reveals a key role for Vibrio cholerae Mak toxins in Tetrahymena pyriformis killing and bacterial survival.","date":"2026","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41657991","citation_count":0,"is_preprint":false},{"pmid":"41586081","id":"PMC_41586081","title":"N,N-Dimethyl-p-toluidine: MAK Value Documentation - Translation of the German version from 2022.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41586081","citation_count":0,"is_preprint":false},{"pmid":"41971568","id":"PMC_41971568","title":"Zinc diamyldithiocarbamate: MAK Value Documentation - Translation of the German version from 2023.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41971568","citation_count":0,"is_preprint":false},{"pmid":"41586701","id":"PMC_41586701","title":"Naphthalene: MAK Value Documentation, addendum - Translation of the German version from 2022.","date":"2025","source":"The MAK collection for occupational health and safety","url":"https://pubmed.ncbi.nlm.nih.gov/41586701","citation_count":0,"is_preprint":false},{"pmid":"12068635","id":"PMC_12068635","title":"[The use of the two-hybrid cloning in yeast for functional characterization of protein kinase MAK-V].","date":"2002","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/12068635","citation_count":0,"is_preprint":false},{"pmid":"125971","id":"PMC_125971","title":"[Characterisation of RNA from synchronously growing yeast cells (Saccharomyces cerevisiae) as separated by columns of methylated albumin on Kieselgur (MAK) (author's transl)].","date":"1975","source":"Zeitschrift fur Naturforschung. Section C, Biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/125971","citation_count":0,"is_preprint":false},{"pmid":"8679938","id":"PMC_8679938","title":"Protoplast culture and plant regeneration from the suspension cells of Gynostemma pentaphyllum (Thumb) Mak.","date":"1995","source":"Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/8679938","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41667,"output_tokens":3968,"usd":0.09226,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11725,"output_tokens":4188,"usd":0.081662,"stage2_stop_reason":"end_turn"},"total_usd":0.173922,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"MAK (male germ cell-associated kinase) encodes a novel serine/threonine protein kinase whose predicted product contains protein kinase consensus motifs in its amino-terminal region and is approximately 40% identical to the cdc2-CDC28 gene family. Its transcripts are expressed almost exclusively in testicular germ cells entering and after meiosis.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA cloning with sequence analysis and tissue expression profiling; single lab, foundational characterization\",\n      \"pmids\": [\"2183027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"MAK mRNA is specifically localized in late pachytene (stage X) and diplotene (stage XI) spermatocytes, and faintly in dividing spermatocytes (stage XII) and early round spermatids, indicating expression is concentrated around meiotic cell division.\",\n      \"method\": \"Non-radioactive in situ hybridization on frozen mouse testis sections\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in situ localization experiment, single lab, single method\",\n      \"pmids\": [\"1473268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"MAK protein products (66- and 60-kDa) are most abundant in late pachytene spermatocytes, localized mostly in the cytoplasm as a soluble form, and are associated with a 210-kDa cellular phosphoprotein that MAK phosphorylates on serine and threonine residues both in vitro (immunoprecipitate kinase assay) and in vivo.\",\n      \"method\": \"Immunoprecipitation, in vitro kinase assay, subcellular fractionation, [35S]methionine labeling, 32Pi in vivo labeling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with immunoprecipitates demonstrating phosphorylation of 210-kDa substrate on Ser/Thr, corroborated by in vivo 32Pi labeling; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"8321219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MAK is dispensable for spermatogenesis and male fertility in mice; Mak-null mice develop normally with intact spermatogenesis, though litter sizes and sperm motility in vitro are mildly reduced.\",\n      \"method\": \"Gene targeting to generate Mak−/− mice; fertility assays, histological analysis of spermatogenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with specific phenotypic readout, single lab but rigorous genetic loss-of-function study\",\n      \"pmids\": [\"11971961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAK and its related kinase MRK/ICK require dual phosphorylation in a TDY activation-loop motif: an unidentified threonine kinase (CCRK for MRK) phosphorylates T157, and tyrosine autophosphorylation also occurs. CCRK is the activating T157 kinase for MRK (not CDK7/cyclin H/MAT1). Protein phosphatase 5 (PP5) interacts with MRK and dephosphorylates it at T157, acting as the opposing phosphatase. MRK preferentially phosphorylates R-P-X-S/T-P consensus sites (most stringent requirement: Arg at P-3). MRK phosphorylates the antiapoptotic protein Scythe at T1080 in vitro, validated by site-directed mutagenesis and mass spectrometry.\",\n      \"method\": \"In vitro kinase assay, combinatorial peptide library screening, site-directed mutagenesis, mass spectrometry, co-immunoprecipitation, in situ phosphatase assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, mass spectrometry, and peptide library screening; multiple orthogonal methods; directly relevant to MAK family activation mechanism\",\n      \"pmids\": [\"16954377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mak negatively regulates ciliary length in retinal photoreceptors. Mak localizes to connecting cilia and outer-segment axonemes. In Mak-null mice, photoreceptors exhibit elongated cilia, accumulation of IFT88 and IFT57, expansion of Kif3a and acetylated α-tubulin signals in cilia, and abnormal rhodopsin accumulation in cell bodies at P14, followed by progressive degeneration. Overexpression of RP1 (a microtubule-associated protein in outer-segment axonemes) induces ciliary elongation, and co-expression of Mak rescues this elongation. The RP1 N-terminal portion is phosphorylated by Mak in vitro.\",\n      \"method\": \"Mak-null mouse generation, immunohistochemistry, immunofluorescence, in vitro kinase assay, overexpression rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — loss-of-function mouse with specific ciliary phenotype, in vitro kinase assay showing RP1 phosphorylation, rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"21148103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors in human donor tissue. An Alu insertion in exon 9 of MAK causes loss of the exon 9+12 retinal transcript isoform, which normally predominates in retinal precursors differentiated from iPSCs. The developmental switch from the exon-9-lacking to the exon-9/12-bearing transcript does not occur in patient-derived cells.\",\n      \"method\": \"Immunohistochemistry of human donor tissue, iPSC differentiation to retinal precursors, RT-PCR isoform analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunohistochemistry for subcellular localization combined with iPSC functional isoform analysis; single lab\",\n      \"pmids\": [\"21825139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Missense mutations in MAK that alter conserved kinase residues result in loss of kinase activity as demonstrated by in vitro kinase assay, establishing that kinase activity is critical for MAK function in humans.\",\n      \"method\": \"In vitro kinase assay on patient-derived missense mutant MAK proteins\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay demonstrating loss of activity with disease mutations; single lab, single method\",\n      \"pmids\": [\"21835304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In C. elegans, DYF-5/MAK (ortholog of mammalian MAK) acts downstream of DYF-18/CCRK in a kinase cascade to regulate ciliary length and branching morphology. Loss of dyf-5/MAK results in dramatically elongated, unbranched AWA cilia. Axonemal microtubules in dyf-18/CCRK mutants are decorated by EBP-2 end-binding protein along their lengths and show increased tubulin load and reduced tubulin turnover, indicating that CCRK-MAK activity tunes cilia length and shape by modulating axonemal microtubule stability.\",\n      \"method\": \"Genetic epistasis (double mutants), live imaging of IFT motor proteins, EBP-2 end-binding protein dynamics, microtubule-destabilizing tubulin mutations, IFT protein mutations as suppressors\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with suppressor analysis and multiple orthogonal imaging methods; directly establishes pathway position and mechanism\",\n      \"pmids\": [\"30955935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ciliary kinase DYF-5/MAK phosphorylates multiple sites within the tubulin-binding module of IFT-74, reducing the tubulin-binding affinity of the IFT-74/81 module approximately sixfold. Ablation or constitutive activation of IFT-74 phosphorylation abnormally elongates or shortens sensory cilia in C. elegans, respectively, establishing that MAK-dependent phosphorylation of IFT-74 regulates ciliary tubulin unloading at the tip.\",\n      \"method\": \"In vitro phosphorylation assay, binding affinity measurements, C. elegans genetics with phospho-ablating and phospho-mimetic IFT-74 mutants, ciliary length phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of kinase-substrate phosphorylation with affinity quantification, corroborated by in vivo genetic phenotypes with gain- and loss-of-phosphorylation alleles\",\n      \"pmids\": [\"35969738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gene delivery of retinal MAK transgene to patient iPSC-derived photoreceptor precursor cells and mak-knockdown zebrafish restores the ability to regulate primary cilia length, confirming that MAK kinase function is necessary and sufficient for ciliary length control in photoreceptors.\",\n      \"method\": \"Viral gene augmentation in patient iPSC-derived cells, mak knockdown zebrafish model, cilia length assay, rt-PCR and western blotting for transgene expression\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment in patient-derived cells and animal model with defined ciliary phenotype; single lab\",\n      \"pmids\": [\"34518651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCARE contains an evolutionarily conserved binding site for the photoreceptor kinase MAK (RP62). The MAK-binding motif within PCARE is required for PCARE's proper localization and function at the ciliary tip membrane expansion in photoreceptors.\",\n      \"method\": \"Domain deletion mutagenesis, ciliary localization assays, co-expression with WASF3 for membrane expansion measurement\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutagenesis with functional ciliary localization readout; establishes MAK-binding motif in PCARE but does not directly demonstrate MAK-PCARE interaction in vitro; single lab\",\n      \"pmids\": [\"35253837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAK is a ciliary tip-localized IFT regulator that cooperatively acts with the related kinase ICK. Simultaneous disruption of Mak and Ick in mice results in loss of photoreceptor ciliary axonemes and severe retinal degeneration, a more severe phenotype than either single knockout. CCRK kinase acts as an upstream activator of both Mak and Ick in retinal photoreceptor cells. Gene delivery of Ick and pharmacological inhibition of FGF receptors (negative regulators of Ick) ameliorate retinal degeneration in Mak-null mice.\",\n      \"method\": \"Conditional double knockout (Mak/Ick), histology, gene delivery rescue, pharmacological FGF receptor inhibition, genetic epistasis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double knockout epistasis with defined photoreceptor phenotype, upstream kinase (CCRK) pathway placement, rescue experiments; multiple orthogonal approaches\",\n      \"pmids\": [\"39293864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Chlamydomonas MAK (CrMAK), related to mammalian ICK/MAK, localizes to cilia via its C-terminal tail and is enriched at the ciliary tip during active ciliary assembly. CrMAK is constitutively active during ciliary assembly, acts downstream of the LF1/LF3/LF2 (CCRK homologue) ciliary length-regulatory complex, and phosphorylates FAP256/CEP104 (a microtubule plus-end tracking protein). Loss of CrMAK or its kinase activity leads to aciliated cells; dephosphorylation of FAP256/CEP104 impairs ciliary assembly.\",\n      \"method\": \"Genetic loss-of-function, live cell imaging of CrMAK-GFP fusion, in vitro kinase assay showing FAP256/CEP104 phosphorylation, kinase-dead mutants, dephosphorylation experiments, epistasis with LF complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with substrate identification, kinase-dead mutagenesis, live localization imaging, and genetic epistasis placing MAK downstream of CCRK/LF complex; multiple orthogonal methods\",\n      \"pmids\": [\"41231942\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAK (male germ cell-associated kinase) is a serine/threonine kinase activated by CCRK-mediated phosphorylation of its TDY activation-loop motif, which localizes to the ciliary tip of photoreceptors and sensory neurons, where it negatively regulates ciliary length by phosphorylating IFT-74 to reduce tubulin-binding affinity and promote tubulin unloading, phosphorylating RP1 to limit axonemal elongation, and phosphorylating FAP256/CEP104 to control axonemal microtubule assembly; loss of MAK causes ciliary elongation, IFT protein accumulation, mislocalized rhodopsin, and progressive photoreceptor degeneration, and MAK cooperates with the related kinase ICK downstream of CCRK in an essential IFT-regulatory axis required for photoreceptor survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAK (male germ cell-associated kinase) is a CDC2/CDC28-related serine/threonine protein kinase that functions as a ciliary length regulator in photoreceptors and other sensory cells [#0, #5]. Its catalytic activation requires dual phosphorylation of a TDY activation-loop motif, with CCRK serving as the upstream activating kinase that phosphorylates the activation-loop threonine, while protein phosphatase 5 provides opposing dephosphorylation; MAK family kinases recognize an R-P-X-S/T-P consensus with a stringent Arg at the P-3 position [#4]. Within sensory cilia, MAK localizes to the connecting cilium and outer-segment axoneme/ciliary tip, where it negatively regulates axonemal length by phosphorylating substrates that govern microtubule and IFT dynamics: it phosphorylates the axonemal microtubule-associated protein RP1 to limit elongation [#5], phosphorylates multiple sites in the tubulin-binding module of IFT-74 to reduce tubulin-binding affinity and promote tubulin unloading at the ciliary tip [#9], and phosphorylates the microtubule plus-end tracking protein FAP256/CEP104 to control axonemal assembly [#13]. Loss of MAK produces elongated cilia, accumulation of IFT proteins (IFT88, IFT57) and acetylated tubulin, mislocalized rhodopsin, and progressive photoreceptor degeneration [#5]. MAK acts in a conserved CCRK-headed kinase axis together with the related kinase ICK, and combined loss of MAK and ICK causes loss of photoreceptor axonemes and severe retinal degeneration that is partially rescued by ICK gene delivery or FGF receptor inhibition [#8, #12]. In humans, loss-of-function MAK mutations—including an Alu insertion disrupting the retina-specific exon-9/12 transcript isoform and kinase-inactivating missense changes—cause inherited photoreceptor degeneration, and restoring MAK expression rescues ciliary length control [#6, #7, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established MAK as a distinct serine/threonine kinase, defining the molecular identity and tissue context that any later mechanism would have to explain.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and Northern blot in mouse testis\",\n      \"pmids\": [\"2183027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrates or activation mechanism identified\", \"Restricted to expression profiling, no functional assay\", \"Apparent germ-cell restriction later proven incomplete given retinal roles\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Refined MAK expression to specific meiotic spermatocyte stages, suggesting a role tied to meiotic cell division.\",\n      \"evidence\": \"Non-radioactive in situ hybridization on mouse testis sections\",\n      \"pmids\": [\"1473268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localizes mRNA but not protein function\", \"No causal link to meiotic events\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrated MAK is a functional kinase by showing it phosphorylates a 210-kDa cellular phosphoprotein on Ser/Thr in vitro and in vivo, establishing catalytic activity against a cellular substrate.\",\n      \"evidence\": \"Immunoprecipitate kinase assay, subcellular fractionation, in vivo 32Pi labeling\",\n      \"pmids\": [\"8321219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the 210-kDa substrate never determined\", \"Cytoplasmic soluble localization not connected to a pathway\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout showed MAK is dispensable for spermatogenesis, redirecting the search for its essential physiological role away from male fertility.\",\n      \"evidence\": \"Mak-null mouse generation with fertility and histological analysis\",\n      \"pmids\": [\"11971961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reveal where MAK is essential\", \"Mild motility/litter phenotype mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the activation mechanism of the MAK family: CCRK-dependent TDY activation-loop phosphorylation, PP5 as the opposing phosphatase, and an R-P-X-S/T-P substrate consensus, providing the biochemical framework for MAK regulation.\",\n      \"evidence\": \"In vitro kinase assays, peptide library screening, mass spectrometry, co-IP, and phosphatase assays on MAK/MRK(ICK)\",\n      \"pmids\": [\"16954377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Much of the detailed work was on the related MRK/ICK rather than MAK itself\", \"Physiological substrates not yet identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified ciliary length control as MAK's essential function, linking its kinase activity to RP1 phosphorylation, IFT regulation, and photoreceptor survival.\",\n      \"evidence\": \"Mak-null mouse immunohistochemistry, in vitro RP1 phosphorylation, and overexpression rescue of ciliary elongation\",\n      \"pmids\": [\"21148103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phospho-sites on RP1 not mapped in vivo\", \"Mechanism by which IFT proteins accumulate not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected MAK to human inherited retinal degeneration, showing both disrupted retina-specific isoform expression and loss of kinase activity in patient mutations established kinase function as disease-critical.\",\n      \"evidence\": \"Human donor tissue immunohistochemistry, iPSC retinal differentiation isoform analysis, and in vitro kinase assays on patient missense mutants\",\n      \"pmids\": [\"21825139\", \"21835304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro kinase loss not directly tied to ciliary phenotype in same study\", \"Functional consequence of isoform switch on cilia not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed MAK genetically downstream of CCRK in a conserved ciliary kinase cascade controlling axonemal microtubule stability, length, and branching.\",\n      \"evidence\": \"C. elegans genetic epistasis, IFT and EBP-2 live imaging, and suppressor analysis in dyf-5/MAK and dyf-18/CCRK mutants\",\n      \"pmids\": [\"30955935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrates within the axoneme not identified in this study\", \"Mechanism connecting microtubule turnover to length not molecularly resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified IFT-74 as a direct MAK substrate and showed phosphorylation of its tubulin-binding module reduces tubulin affinity, providing a molecular mechanism for tubulin unloading at the ciliary tip.\",\n      \"evidence\": \"In vitro phosphorylation and binding-affinity measurements with phospho-ablating/mimetic IFT-74 alleles in C. elegans\",\n      \"pmids\": [\"35969738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same phospho-regulation operates on mammalian IFT-74 not shown\", \"Spatial control of phosphorylation at the tip not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated MAK function is necessary and sufficient for photoreceptor ciliary length control, supporting gene augmentation as a corrective strategy.\",\n      \"evidence\": \"Viral MAK gene augmentation in patient iPSC-derived photoreceptor precursors and mak-knockdown zebrafish with cilia length assays\",\n      \"pmids\": [\"34518651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Durability and substrate-level rescue not assessed\", \"Single-lab rescue without independent replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a conserved MAK-binding motif in PCARE required for proper ciliary-tip localization, linking MAK to ciliary membrane expansion machinery.\",\n      \"evidence\": \"Domain deletion mutagenesis and ciliary localization/membrane-expansion assays with WASF3 co-expression\",\n      \"pmids\": [\"35253837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MAK-PCARE physical interaction not demonstrated in vitro\", \"Whether PCARE is a MAK substrate unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established MAK and ICK as cooperative, partially redundant CCRK-controlled regulators of photoreceptor axonemes, defining an essential IFT-regulatory axis for photoreceptor survival.\",\n      \"evidence\": \"Conditional Mak/Ick double knockout, genetic epistasis, ICK gene delivery, and FGF receptor inhibition rescue in mice\",\n      \"pmids\": [\"39293864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct versus shared substrates of MAK and ICK not defined\", \"Mechanism of FGFR-mediated ICK regulation incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FAP256/CEP104 as a MAK substrate and placed MAK downstream of the CCRK-homologous LF complex, showing kinase activity is required for ciliary assembly.\",\n      \"evidence\": \"Chlamydomonas loss-of-function, CrMAK-GFP live imaging, in vitro kinase assay on FAP256/CEP104, kinase-dead mutants, and LF-complex epistasis\",\n      \"pmids\": [\"41231942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian MAK phosphorylates CEP104 not shown\", \"How FAP256/CEP104 phosphorylation mechanistically promotes assembly not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAK integrates its multiple ciliary substrates (RP1, IFT-74, FAP256/CEP104, PCARE) into coordinated length and assembly control, and the identity of its original germ-cell 210-kDa substrate, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the distinct substrates spatially and temporally\", \"Germ-cell substrate and meiotic role uncharacterized\", \"Mammalian counterparts of invertebrate/algal substrate findings not directly confirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 5, 9, 13]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 9, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5, 8, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 8, 9, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCRK\", \"ICK\", \"RP1\", \"IFT74\", \"CEP104\", \"PCARE\", \"PP5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}