Affinage

MKS1

Tectonic-like complex member MKS1 · UniProt Q9NXB0

Length
559 aa
Mass
64.5 kDa
Annotated
2026-06-10
37 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Human MKS1 is a B9-domain protein that operates at the ciliary transition zone to govern ciliogenesis, ciliary membrane composition, and ciliary signaling (PMID:19776033, PMID:32726168). It localizes to basal bodies and the mother centriole from which the cilium grows, and its loss disrupts cilium formation across most tissues; the B9 domain is required for MKS1's own centriolar/transition-zone localization, and its deletion causes ciliogenesis failure (PMID:17185389, PMID:21045211). At the transition zone MKS1 assembles with B9D2 and B9D1 into an ordered MKS1-B9D2-B9D1 complex whose members localize interdependently and which functions as a diffusion barrier for ciliary membrane proteins (PMID:32726168). Through this position MKS1 regulates ciliary levels of ARL13B and INPP5E and cooperates with the BBSome (BBS4) and IFT machinery (IFT172, DYNC2H1) to traffic ARL13B and execute Hedgehog patterning, with loss of Mks1 expanding Shh signaling domains and impairing Gli3 repressor function (PMID:21045211, PMID:26490104, PMID:28291807). MKS1 additionally interacts with the E2 ubiquitin-conjugating enzyme UBE2E1 and the E3 ligase RNF34: UBE2E1 ubiquitinates MKS1 reciprocally and, through a MKS1-UBE2E1 interaction at the ciliary base, processes phosphorylated β-catenin to regulate canonical Wnt signaling (PMID:35170427). Pathogenic MKS1 mutations that disrupt the B9 domain attenuate the MKS1-B9D2 interaction and abolish transition-zone localization, linking MKS1 to ciliopathy (PMID:33193692).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 High

    Established MKS1 as a ciliary protein by placing it at the basal body and showing it is required for centriole migration and cilium formation, while identifying a physical partner.

    Evidence siRNA knockdown, reciprocal co-immunoprecipitation, and immunofluorescence in ciliated epithelial cells; parallel basal-body proteomics

    PMID:16415886 PMID:17185389

    Open questions at the time
    • Molecular function within the cilium not defined
    • Mechanism of meckelin interaction not resolved
  2. 2009 High

    In vivo loss-of-function defined MKS1 as required for ciliogenesis and for restraining Hedgehog signaling, connecting it to developmental patterning.

    Evidence Mouse knockout with neural tube and limb patterning analysis; stable shRNA in IMCD3 cells; C. elegans B9-protein localization and genetics

    PMID:19208769 PMID:19515853 PMID:19776033

    Open questions at the time
    • How MKS1 limits the Shh domain mechanistically unclear
    • Centrosome-duplication role from cell-line KD not validated in vivo
  3. 2010 High

    Domain mapping showed the B9 domain is required for MKS1 localization to the centriole, separating its targeting from centriole assembly itself.

    Evidence Mouse del64-323 mutant analysis with localization, Shh readouts, and node flow assay; C. elegans epistasis with mks-3 and nphp pathways

    PMID:20150540 PMID:21045211

    Open questions at the time
    • Structural basis of B9-domain targeting unknown
    • Relationship between transition-zone and centriolar pools not resolved
  4. 2015 Medium

    Linked MKS1 transition-zone function to control of specific ciliary membrane proteins, defining an ARL13B-dependent route for INPP5E enrichment.

    Evidence Patient fibroblast immunofluorescence and 3D spheroid rescue with mutant MKS1 alleles

    PMID:26490104

    Open questions at the time
    • Direct biochemical link between MKS1 and ARL13B/INPP5E not shown
    • Single lab
  5. 2017 High

    Genetic epistasis placed the MKS transition-zone complex upstream of, and cooperating with, the BBSome and IFT machinery in trafficking ARL13B for Hedgehog signaling.

    Evidence Mouse Mks1;Bbs4, Mks1;Ift172, Mks1;Dync2h1 double-mutant analysis with ARL13B localization and Hedgehog readouts

    PMID:28291807

    Open questions at the time
    • Whether interactions with BBSome/IFT are physical or purely genetic not established
    • Direct cargo-recognition mechanism unknown
  6. 2020 High

    Reconstituted the ordered MKS1-B9D2-B9D1 complex and showed its essential role is the ciliary diffusion barrier rather than cilium biogenesis per se.

    Evidence Co-IP, CRISPR KO cells with rescue, and FRAP-based diffusion-barrier assay; patient c.1058delG mutation disrupting B9 domain and B9D2 binding

    PMID:32726168 PMID:33193692

    Open questions at the time
    • Structure of the assembled complex not determined
    • How the barrier discriminates among membrane proteins unknown
  7. 2022 High

    Identified a ubiquitin-pathway role for MKS1, coupling it to UBE2E1/RNF34 and to processing of phosphorylated β-catenin at the ciliary base to regulate canonical Wnt signaling.

    Evidence Co-IP, Mks1-loss mouse model, ubiquitination assays, and Wnt/β-catenin reporter assays; additional patient mutations attenuating B9D2 binding

    PMID:35170427 PMID:35360848

    Open questions at the time
    • Direct enzymatic relationship between MKS1 and β-catenin ubiquitination not fully resolved
    • How ciliary localization gates Wnt processing unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MKS1's transition-zone barrier function, IFT/BBSome cooperation, and UBE2E1-Wnt activities are mechanistically integrated, and the structural basis of cargo selectivity, remain open.
  • No high-resolution structure of the MKS1-B9D2-B9D1 complex
  • Direct substrate/cargo recognition mechanism undefined
  • Integration of ciliary and ubiquitin/Wnt functions unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005929 cilium 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
B9D1B9D2MKS3RNF34UBE2E1
Complex memberships
MKS1-B9D2-B9D1 transition zone complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 MKS1 protein localizes to basal bodies in ciliated epithelial cells; siRNA-mediated knockdown of Mks1 blocks centriole migration to the apical membrane and consequent primary cilium formation. Co-immunoprecipitation shows MKS1 physically interacts with meckelin (MKS3 gene product). siRNA knockdown, co-immunoprecipitation, immunofluorescence localization Human molecular genetics High 17185389
2006 MKS1 was identified as a component of the flagellar apparatus basal body proteome by comparative genomics and proteomics, implicating it in ciliary functions. Comparative genomics/proteomics, in situ hybridization in mouse embryos Nature genetics Medium 16415886
2009 In vivo loss of mouse Mks1 leads to defective cilia formation in most tissues (but does not interfere with apical localization of epithelial basal bodies), and causes altered Hedgehog pathway signaling (expansion of Shh signaling domain in neural tube and limb). Mouse knockout, neural tube/limb patterning analysis, in vivo ciliogenesis assessment Human molecular genetics High 19776033
2009 Stable shRNA knockdown of Mks1 in IMCD3 cells induced multi-ciliated and multi-centrosomal phenotypes, demonstrating that MKS1 is required for regulating cilia length and number through modulation of centrosome duplication. Stable shRNA knockdown, immunofluorescence for cilia and centrosomes Human molecular genetics Medium 19515853
2009 C. elegans MKS-1 and its related proteins MKSR-1 and MKSR-2 (B9-domain proteins) all localize to transition zones/basal bodies of sensory cilia in a largely co-dependent manner, indicating functional interdependence. Disrupting human MKSR1 or MKSR2 causes ciliogenesis defects. Genetic interactions between double mks/mksr C. elegans mutants manifest as increased lifespan due to abnormal insulin-IGF-I signaling. Fluorescence localization in C. elegans, RNAi/genetic knockouts, epistasis analysis, lifespan assay Journal of cell science High 19208769
2010 Mks1 localizes to the mother centriole from which the cilium is generated in wild-type cells. A deletion mutation (del64-323) spanning the B9 domain prevents Mks1 from localizing to the centriole without disrupting centriole assembly itself, causing ciliogenesis failure in motile and non-motile cilia and disrupted Shh signaling (failed floor plate specification, expanded anterior Shh domain, reduced Gli3 repressor function). Mouse mutant analysis, immunofluorescence localization, Shh pathway readout (Gli2/Gli3 expression), fluorescent bead node flow assay Disease models & mechanisms High 21045211
2010 Genetic epistasis in C. elegans shows mks-1 and mks-3 function in a pathway together, and this pathway interacts with a separate nphp-1/nphp-4 pathway to influence cilia positioning, orientation, and formation; combined disruption of both pathways has cell non-autonomous effects on sensilla. C. elegans genetic epistasis, double mutant analysis, cilia phenotype scoring Journal of the American Society of Nephrology Medium 20150540
2011 MKS1-related B9-domain protein B9d2 binds IFT particle components and contributes to ciliary localization of Inversin (Nephrocystin 2), supporting transport of Opsin but not Peripherin to photoreceptor cilia. Co-immunoprecipitation, zebrafish in vivo knockdown, ciliary cargo trafficking assay The EMBO journal Medium 21602787
2015 MKS1 functions at the transition zone to regulate ciliary INPP5E content through an ARL13B-dependent mechanism; patient fibroblasts with MKS1 mutations show decreased ciliary ARL13B and INPP5E levels, and this is recapitulated in 3D spheroid rescue assays with mutant MKS1 alleles. Immunofluorescence in patient fibroblasts, 3D spheroid rescue assay, quantification of ciliary protein levels Journal of medical genetics Medium 26490104
2017 Genetic double-mutant analysis shows Mks1 cooperates with BBS4 (BBSome) to mediate trafficking of ARL13B (a ciliary membrane protein) to the cilium; Mks1;Bbs4 double mutants have exacerbated Hedgehog patterning defects and disrupted ciliary structure. Mks1 also genetically interacts with IFT-B component Ift172 and retrograde motor Dync2h1, demonstrating that the MKS transition zone complex facilitates IFT for cilium assembly. Mouse double-mutant epistasis, immunofluorescence for ARL13B ciliary localization, Hedgehog pathway readouts PloS one High 28291807
2020 MKS1, B9D2, and B9D1 form a complex in the order MKS1-B9D2-B9D1; their localization to the transition zone is interdependent. This B9-domain complex acts as a diffusion barrier for ciliary membrane proteins. MKS1-KO and B9D2-KO cells show that the complex is involved in, but not essential for, normal cilia biogenesis, whereas complex formation is crucial for the diffusion barrier function. Co-immunoprecipitation, CRISPR knockout cells, rescue experiments, fluorescence recovery after photobleaching (diffusion barrier assay) Molecular biology of the cell High 32726168
2020 The c.1058delG mutation disrupts the B9 domain of MKS1, attenuates MKS1 interaction with B9D2, and impairs ciliary localization at the transition zone, demonstrating that the B9 domain is essential for integrity of the B9 protein complex and TZ localization. Functional studies in patient-derived cells, co-immunoprecipitation, immunofluorescence localization Frontiers in genetics Medium 33193692
2022 MKS1 physically interacts with UBE2E1 (an E2 ubiquitin-conjugating enzyme) and RNF34 (an E3 ligase); UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1, and UBE2E1 levels are co-dependent with MKS1. Loss of Mks1 sensitizes cells to proteasomal disruption, causing abnormal accumulation of ubiquitinated proteins. UBE2E1 polyubiquitinates β-catenin, and processing of phosphorylated β-catenin occurs at the ciliary base through MKS1-UBE2E1 functional interaction, regulating canonical Wnt signaling. Co-immunoprecipitation, mouse model (Mks1 loss), immunofluorescence colocalization, Wnt/β-catenin reporter assays, ubiquitination assays eLife High 35170427
2022 Two novel MKS1 mutations (c.350C>A nonsense and c.1408-14A>G splice) disrupt the B9-C2 domain and attenuate MKS1 interaction with B9D2, the essential component of the ciliary transition zone. RT-PCR for aberrant splicing, Co-immunoprecipitation for B9D2 interaction Frontiers in genetics Low 35360848
2002 In yeast Saccharomyces cerevisiae, Mks1p is a negative regulator of the RTG mitochondria-to-nucleus signaling pathway, acting between Rtg2p and the bHLH transcription factors Rtg1p/Rtg3p; Mks1p is a phosphoprotein that forms a complex with Rtg2p. In mks1Δ cells, RTG target gene expression is constitutive and bypasses Rtg2p requirement. Genetic epistasis (mks1Δ, rtgΔ mutants), phosphorylation analysis, co-complex detection Molecular biology of the cell Medium 11907262
2000 In yeast, Mks1p is required for de novo generation of the [URE3] prion; mks1Δ strains cannot generate [URE3] de novo but can propagate introduced [URE3]. Mks1p negatively regulates Ure2p and is itself negatively regulated by ammonia and the Ras-cAMP pathway. Yeast genetics (mks1Δ), prion induction/propagation assays Proceedings of the National Academy of Sciences of the United States of America Medium 10823922
1993 In S. cerevisiae, MKS1 encodes a negative regulator acting downstream of the Ras-cAMP pathway: overexpression inhibits growth of cyr1 disruptants, and mks1 disruption partially suppresses the cyr1-230 temperature-sensitive mutation. MKS1 is involved in transcriptional regulation of several genes by cAMP. Yeast genetic overexpression and disruption, growth phenotype assays, suppressor analysis Molecular & general genetics Medium 8386801

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The MAP kinase substrate MKS1 is a regulator of plant defense responses. The EMBO journal 372 15990873
2006 MAPKAP kinases - MKs - two's company, three's a crowd. Nature reviews. Molecular cell biology 325 16421520
2006 The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Human molecular genetics 209 17185389
2006 MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nature genetics 184 16415886
2009 A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling. Human molecular genetics 113 19776033
2009 Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3. Human molecular genetics 100 19515853
2002 RTG-dependent mitochondria-to-nucleus signaling is regulated by MKS1 and is linked to formation of yeast prion [URE3]. Molecular biology of the cell 86 11907262
2011 Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos. The EMBO journal 81 21602787
2016 MAPK-Activated Protein Kinases (MKs): Novel Insights and Challenges. Frontiers in cell and developmental biology 73 26779481
2010 Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome. Disease models & mechanisms 73 21045211
2007 Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online. Human mutation 72 17397051
2011 B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Human molecular genetics 67 21493627
2009 Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. Journal of cell science 66 19208769
2007 Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Human genetics 58 17377820
2010 Normal ciliogenesis requires synergy between the cystic kidney disease genes MKS-3 and NPHP-4. Journal of the American Society of Nephrology : JASN 53 20150540
1993 Characterization of the MKS1 gene, a new negative regulator of the Ras-cyclic AMP pathway in Saccharomyces cerevisiae. Molecular & general genetics : MGG 43 8386801
2015 MKS1 regulates ciliary INPP5E levels in Joubert syndrome. Journal of medical genetics 42 26490104
2017 The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling. PloS one 38 28291807
2015 Identification of a novel MKS locus defined by TMEM107 mutation. Human molecular genetics 38 26123494
2000 A protein required for prion generation: [URE3] induction requires the Ras-regulated Mks1 protein. Proceedings of the National Academy of Sciences of the United States of America 38 10823922
2020 MKS-NPHP module proteins control ciliary shedding at the transition zone. PLoS biology 31 32163404
2020 Formation of the B9-domain protein complex MKS1-B9D2-B9D1 is essential as a diffusion barrier for ciliary membrane proteins. Molecular biology of the cell 26 32726168
2011 Constitutive expression of MKS1 confers susceptibility to Botrytis cinerea infection independent of PAD3 expression. Plant signaling & behavior 21 21900742
2007 Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber syndrome. Human mutation 21 17437276
2016 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4. PLoS genetics 17 26863025
2007 A disease causing deletion of 29 base pairs in intron 15 in the MKS1 gene is highly associated with the campomelic variant of the Meckel-Gruber syndrome. Clinical genetics 17 17935508
2016 MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum. European journal of medical genetics 14 27377014
2022 Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1. eLife 12 35170427
1989 Analysis of a large-T-antigen variant expressed in simian virus 40-transformed mouse cell line mKS-A. Journal of virology 8 2542592
2016 Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies. American journal of medical genetics. Part A 7 27570071
1991 SDZ MKS 492. Agents and actions. Supplements 7 1793072
2021 Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants. Diagnostics (Basel, Switzerland) 6 34359301
2020 Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome. Frontiers in genetics 6 33193692
2022 Case Report: Preimplantation Genetic Testing for Meckel Syndrome Induced by Novel Compound Heterozygous Mutations of MKS1. Frontiers in genetics 4 35360848
2025 Adiponectin Assists Thrombopoietic Agents in ITP Treatment by Enhancing Myosin-9/Rab6A-Mediated Trafficking of c-Mpl in MKs. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 40558825
2021 Immunophenotyping and Cell Sorting of Human MKs from Human Primary Sources or Differentiated In Vitro from Hematopoietic Progenitors. Journal of visualized experiments : JoVE 1 34424238
2024 Deciphering Transcriptomic Variations in Hematopoietic Lineages: HSCs, EBs, and MKs. International journal of molecular sciences 0 39337559

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