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Showing CIMAP3 — PIFO is a alias.

CIMAP3

Ciliary microtubule-associated protein 3 · UniProt Q8TCI5

Length
191 aa
Mass
22.0 kDa
Annotated
2026-06-09
51 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIMAP3 (PIFO/Pitchfork) is a basal body-associated protein that governs primary cilium dynamics and ciliary signaling during development (PMID:20643351, PMID:26901434). It accumulates at the basal body during cilia disassembly and, in its wild-type form (but not the patient-derived R80K mutant), activates Aurora A kinase to drive cilia retraction; loss of one copy in mice causes node cilia duplication, left-right asymmetry defects, basal body liberation, overreplication, and heart failure (PMID:20643351). Independently of its disassembly role, CIMAP3 forms an essential ciliary targeting complex with GPRASP2 that mediates Smoothened translocation into the primary cilium and is required for Hedgehog target gene activation (PMID:26901434). CIMAP3 is expressed in the developing secondary palate, where its over-expression triggers cilia disassembly and alters Sonic hedgehog and Patched1 expression, linking it to palate morphogenesis (PMID:25080064). Human PIFO variants are associated with laterality defects, consistent with its role in left-right patterning (PMID:35547246).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2010 High

    Established CIMAP3/PIFO as a basal body regulator of cilia disassembly by showing it activates Aurora A kinase and that its dysfunction disrupts left-right asymmetry, answering how a single protein couples ciliary targeting machinery to cilia retraction.

    Evidence Mouse haploinsufficiency model, co-immunoprecipitation with ciliary targeting complexes, Aurora A activation assays, and R80K human mutation functional comparison

    PMID:20643351

    Open questions at the time
    • Molecular mechanism by which PIFO activates Aurora A (direct vs. scaffolded) not resolved
    • Identity of the ciliary targeting complex components beyond the interaction not defined
    • Structural basis for the R80K loss of function unknown
  2. 2014 Medium

    Extended CIMAP3 function to tissue morphogenesis by showing its expression and over-expression in the secondary palate drive cilia disassembly and modulate Hedgehog component expression.

    Evidence In situ expression analysis and in vitro palate culture with Pitchfork over-expression, with Shh/Ptc1 readouts

    PMID:25080064

    Open questions at the time
    • No loss-of-function genetic model in palate
    • Single-lab over-expression phenotype
    • Mechanistic link between cilia disassembly and Shh/Ptc1 changes not dissected
  3. 2016 High

    Defined a distinct CIMAP3 function in ciliary signaling input by showing a PIFO-GPRASP2 complex is required for Smoothened entry into the cilium and Hedgehog activation, separating its disassembly role from a Hedgehog-targeting role.

    Evidence siRNA depletion of Pifo and Gprasp2 with Smo immunofluorescence and Hh target gene assays plus complex identification

    PMID:26901434

    Open questions at the time
    • Direct binding interface between PIFO and GPRASP2 not mapped
    • How the same protein governs both cilia assembly/disassembly and Smo trafficking unresolved
    • Stoichiometry and dynamics of the Smo-GPRASP2-PIFO complex unknown
  4. 2021 Low

    Reframed the Smoothened-GPRASP2-PIFO complex as a candidate therapeutic target by identifying small-molecule inhibitors against drug-resistant Smoothened cancers.

    Evidence Complex characterization summarized with referenced functional experiments in a review

    PMID:33267763

    Open questions at the time
    • Review-level summary without primary experimental detail in this entry
    • Specificity and on-target action of inhibitors for PIFO not demonstrated here
    • No structural validation of the inhibitor-complex interaction
  5. 2022 Low

    Provided human genetic support for the left-right patterning role by identifying PIFO variants in patients with laterality defects.

    Evidence Whole-exome sequencing with CNV analysis in consanguineous families

    PMID:35547246

    Open questions at the time
    • No functional validation of the patient variants in this study
    • Causality versus association not established
    • No mechanism linking specific variants to phenotype demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CIMAP3 mechanistically partitions between promoting cilia disassembly (via Aurora A) and enabling ciliary Hedgehog signaling (via GPRASP2/Smoothened) within a single basal body context remains unresolved.
  • No structural model of PIFO or its complexes
  • Mechanism of Aurora A activation undefined
  • Spatiotemporal regulation distinguishing its two functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005929 cilium 2 GO:0005815 microtubule organizing center 1
Partners
AURKAGPRASP2SMO
Complex memberships
Smoothened-GPRASP2-PIFO complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Pitchfork (Pifo/CIMAP3) associates with ciliary targeting complexes and accumulates at the basal body during cilia disassembly. Haploinsufficiency causes node cilia duplication, left-right asymmetry defects, and heart failure in mice. PIFO (but not the R80K mutant) is sufficient to activate Aurora A kinase, which induces cilia retraction. Pifo/PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects. Mouse genetics (haploinsufficiency model), co-immunoprecipitation with ciliary targeting complexes, functional assays for Aurora A activation, human patient mutation (R80K) functional comparison, in vivo phenotypic analysis Developmental cell High 20643351
2016 Pitchfork (Pifo/CIMAP3) and GPRASP2 form an essential ciliary targeting complex that regulates Smoothened (Smo) translocation to the primary cilium. Depletion of Pifo or Gprasp2 leads to failure of Smo translocation to the primary cilium and lack of Hedgehog (Hh) target gene activation. siRNA depletion of Pifo and Gprasp2, immunofluorescence for Smo localization to primary cilia, Hh target gene expression assays, protein complex identification PloS one High 26901434
2014 Pitchfork is highly expressed in the developing mouse secondary palate (E12.5–E13.5). Pitchfork over-expression in cultured palates induces primary cilia disassembly, alters Sonic hedgehog and Patched1 expression levels, and changes palatine rugae morphology, indicating a role in normal secondary palate morphogenesis. In situ expression analysis, in vitro palate culture with Pitchfork over-expression, immunostaining for primary cilia, Shh/Ptc1 expression analysis Cell and tissue research Medium 25080064
2021 GPRASP2 plays a key role in Hedgehog pathway signaling in the primary cilium through a Smoothened-GPRASP2-Pifo complex, and small compound inhibitors of this complex have been identified as potential treatments for drug-resistant Smoothened-derived cancers. Complex characterization (Smoothened-GPRASP2-Pifo), in vitro and in vivo functional experiments referenced in review context Current topics in medicinal chemistry Low 33267763
2022 Variants in PIFO (CIMAP3) were identified in patients with laterality defects in a whole-exome sequencing study, suggesting that dysfunction of PIFO results in laterality defects in humans. Whole-exome sequencing with CNV analysis in consanguineous families with laterality defects; patient variant identification Frontiers in genetics Low 35547246

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Bistability, bifurcations, and Waddington's epigenetic landscape. Current biology : CB 233 22677291
2010 Pitchfork regulates primary cilia disassembly and left-right asymmetry. Developmental cell 111 20643351
2019 Modeling Retinitis Pigmentosa: Retinal Organoids Generated From the iPSCs of a Patient With the USH2A Mutation Show Early Developmental Abnormalities. Frontiers in cellular neuroscience 70 31481876
2011 ASYMPTOTIC AND BIFURCATION ANALYSIS OF WAVE-PINNING IN A REACTION-DIFFUSION MODEL FOR CELL POLARIZATION. SIAM journal on applied mathematics 66 22171122
2011 A mathematical model for the reciprocal differentiation of T helper 17 cells and induced regulatory T cells. PLoS computational biology 58 21829337
2006 Diffusion of calcium and metabolites in pancreatic islets: killing oscillations with a pitchfork. Biophysical journal 52 16500973
2013 High-throughput deterministic single-cell encapsulation and droplet pairing, fusion, and shrinkage in a single microfluidic device. Electrophoresis 48 23856757
2009 Stochastic bifurcation, slow fluctuations, and bistability as an origin of biochemical complexity. Physical chemistry chemical physics : PCCP 46 19506761
2014 Exploring the mechanisms of differentiation, dedifferentiation, reprogramming and transdifferentiation. PloS one 41 25133589
2022 Epithelial-to-mesenchymal transition proceeds through directional destabilization of multidimensional attractor. eLife 34 35188459
2007 Dynamic patterns of gene regulation I: simple two-gene systems. Journal of theoretical biology 30 17337276
2024 RETINAL OPTICAL COHERENCE TOMOGRAPHY IMAGING BIOMARKERS: A Review of the Literature. Retina (Philadelphia, Pa.) 26 37903455
2016 Pitchfork and Gprasp2 Target Smoothened to the Primary Cilium for Hedgehog Pathway Activation. PloS one 24 26901434
2018 Identification of novel variants associated with osteoporosis, type 2 diabetes and potentially pleiotropic loci using pleiotropic cFDR method. Bone 19 30172742
2018 Molecular markers used in forensic genetics. Medicine, science, and the law 19 30269675
2017 Processes on the emergent landscapes of biochemical reaction networks and heterogeneous cell population dynamics: differentiation in living matters. Journal of the Royal Society, Interface 17 28490602
2021 GPRASP/ARMCX Protein Family: Potential Involvement in Health and Diseases Revealed by their Novel Interacting Partners. Current topics in medicinal chemistry 15 33267763
2014 Non-genetic heterogeneity, criticality and cell differentiation. Physical biology 14 25429686
1984 Regulation of the F-factor pif operon: pifO, a site required in cis for autoregulation, titrates the pifC product in trans. Journal of bacteriology 14 6090412
2020 Chiral stresses in nematic cell monolayers. Soft matter 13 31830190
2010 Focusing and trapping of DNA molecules by head-on ac electrokinetic streaming through join asymmetric polarization. Biomicrofluidics 10 20838480
2003 Modulated structures in electroconvection in nematic liquid crystals. Physical review. E, Statistical, nonlinear, and soft matter physics 10 12689082
1986 Mutational and in vivo methylation analysis of F-factor PifC protein binding to the pif operator and the region containing the primary origin of mini-F replication. Proceedings of the National Academy of Sciences of the United States of America 9 3513175
2022 Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases. Frontiers in genetics 8 35547246
2014 Breaking an epigenetic chromatin switch: curious features of hysteresis in Saccharomyces cerevisiae telomeric silencing. PloS one 8 25536038
2009 Pitchfork and Hopf bifurcation thresholds in stochastic equations with delayed feedback. Physical review. E, Statistical, nonlinear, and soft matter physics 8 20365203
2024 Mechanochemical dynamics of collective cells and hierarchical topological defects in multicellular lumens. Science advances 7 38691595
2021 Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity. Molecules (Basel, Switzerland) 7 34770976
2015 Subcriticality of the zigzag transition: A nonlinear bifurcation analysis. Physical review. E, Statistical, nonlinear, and soft matter physics 6 25871182
2014 Feedback mechanisms in a mechanical model of cell polarization. Physical biology 6 25313164
2025 Nonlinear Spontaneous Flow Instability in Active Nematics. Physical review letters 5 40577773
2023 Contractility-Induced Phase Separation in Active Solids. Physical review letters 5 37862637
2020 Read-through transcripts in lung: germline genetic regulation and correlation with the expression of other genes. Carcinogenesis 5 32157280
2023 Identification of potential molecular targets for the treatment of cluster 1 human pheochromocytoma and paraganglioma via comprehensive proteomic characterization. Clinical proteomics 4 37749499
2019 A three-pronged "Pitchfork" strategy enables an extensive description of the human membrane proteome and the identification of missing proteins. Journal of proteomics 4 31176011
2016 Dynamics of a double-stranded DNA segment in a shear flow. Physical review. E 4 27176342
2001 Wave fronts and spatiotemporal chaos in an array of coupled Lorenz oscillators. Physical review. E, Statistical, nonlinear, and soft matter physics 4 11415205
1986 The miniF plasmid C protein: sequence, purification and DNA binding. Nucleic acids research 4 3027660
2022 Robust controlled formation of Turing patterns in three-component systems. Physical review. E 3 35193238
2014 Morphological and molecular changes associated with Pitchfork during mouse palate development. Cell and tissue research 3 25080064
2012 Trajectories of Listeria-type motility in two dimensions. Physical review. E, Statistical, nonlinear, and soft matter physics 3 23367971
2011 Structural analysis of a 4414-bp element in Drosophila melanogaster. Genetics and molecular research : GMR 3 21523651
2010 Two-time-scale analysis of a ring of coupled vibratory gyroscopes. Physical review. E, Statistical, nonlinear, and soft matter physics 3 20365698
2025 Active gel theory for cell migration with two myosin isoforms. Physical review. E 1 40954809
2019 The correlative hypotheses between Pitchfork and Kif3a in palate development. Medical hypotheses 1 31010494
2025 A solvable neural circuit model revealing the dynamical principle of non-optimal temporal weighting in perceptual decision making. Journal of computational neuroscience 0 40728813
2024 Dynamics aspects and bifurcations of a tumor-immune system interaction under stationary immunotherapy. Mathematical biosciences 0 38232943
2020 Effect of parametric excitation on a bifractional-order damped system with a fractional-power nonlinearity. Chaos (Woodbury, N.Y.) 0 32113246
2017 Bogdanov-Takens bifurcations in the enzyme-catalyzed reaction comprising a branched network. Mathematical biosciences and engineering : MBE 0 29161873
2013 Pitchfork bifurcation in a receptor theory-based model of the serotonergic system. Molecular bioSystems 0 23694924
2004 9649 forensic web watch--DNA in forensic science. Journal of clinical forensic medicine 0 15704281

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