Affinage

ANKRD26

Ankyrin repeat domain-containing protein 26 · UniProt Q9UPS8

Length
1710 aa
Mass
196.4 kDa
Annotated
2026-04-28
48 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKRD26 is an ankyrin repeat protein that functions at centrosomes and the plasma membrane to integrate cytokine receptor signaling, centrosome surveillance, and ciliogenesis. During megakaryopoiesis, ANKRD26 is normally silenced by RUNX1/FLI1 binding to its 5′ UTR; gain-of-function mutations that prevent this silencing cause persistent ANKRD26 expression, which blocks internalization of type I cytokine receptors (MPL, EPOR, G-CSFR), hyperactivates MAPK/ERK signaling, and impairs proplatelet formation, causing thrombocytopenia 2 (THC2) with predisposition to myeloid malignancies (PMID:24430186, PMID:36794499, PMID:33857290). At centriolar distal appendages, ANKRD26 recruits PIDD1 to activate the PIDDosome–Caspase-2–MDM2–p53 axis as a checkpoint against centrosome amplification, and cooperates with TALPID3 to recruit FBF1 for cilia gating (PMID:33350486, PMID:32366837). ANKRD26 also uses an N-terminal amphipathic structure for plasma membrane binding and self-assembly, and its loss in mice causes obesity, hyperphagia, enhanced adipogenesis via constitutive ERK activation, and CNS ciliary defects (PMID:38493476, PMID:18162531, PMID:21669876, PMID:24633808).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    The first in vivo loss-of-function study established that ANKRD26 is required for metabolic homeostasis, as partial inactivation caused extreme obesity, hyperphagia, and insulin resistance linked to elevated Akt/mTOR signaling in mice.

    Evidence Mutant mouse model with metabolic phenotyping, hypothalamic immunohistochemistry, and western blot

    PMID:18162531

    Open questions at the time
    • Mechanism by which hypothalamic ANKRD26 controls appetite not defined
    • Direct molecular target in arcuate/ventromedial nuclei unknown
  2. 2011 High

    ANKRD26 was placed upstream of MAPK/ERK in adipogenesis: Ankrd26 disruption constitutively activated ERK and enhanced adipocyte differentiation, while separate reporter assays showed that THC2-associated 5′ UTR mutations increase rather than decrease ANKRD26 expression.

    Evidence Ankrd26−/− MEF adipogenesis assays with MEK inhibitor rescue; luciferase reporter assays with THC2 5′ UTR constructs

    PMID:21211618 PMID:21669876

    Open questions at the time
    • Mechanism connecting ANKRD26 to ERK activation (direct or indirect) not resolved
    • Reporter assays did not identify the specific trans-acting factors
  3. 2012 Medium

    Identification of direct protein partners (TRIO, GPS2, DIPA, HMMR) revealed that ANKRD26 sequesters nuclear factors to the cytoplasm and that each partner functionally opposes adipogenesis.

    Evidence Yeast two-hybrid, Co-IP, subcellular localization, siRNA knockdown in 3T3-L1 cells

    PMID:22666460

    Open questions at the time
    • Y2H interactions lack reciprocal validation in some cases
    • Stoichiometry and whether these form a single complex or separate binary interactions unknown
    • Relevance beyond adipogenesis not tested
  4. 2014 High

    The disease mechanism for THC2 was resolved: 5′ UTR mutations disrupt RUNX1/FLI1 binding, preventing transcriptional silencing of ANKRD26 during late megakaryopoiesis; persistent expression hyperactivates TPO/MPL–ERK signaling and blocks proplatelet formation, with ERK inhibition rescuing the defect.

    Evidence Patient-derived megakaryocytes, ChIP/binding assays for RUNX1/FLI1, ERK inhibitor rescue

    PMID:24430186

    Open questions at the time
    • Whether ANKRD26 directly binds MPL or acts via an adaptor not determined
    • Mechanism of leukemia predisposition not explained by ERK hyperactivation alone
  5. 2014 Medium

    The obesity phenotype was connected to ciliogenesis: Ankrd26 knockout mice showed defective primary cilia in CNS appetite-regulating centers, establishing a ciliopathy mechanism for the metabolic phenotype.

    Evidence Histological and electron microscopic analysis of cilia in Ankrd26−/− mouse CNS

    PMID:24633808

    Open questions at the time
    • Molecular role of ANKRD26 in cilia assembly versus maintenance not distinguished
    • Whether ciliary defects are cell-autonomous not tested
  6. 2020 High

    Two independent studies established ANKRD26 as a centriolar distal appendage protein that recruits PIDD1 to activate the PIDDosome checkpoint against centrosome amplification, and a parallel study showed ANKRD26 cooperates with TALPID3 to recruit FBF1 to transition fibers for cilia gating.

    Evidence Genome-wide screens, Co-IP, immunofluorescence, Caspase-2 activity assays, genetic epistasis in C. elegans and mammalian cells

    PMID:32366837 PMID:33350486 PMID:33350495

    Open questions at the time
    • How ANKRD26 is itself recruited to distal appendages not known
    • Whether cilia gating and PIDDosome functions are coordinated or independent unclear
    • Structural basis of ANKRD26–PIDD1 interaction not resolved
  7. 2023 High

    The receptor-level mechanism was clarified: elevated ANKRD26 directly interacts with and prevents internalization of MPL, EPOR, and G-CSFR, explaining cytokine hypersensitivity across multiple hematopoietic lineages in THC2.

    Evidence Co-IP in cell lines and patient iPSC-derived cells, receptor internalization and cytokine sensitivity assays

    PMID:36794499

    Open questions at the time
    • Binding interface on the receptors not mapped
    • Whether ANKRD26 blocks ubiquitin-dependent or clathrin-dependent internalization specifically is unknown
  8. 2024 Medium

    ANKRD26 was shown to bind and bend membranes via an N-terminal amphipathic structure, self-assemble into plasma membrane clusters in response to retinoic acid, and be required for neuroblastoma differentiation — with an AML-linked truncation abolishing membrane association.

    Evidence Live imaging, domain mutagenesis, gain/loss-of-function and rescue experiments in neuroblastoma cells

    PMID:38493476

    Open questions at the time
    • Lipid specificity of membrane binding not characterized
    • Relevance of membrane remodeling to megakaryocyte biology not tested
  9. 2024 Medium

    An ANKRD26–GPS2–ETV6 cytoplasmic retention axis was identified, explaining how ANKRD26 overexpression deregulates the tumor suppressor ETV6, providing a mechanistic link between THC2 and leukemia predisposition.

    Evidence Co-IP, subcellular localization, transcriptional reporter assays

    PMID:39791724

    Open questions at the time
    • Single study without independent replication
    • In vivo relevance to leukemogenesis not demonstrated
    • Whether GPS2 bridges or stabilizes the ANKRD26–ETV6 interaction directly is unclear
  10. 2025 Medium

    In polyploid megakaryocytes, elevated ANKRD26 drives apoptosis through JUNB-mediated CDKN1A (p21) induction independently of the canonical p53–PIDDosome pathway, revealing a p53-independent arm of ANKRD26 centrosomal signaling.

    Evidence Single-cell transcriptomics of patient bone marrow, confocal centrosome imaging in megakaryocytes

    PMID:41538704

    Open questions at the time
    • Mechanism linking centrosomal ANKRD26 to JUNB activation not defined
    • Single study requiring independent confirmation
    • Relationship to PIDDosome-dependent p21 induction in cardiomyocytes unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how ANKRD26 is recruited to distal appendages, whether its membrane-remodeling and centrosome functions are coordinated, the structural basis of receptor interaction and internalization blockade, and the mechanistic pathway from ANKRD26 overexpression to myeloid transformation.
  • No structural model of ANKRD26 or its complexes exists
  • Direct in vivo demonstration of leukemia initiation by ANKRD26 overexpression is lacking
  • Relative contribution of PIDDosome-dependent versus JUNB/p21-dependent pathways in megakaryocytes not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005886 plasma membrane 2 GO:0005929 cilium 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1640170 Cell Cycle 1
Partners
ETV6FBF1GPS2HMMRPIDD1TALPID3TRIO
Complex memberships
PIDDosome

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 THC2-associated mutations in the 5' UTR of ANKRD26 disrupt binding of transcription factors RUNX1 and FLI1, preventing ANKRD26 silencing during late megakaryopoiesis. Persistent ANKRD26 expression increases signaling via the TPO/MPL pathway and impairs proplatelet formation; ERK inhibition rescues proplatelet formation in vitro. Patient-derived megakaryocytes, reporter assays, RUNX1/FLI1 ChIP/binding assays, ERK inhibitor rescue experiments The Journal of clinical investigation High 24430186
2020 ANKRD26 localizes to centriolar distal appendages and recruits PIDD1 to this location; this interaction is required for PIDDosome activation (Caspase-2 cleavage of MDM2) following centrosome amplification, linking extra centrosomes to p53 stabilization and cell cycle arrest. Genome-wide screen, Co-IP, immunofluorescence localization, Caspase-2 activity assays, PIDD1 autoproteolysis assays, genetic knockouts The EMBO journal High 33350486 33350495
2020 TALPID3 and ANKRD26 form a complex with FBF1 at transition fibers (distal appendages) to regulate cilia gating; co-depletion of TALPID3 and ANKRD26 specifically impairs FBF1 recruitment to transition fibers in both C. elegans and mammalian cells. Forward genetic screen in C. elegans, Co-IP, immunofluorescence, genetic epistasis (double depletion), mammalian cell validation Nature communications High 32366837
2023 ANKRD26 interacts with and modulates the activity of three homodimeric type I cytokine receptors (MPL, EPOR, G-CSFR); elevated ANKRD26 prevents receptor internalization, leading to increased downstream signaling and cytokine hypersensitivity in erythroid, megakaryocyte, and granulocyte progenitors. Co-IP in cell lines and primary patient cells, patient-derived iPSC models, receptor internalization assays, cytokine sensitivity assays Haematologica High 36794499
2007 Partial inactivation of Ankrd26 in mice causes extreme obesity, insulin resistance, hyperphagia, and gigantism; the protein is expressed in hypothalamic arcuate and ventromedial nuclei, and loss leads to elevated phospho-Akt and mTOR in enlarged hearts. Mutant mouse model (partial gene inactivation), metabolic phenotyping, immunohistochemistry, western blot for phospho-Akt/mTOR Proceedings of the National Academy of Sciences of the United States of America High 18162531
2011 Ankrd26 disruption in mouse embryonic fibroblasts enhances adipogenesis via constitutive ERK activation; MEK inhibition blocks ERK activation and reduces adipogenesis induction, placing ANKRD26 upstream of ERK in the adipogenic pathway. Ankrd26-/- MEF adipogenesis assays, gene expression analysis, MEK inhibitor rescue experiments, western blot for phospho-ERK The Journal of biological chemistry High 21669876
2012 ANKRD26 interacts with TRIO, GPS2, DIPA, and HMMR (identified by yeast two-hybrid and co-immunoprecipitation); the C-terminus of ANKRD26 causes nuclear GPS2 and DIPA to translocate to the cytoplasm; knockdown of each partner increases adipogenesis in 3T3-L1 cells. Yeast two-hybrid, co-immunoprecipitation, subcellular localization by microscopy, siRNA knockdown with adipogenesis readout PloS one Medium 22666460
2014 Disruption of Ankrd26 causes defects in primary cilia in CNS regions controlling appetite and energy homeostasis, representing a novel ciliopathy mechanism underlying hyperphagia and obesity in Ankrd26 knockout mice. Ankrd26-/- mouse model, histological and electron microscopic analysis of primary cilia in CNS Brain structure & function Medium 24633808
2011 5' UTR mutations in ANKRD26 likely enhance ANKRD26 expression rather than cause haploinsufficiency, as demonstrated by luciferase reporter assay showing increased promoter activity with THC2-associated mutations. Luciferase reporter assay with 5' UTR constructs carrying THC2 mutations American journal of human genetics Medium 21211618
2017 N-terminal truncating ANKRD26 coding mutations (c.3G>A and c.105C>G) produce stable isoforms with strong ability to activate MAPK/ERK signaling, and are associated with ANKRD26 overexpression in AML patients. Patient cell functional studies, western blot, ERK signaling assays Journal of hematology & oncology Medium 28100250
2024 ANKRD26 uses an N-terminal amphipathic structure for plasma membrane binding and bending, self-associates to form clusters at the plasma membrane in response to retinoic acid, and is required for retinoic acid/BDNF-induced neuroblastoma differentiation; an AML-associated N-terminal truncating mutation abolishes membrane association and impairs differentiation. Subcellular localization by live imaging, gain-of-function and loss-of-function/rescue experiments, structural domain mutagenesis Cell reports Medium 38493476
2021 A large complex structural variant (paired-duplication inversion) creates a pathogenic gain-of-function WAC-ANKRD26 fusion transcript that causes inherited thrombocytopenia resembling THC2, demonstrating that persistent ANKRD26 expression (via fusion) during hematopoietic differentiation is the pathogenic mechanism. Long-read whole-genome sequencing, functional studies of fusion transcript expression and effect on ANKRD26 silencing The Journal of experimental medicine Medium 33857290
2024 ANKRD26 interacts with ETV6 and retains it in the cytoplasm; GPS2 (a component of the NCoR complex) binds both ANKRD26 and ETV6, mediating their interaction; ANKRD26 overexpression deregulates ETV6 transcriptional repression, revealing an ANKRD26-ETV6-GPS2 axis. Co-IP, subcellular localization studies, transcriptional reporter assays Cells Medium 39791724
2024 A novel 5' UTR variant (c.-107C>T) in the FLI1 binding site (not the RUNX1 site) of ANKRD26 disrupts FLI1 binding, sustains ANKRD26 expression in differentiating megakaryocytes, and impairs proplatelet formation, extending the functional regulatory region of ANKRD26. PBMCs differentiation assays, reporter assay, platelet ANKRD26 expression by qPCR, megakaryocyte functional studies Clinical genetics Medium 38757516
2025 Elevated ANKRD26 induces apoptosis in polyploid megakaryocytes via JUNB-mediated transcriptional activation of CDKN1A (p21), operating independently of the canonical p53-PIDDosome axis; ANKRD26 protein localizes to the centrosome in megakaryocytes. Single-cell transcriptomics of patient bone marrow, confocal imaging for centrosome localization, mechanistic pathway analysis in primary megakaryocytes Blood Medium 41538704
2024 PIDDosome activation requires ANKRD26 to target PIDD1 to mother centrioles in cardiomyocytes during postnatal heart development; this limits CM polyploidization in a p53-independent but p21/Cdkn1a-dependent manner. Genetic deletion of PIDDosome components, nuclear RNA sequencing, DNA content analyses, postnatal developmental time course experiments in mice bioRxivpreprint Medium

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 224 21467542
2011 Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. American journal of human genetics 174 21211618
2014 Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. The Journal of clinical investigation 141 24430186
2007 A model for obesity and gigantism due to disruption of the Ankrd26 gene. Proceedings of the National Academy of Sciences of the United States of America 60 18162531
2020 Centriolar distal appendages activate the centrosome-PIDDosome-p53 signalling axis via ANKRD26. The EMBO journal 59 33350486
2020 ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification. The EMBO journal 59 33350495
2012 Ubiquitin/proteasome-rich particulate cytoplasmic structures (PaCSs) in the platelets and megakaryocytes of ANKRD26-related thrombo-cytopenia. Thrombosis and haemostasis 49 23223974
2011 Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts. The Journal of biological chemistry 46 21669876
2017 5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia. Journal of hematology & oncology 37 28100250
2017 Specific CpG hyper-methylation leads to Ankrd26 gene down-regulation in white adipose tissue of a mouse model of diet-induced obesity. Scientific reports 37 28266632
2014 A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice. Brain structure & function 30 24633808
2012 ANKRD26 and its interacting partners TRIO, GPS2, HMMR and DIPA regulate adipogenesis in 3T3-L1 cells. PloS one 30 22666460
2017 Inherited thrombocytopenia caused by ANKRD26 mutations misdiagnosed and treated as myelodysplastic syndrome: report on two cases. Journal of thrombosis and haemostasis : JTH 28 28976612
2010 Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26. Journal of Cancer 26 20842219
2022 Exosome‑derived lncRNA‑Ankrd26 promotes dental pulp restoration by regulating miR‑150‑TLR4 signaling. Molecular medicine reports 25 35244185
2020 TALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating. Nature communications 23 32366837
2021 Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript. The Journal of experimental medicine 22 33857290
2022 Prevalence and natural history of variants in the ANKRD26 gene: a short review and update of reported cases. Platelets 21 35587581
2011 Partial inactivation of Ankrd26 causes diabetes with enhanced insulin responsiveness of adipose tissue in mice. Diabetologia 19 21842266
2022 ANKRD26-Related Thrombocytopenia and Predisposition to Myeloid Neoplasms. Current hematologic malignancy reports 18 35751752
2016 Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: A detailed phenotypic study of a family. Platelets 18 27123948
2019 Epigenetic silencing of the ANKRD26 gene correlates to the pro-inflammatory profile and increased cardio-metabolic risk factors in human obesity. Clinical epigenetics 16 31801613
2019 ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma. Cancer genetics 15 31425920
2018 An ANKRD26 nonsense somatic mutation in a female with epidermodysplasia verruciformis (Tree Man Syndrome). Clinical case reports 15 30147876
2017 Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation. Platelets 15 29185836
2011 Thrombocytopenias due to gray platelet syndrome or THC2 mutations. Seminars in thrombosis and hemostasis 10 22102272
2023 ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis. Haematologica 9 36794499
2020 Inherited Thrombocytopenia Caused by Germline ANKRD26 Mutation Should Be Considered in Young Patients With Suspected Myelodysplastic Syndrome. Journal of investigative medicine high impact case reports 9 32618208
2020 Relation between mutations in the 5' UTR of ANKRD26 gene and inherited thrombocytopenia with predisposition to myeloid malignancies. An Egyptian study. Platelets 6 32659145
2017 Idiopathic Pulmonary Embolism in a case of Severe Family ANKRD26 Thrombocytopenia. Mediterranean journal of hematology and infectious diseases 5 28698781
2024 Inherited thrombocytopenia associated with a variant in the FLI1 binding site in the 5' UTR of ANKRD26. Clinical genetics 3 38757516
2023 Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non-Langerhans cell histiocytosis: Case report and literature review. Journal of cutaneous pathology 3 36753059
2023 Analysis of clinical characteristics and treatment efficacy in two pediatric cases of ANKRD26-related thrombocytopenia. Platelets 3 37852929
2020 A novel RUNX1 mutation with ANKRD26 dysregulation is related to thrombocytopenia in a sporadic form of myelodysplastic syndrome. Aging clinical and experimental research 3 32944898
2020 Generation of the human induced pluripotent stem cell line (SHAMUi001-A) carrying the heterozygous c.-128G>T mutation in the 5'-UTR of the ANKRD26 gene. Stem cell research 3 32979630
2016 ANKRD26 normocytic thrombocytopenia: a family report. Annales de biologie clinique 3 27108925
2025 Chromosomal Deletion Involving ANKRD26 Leads to Expression of a Fusion Protein Responsible for ANKRD26-Related Thrombocytopenia. International journal of molecular sciences 2 40806462
2023 A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications. Journal of clinical medicine 2 37176611
2019 Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant. Case reports in hematology 2 31281687
2025 Modeling ANKRD26 5'-UTR mutation-related thrombocytopenia. Disease models & mechanisms 1 40170493
2024 Ankrd26 is a retinoic acid-responsive plasma membrane-binding and -shaping protein critical for proper cell differentiation. Cell reports 1 38493476
2024 Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree. Platelets 1 39212265
2023 ANKRD26 Gene Variant of Uncertain Significance in a Patient With Acute Myeloid Leukemia. Cureus 1 37065357
2026 Single-cell profiling of ANKRD26 thrombocytopenia reveals progenitor expansion and polyploid apoptosis via JUNB-p21. Blood 0 41538704
2026 Generation of an induced pluripotent stem cell line CGOi001-A from a patient with hereditary thrombocytopenia and a germline ANKRD26 mutation. Stem cell research 0 41643484
2025 ANKRD26 Gene Mutation and Thrombocytopenia-Is the Risk of Malignancy Dependent on the Mutation Variant? Hematology reports 0 40863182
2025 Differential transcript level of ANKRD26 and clinical phenotype among the ANKRD26 variants in the Japanese registry for congenital thrombocytopenia. British journal of haematology 0 40954090
2024 Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6. Cells 0 39791724