Affinage

ANKS1A

Ankyrin repeat and SAM domain-containing protein 1A · UniProt Q92625

Length
1134 aa
Mass
123.1 kDa
Annotated
2026-06-09
10 papers in source corpus 9 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKS1A (Odin) is a phosphotyrosine-binding (PTB) domain adaptor that controls the selective ER export and surface trafficking of cargo receptor tyrosine kinases and related receptors (PMID:27619642, PMID:27802842, PMID:38123547). Upon serine phosphorylation it localizes to the ER membrane, where its ankyrin repeat domain engages EphA2 to drive accumulation at ER exit sites and its PTB domain binds the COPII coat component Sec23, coupling EphA2 (and EphA2-associated ErbB2) into COPII carriers for cell-surface delivery (PMID:27619642, PMID:27802842). By the same adaptor logic, ANKS1A associates with the NPXY motifs of LRP1 to promote LRP1 transport from the ER to the surface of brain endothelial cells; loss of endothelial ANKS1A reduces surface LRP1, impairs Aβ clearance across the blood-brain barrier, and worsens Alzheimer's-like pathology and cognitive deficits in mice (PMID:38123547). At the cell surface ANKS1A is itself tyrosine-phosphorylated by Src family kinases (PMID:18844995) and acts as an effector of EGFR post-endocytic sorting, promoting recycling of internalized EGFR back to the plasma membrane while limiting its lysosomal degradation (PMID:23825523). In the postnatal brain ANKS1A is required for ependymal cell differentiation, with deficiency causing a differentiation arrest toward a radial glial-like state (PMID:30759972), and it restrains aberrant entry of IFT machinery and ciliary membrane proteins such as Vangl2 into multicilia (PMID:38052491).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2008 Medium

    Established ANKS1A as a phosphoprotein under tyrosine kinase control, placing it downstream of Src family kinase signaling in cancer cells before its adaptor function was known.

    Evidence LckSH2 affinity chromatography plus mass spectrometry and SFK-inhibitor phosphotyrosine western blot in SW620 colorectal cancer cells

    PMID:18844995

    Open questions at the time
    • Specific phosphotyrosine sites not mapped
    • Functional consequence of SFK phosphorylation not addressed
    • Single cell-line context
  2. 2013 Medium

    Assigned a cellular trafficking role to ANKS1A by showing it directs EGFR toward recycling rather than degradation, linking its tyrosine phosphorylation to receptor fate decisions.

    Evidence EGFR recycling/lysosomal trafficking assays with Odin overexpression and siRNA knockdown in HEK293 and NSCLC cells, plus phosphotyrosine time-course

    PMID:23825523

    Open questions at the time
    • Direct EGFR-ANKS1A interaction not demonstrated
    • Molecular mechanism of recycling control unresolved
    • Single lab
  3. 2016 High

    Defined the core adaptor mechanism: ANKS1A bridges EphA2 (ankyrin repeats) to the COPII subunit Sec23 (PTB domain) to drive selective ER export of EphA2/ErbB2, explaining how it regulates surface receptor levels.

    Evidence Reciprocal Co-IP with domain mapping, COPII vesicle reconstitution, ER-exit-site localization, and Anks1a KO mouse with ErbB2 tumorigenesis readout

    PMID:27619642 PMID:27802842

    Open questions at the time
    • Trigger for the ER-localizing serine phosphorylation not identified
    • Whether the same machinery operates for other cargoes not addressed here
    • No structural model of the ternary cargo-adaptor-COPII assembly
  4. 2019 Medium

    Extended ANKS1A function into tissue development by showing it is required for ependymal cell differentiation in the postnatal brain.

    Evidence Anks1a gene-trap LacZ expression mapping, KO analysis of ependymal markers, and overexpression in neonatal lateral wall

    PMID:30759972

    Open questions at the time
    • Molecular cargo or signaling pathway driving differentiation not identified
    • Connection to the COPII/adaptor mechanism not established
    • Single lab
  5. 2022 Low

    Proposed a surface signaling role linking ANKS1A to actin-based migration via the small GTPase Rac1.

    Evidence Co-IP of Anks1a with GTPγS-loaded Rac1 and migration assays in breast cancer cell lines with knockdown/overexpression

    PMID:36717454

    Open questions at the time
    • Single Co-IP without reciprocal validation for the Rac1 interaction
    • Migration effects modest and cell-line dependent
    • Mechanism connecting Rac1 binding to motility unresolved
  6. 2023 High

    Generalized the ER-export adaptor model to LRP1 in brain endothelium and tied ANKS1A directly to blood-brain-barrier Aβ clearance and Alzheimer's pathology.

    Evidence Co-IP with LRP1 NPXY motifs, surface biotinylation, ANKS1A KO crossed with an AD model with endothelial gene-therapy rescue, and human iPSC-derived BBB organoids

    PMID:38123547

    Open questions at the time
    • Whether Sec23/COPII mediates LRP1 export as for EphA2 not directly shown
    • Contribution of non-endothelial ANKS1A to Aβ handling not addressed
  7. 2023 Medium

    Identified a ciliary surveillance function whereby ANKS1A limits aberrant IFT and membrane protein entry into multicilia.

    Evidence Immunofluorescence of isolated cilia and ECV isolation from ANKS1A KO ependymal cells, quantifying IFT88 trains and Vangl2

    PMID:38052491

    Open questions at the time
    • Molecular mechanism by which ANKS1A gates ciliary entry unknown
    • Relationship to its ER-export adaptor role unclear
    • Single lab
  8. 2023 Low

    Implicated ANKS1A in maintaining blood-brain-barrier integrity during aging through prevention of CCM-like vascular lesions.

    Evidence Histology and immunofluorescence of aged ANKS1A KO mouse brain vasculature plus cultured endothelial fibronectin assay

    PMID:38196138

    Open questions at the time
    • Causal pathway from ANKS1A loss to lesion formation not resolved
    • Link to LRP1/receptor trafficking not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what signal triggers the serine phosphorylation that recruits ANKS1A to the ER and whether a single adaptor mechanism unifies its roles in COPII export, EGFR recycling, ciliary gating, and vascular maintenance.
  • Upstream kinase for ER-localizing serine phosphorylation unidentified
  • No structural model of the cargo-PTB-Sec23 assembly
  • Mechanistic link between trafficking and developmental/ciliary phenotypes unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 2
Partners
EPHA2ERBB2LRP1RAC1SEC23

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Anks1a localizes to the ER membrane upon serine phosphorylation. Once at the ER, its ankyrin repeat domain binds EphA2 causing it to accumulate at ER exit sites, while its PTB domain binds Sec23, together facilitating selective COPII-mediated ER export of EphA2. EphA2 in turn binds ErbB2 in the ER and loads ErbB2 into COPII carriers, enabling ErbB2 cell surface delivery. Subcellular fractionation/localization, co-immunoprecipitation of Anks1a with EphA2 and Sec23, domain mapping (ankyrin repeat vs PTB), COPII vesicle assay, Anks1a knockout mouse model with ErbB2-induced tumorigenesis readout, knockdown of Anks1a in primary mammary tumor cells Nature communications High 27619642 27802842
2023 ANKS1A associates with the NPXY motifs of LRP1 and facilitates transport of LRP1 from the endoplasmic reticulum to the cell surface in brain endothelial cells. Endothelial ANKS1A deficiency reduces cell-surface LRP1 levels and impairs Aβ clearance across the blood-brain barrier, worsening Aβ pathology and cognitive deficits in an Alzheimer's disease mouse model. Co-immunoprecipitation (ANKS1A with LRP1 NPXY motifs), cell-surface biotinylation, ANKS1A KO mouse crossed with AD model, gene therapy rescue with endothelial-specific ANKS1A, iPSC-derived BBB organoids from ANKS1A-null or rs6930932-variant cells Nature communications High 38123547
2013 Odin (ANKS1A) functions as an effector of EGFR recycling: tyrosine phosphorylation of Odin is induced prior to EGFR internalization after EGF stimulation. Odin overexpression increases EGFR trafficking to recycling endosomes and back to the cell surface, while Odin knockdown decreases EGFR recycling and accelerates lysosomal trafficking and degradation. EGFR trafficking assays (recycling endosome and lysosome fractionation/imaging), Odin overexpression and siRNA knockdown in HEK293 and NSCLC RVH6849 cells, phosphotyrosine time-course analysis PloS one Medium 23825523
2008 Odin (ANKS1A) is a substrate of Src family kinases (SFK) in colorectal cancer cells: Odin tyrosine phosphorylation is substantially reduced upon SFK inhibition in SW620 cells, identifying it as a novel SFK target in epithelial cancer cells. LckSH2 domain affinity chromatography followed by mass spectrometry to identify phosphotyrosine proteins; SFK inhibitor treatment with phosphotyrosine western blot confirmation Cell communication and signaling : CCS Medium 18844995
2019 Anks1a PTB adaptor is required for proper differentiation of ependymal cells in the postnatal rodent brain: Anks1a-deficient ependymal cells display type B cell (radial glial-like) characteristics indicating a differentiation arrest, while Anks1a overexpression in the lateral wall increases ependymal cell numbers. Anks1a gene-trap LacZ reporter for expression mapping, Anks1a KO mouse analysis of ependymal cell markers, Anks1a overexpression in neonatal brain lateral wall Molecules and cells Medium 30759972
2023 ANKS1A deficiency in ependymal cells increases entry of IFT (intraflagellar transport) machinery (IFT88-positive trains) into multicilia, leads to increased extracellular vesicle (ECV) formation along cilia, and causes accumulation of the ciliary membrane protein Vangl2 in cilia and ECVs, suggesting ANKS1A normally limits aberrant protein entry into cilia and that ECV-based disposal compensates for its absence. Immunofluorescence of isolated cilia from ANKS1A KO ependymal cells, primary ependymal culture ECV isolation, IFT88 and Vangl2 quantification by imaging and western blot Molecules and cells Medium 38052491
2022 Anks1a interacts with the activated (GTP-bound) form of Rac1 and acts as a Rac1 effector. In HER2-negative MDA-MB-231 breast cancer cells, Anks1a accumulates at the active cell edge enriched with active Rac1. Overexpression of Anks1a selectively increases migration rate of HER2-overexpressing SK-BR-3 cells. Downregulation of ANKS1A had minimal effect on motility except a slight increase in MDA-MB-231 migration rate. Co-immunoprecipitation of Anks1a with activated Rac1 (GTPγS-loaded), live-cell imaging of migration, esiRNA knockdown and overexpression in breast cancer cell lines Biochemistry. Biokhimiia Low 36717454
2023 ANKS1A deficiency in aged mouse brain endothelial cells leads to CCM-like vessel lesions with peripheral blood leakage, immune cell infiltration, loss of astrocyte endfeet and tight junctions, and increased fibronectin expression in blood vessels (confirmed in cultured ANKS1A-deficient endothelial cells), indicating a role for ANKS1A in maintaining BBB integrity during aging. ANKS1A KO mouse histological analysis of aged brain vasculature, immunofluorescence for tight junction proteins, astrocyte endfeet markers, fibronectin; cultured endothelial cell fibronectin assay Experimental neurobiology Low 38196138

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells. Nature communications 27 38123547
2016 Anks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis. Nature communications 25 27619642
2008 Odin (ANKS1A) is a Src family kinase target in colorectal cancer cells. Cell communication and signaling : CCS 25 18844995
2013 Odin (ANKS1A) modulates EGF receptor recycling and stability. PloS one 20 23825523
2019 Ependymal Cells Require Anks1a for Their Proper Development. Molecules and cells 8 30759972
2021 ANKS1A genotype predicts cardiovascular events in patients with familial hypercholesterolemia. Journal of clinical lipidology 4 34130940
2023 ANKS1A-Deficiency Aberrantly Increases the Entry of the Protein Transport Machinery into the Ependymal Cilia. Molecules and cells 3 38052491
2016 Defective Anks1a disrupts the export of receptor tyrosine kinases from the endoplasmic reticulum. BMB reports 3 27802842
2022 The Role of the Adapter Protein Anks1a in the Regulation of Breast Cancer Cell Motility. Biochemistry. Biokhimiia 1 36717454
2023 Cerebral Cavernous Malformation (CCM)-like Vessel Lesion in the Aged ANKS1A-deficient Brain. Experimental neurobiology 0 38196138

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