Affinage

KTN1

Kinectin · UniProt Q86UP2

Length
1357 aa
Mass
156.3 kDa
Annotated
2026-06-10
49 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/2 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KTN1 (kinectin 1) is an integral endoplasmic reticulum membrane protein that organizes ER sheet architecture and links ER membranes to cytoskeletal motors [PMID:bio_10.1101_2024.11.06.622207]. It serves as the membrane anchor for the dynein adaptor CDR2, recruiting CDR2-dynein complexes to ER sheets; loss of CDR2 and its paralog CDR2L enhances KTN1-dependent ER sheet stacking, while exogenous CDR2 bearing its dynein-binding CC1 box motif reverses stacking and clusters ER sheets near the centrosome, and CDR2 competes with the translation elongation factor subunit eEF1Bβ for the same KTN1 binding site [PMID:bio_10.1101_2024.11.06.622207]. KTN1 also supports the unfolded protein response: its expression is induced by ionizing radiation in keratinocytes, and KTN1 depletion reduces ER expansion and lowers PERK, IRE1α, and ATF6 levels, aggravating DNA damage and suppressing proliferation in a manner reversed by pharmacological UPR reactivation (PMID:38448340). In epithelial cancers KTN1 acts downstream of transcriptional regulators to drive malignant phenotypes—it is a mediator of MALAT1/c-MYC control of EGFR protein levels in cutaneous squamous cell carcinoma (PMID:30683916) and promotes proliferation, invasion, and migration through Rho GTPase (RAC1, RHOA, CDC42) signaling in bladder cancer (PMID:33480975), with its loss impairing viability and arresting the cell cycle in hepatocellular carcinoma cells (PMID:34234850).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2019 Medium

    Established KTN1 as a functional effector node linking an oncogenic transcriptional axis to growth-factor receptor levels, answering how MALAT1/c-MYC controls EGFR.

    Evidence Transcriptomics, promoter binding and Co-IP with gain/loss-of-function in cutaneous squamous cell carcinoma cells and xenografts

    PMID:30683916

    Open questions at the time
    • Mechanism by which KTN1 raises EGFR protein but not mRNA is not defined
    • Whether this depends on KTN1's ER membrane role is untested
  2. 2021 Medium

    Connected KTN1 to actin-regulatory Rho GTPase signaling and identified a cis-acting lncRNA mechanism (KTN1-AS1/EP300) driving its expression, explaining how KTN1 promotes invasion.

    Evidence RIP, ChIP, and KTN1-AS1 knockdown/overexpression with proliferation/invasion/migration assays in bladder cancer models

    PMID:33480975

    Open questions at the time
    • Direct biochemical link between KTN1 and RAC1/RHOA/CDC42 activation not resolved
    • Whether Rho activation requires the ER-anchored protein is unknown
  3. 2021 Medium

    Defined KTN1 as required for cancer cell cycle progression and survival, placing it within proliferation and DNA replication cascades.

    Evidence CRISPR/Cas9 knockout with RNA-seq and viability/migration/apoptosis/cell-cycle assays in Huh7 hepatocellular carcinoma cells

    PMID:34234850

    Open questions at the time
    • Transcriptomic deregulation is correlative; direct targets unidentified
    • Molecular basis of G0/G1 arrest after KTN1 loss not established
  4. 2024 Medium

    Revealed a protective ER-stress function: KTN1 promotes ER expansion and UPR signaling to limit genotoxic damage, answering how it buffers cells against ionizing radiation.

    Evidence TEM, immunoblotting, siRNA, and pharmacological UPR inhibition/activation (4-PBA/tunicamycin) with DNA damage and proliferation readouts in keratinocytes

    PMID:38448340

    Open questions at the time
    • How KTN1 mechanistically activates PERK/IRE1α/ATF6 is unknown
    • Whether UPR support and cancer phenotypes share a common mechanism is untested
  5. 2024 High

    Resolved KTN1's core molecular activity—anchoring CDR2-dynein complexes to organize ER sheet architecture—and identified competitive occupancy of its binding site by eEF1Bβ.

    Evidence Co-IP/pulldown, CDR2/CDR2L double-knockout cells, CC1-box mutant rescue, and eEF1Bβ knockdown with ER morphology assays (preprint)

    PMID:bio_10.1101_2024.11.06.622207

    Open questions at the time
    • Functional consequence of eEF1Bβ competition for translation or ER shape not defined
    • Structural basis of the shared KTN1 binding site is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether KTN1's ER-shaping/dynein-anchoring role mechanistically underlies its UPR-protective and pro-tumorigenic functions remains unresolved.
  • No study links the CDR2-dynein anchoring mechanism to EGFR or Rho GTPase phenotypes
  • No structural model of KTN1 binding interfaces
  • Direct biochemical bridge from KTN1 to UPR sensor activation is missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-8953897 Cellular responses to stimuli 1
Partners
CDR2EEF1BΒ

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 KTN1 protein acts as a key mediator downstream of MALAT1/c-MYC in regulating EGFR protein expression. Mechanistically, MALAT1 interacts with c-MYC to form a complex that directly binds the KTN1 promoter and enhances its transactivation, which in turn positively regulates EGFR protein (but not mRNA) expression in cutaneous squamous cell carcinoma cells. Transcriptomic sequencing, promoter binding assays, co-immunoprecipitation, gain/loss-of-function experiments with phenotypic readouts in vitro and in vivo xenograft models Cell death and differentiation Medium 30683916
2021 KTN1 protein promotes bladder cancer cell proliferation, invasion, and migration via activation of Rho GTPase-mediated signaling (RAC1, RHOA, CDC42). The lncRNA KTN1-AS1 recruits the histone acetyltransferase EP300 to the KTN1 promoter, enriching H3K27 acetylation and thereby upregulating KTN1 expression in cis. RNA immunoprecipitation, chromatin immunoprecipitation (ChIP), KTN1-AS1 knockdown/overexpression with cell proliferation/invasion/migration assays, in vitro and in vivo systems Clinical science (London, England : 1979) Medium 33480975
2021 KTN1 knockout in Huh7 hepatocellular carcinoma cells inhibited cell viability, migration, and invasion, increased the G0/G1 cell cycle fraction, and elevated apoptosis rates. RNA sequencing after KTN1 knockout revealed deregulation of innate immune response, chemical carcinogenesis, and RNA polymerase II transcription pathways, placing KTN1 in cell cycle and DNA replication cascades. CRISPR/Cas9 knockout, RNA sequencing, cell migration/invasion/viability/apoptosis assays Journal of Cancer Medium 34234850
2024 KTN1 is an endoplasmic reticulum protein whose expression is upregulated by ionizing radiation (IR) in keratinocytes. KTN1 depletion reduced ER expansion and downregulated UPR pathway proteins (PERK, IRE1α, ATF6), aggravating IR-induced DNA damage and suppressing cell proliferation. Reactivation of UPR (with tunicamycin) reversed the effects of KTN1 depletion, establishing that KTN1 protects keratinocytes from IR-induced DNA damage through its role in promoting the unfolded protein response. Transmission electron microscopy, immunoblotting, siRNA knockdown, pharmacological UPR inhibition (4-PBA) and activation (tunicamycin), cell proliferation assays, DNA damage readouts Journal of dermatological science Medium 38448340
2024 KTN1 (kinectin), an integral ER membrane protein, recruits the dynein adaptor CDR2 to ER sheets. Loss of CDR2 and its paralog CDR2L enhances KTN1-dependent ER sheet stacking. Exogenous CDR2 (requiring its dynein-binding CC1 box motif) reverses this stacking and promotes centrosome-proximal clustering of ER sheets, demonstrating that KTN1 organizes ER sheet architecture by serving as the membrane anchor for CDR2-dynein complexes. CDR2 competes with eEF1Bβ (translation elongation factor 1 subunit) for binding to KTN1. Biochemical assays (Co-IP/pulldown), double knockout cell lines, exogenous rescue with wild-type and CC1-box mutant CDR2, siRNA knockdown of eEF1Bβ, cell-based ER morphology assays bioRxivpreprint High bio_10.1101_2024.11.06.622207

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The novel δ opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions. Behavioural brain research 86 21565223
2010 Design and synthesis of KNT-127, a δ-opioid receptor agonist effective by systemic administration. Bioorganic & medicinal chemistry letters 68 20850307
2018 LncRNA KTN1-AS1 promotes tumor growth of hepatocellular carcinoma by targeting miR-23c/ERBB2IP axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 64 30551364
2020 LncRNA KTN1-AS1 promotes the progression of non-small cell lung cancer via sponging of miR-130a-5p and activation of PDPK1. Oncogene 49 32820252
2019 MALAT1-KTN1-EGFR regulatory axis promotes the development of cutaneous squamous cell carcinoma. Cell death and differentiation 47 30683916
2014 In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice. British journal of pharmacology 40 25048778
2012 The novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats without producing the adverse effects associated with benzodiazepines. Neuropharmacology 38 23246531
2012 Novel δ1-receptor agonist KNT-127 increases the release of dopamine and L-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex. Neuropharmacology 30 22266218
2020 Long noncoding RNA KTN1-AS1 promotes head and neck squamous cell carcinoma cell epithelial-mesenchymal transition by targeting miR-153-3p. Epigenomics 28 32267161
2016 Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats. Behavioural brain research 23 27916688
2017 The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice. Behavioural brain research 22 28864205
2020 lncRNA KTN1‑AS1 promotes glioma cell proliferation and invasion by negatively regulating miR‑505‑3p. Oncology reports 21 33125151
2021 The long noncoding RNA KTN1-AS1 promotes bladder cancer tumorigenesis via KTN1 cis-activation and the consequent initiation of Rho GTPase-mediated signaling. Clinical science (London, England : 1979) 20 33480975
2020 A non-convulsant delta-opioid receptor agonist, KNT-127, reduces cortical spreading depression and nitroglycerin-induced allodynia. Headache 18 33326598
2013 DOR(2)-selective but not DOR(1)-selective antagonist abolishes anxiolytic-like effects of the δ opioid receptor agonist KNT-127. Neuropharmacology 17 24333676
2019 Selective agonists of the δ-opioid receptor, KNT-127 and SNC80, act differentially on extinction learning of contextual fear memory in mice. Neuropharmacology 16 31553899
2013 The most effective influence of 17-(3-ethoxypropyl) substituent on the binding affinity and the agonistic activity in KNT-127 derivatives, δ opioid receptor agonists. Bioorganic & medicinal chemistry 14 24262888
2023 KNT-127, a selective delta opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a chronic vicarious social defeat stress mouse model. Neuropharmacology 12 37001727
2022 H3K27ac-activated lncRNA KTN1-AS1 aggravates tumor progression by miR-505-3p/ZNF326 axis in ovarian cancer. Annals of translational medicine 12 35722429
2001 Electron microscopic observation of established chondrocytes derived from human intervertebral disc hernia (KTN-1) and role of macrophages in spontaneous regression of degenerated tissues. The spine journal : official journal of the North American Spine Society 12 14588300
2022 The lncRNA KTN1-AS1 co-regulates a variety of Myc-target genes and enhances proliferation of Burkitt lymphoma cells. Human molecular genetics 11 35866590
2022 KTN1-AS1, a SOX2-mediated lncRNA, activates epithelial-mesenchymal transition process in esophageal squamous cell carcinoma. Scientific reports 11 36418920
2021 Long non-coding RNA KTN1-AS1 promotes progression in pancreatic cancer through regulating microRNA-23b-3p/high-mobility group box 2 axis. Aging 11 34461605
2018 A delta opioid receptor agonist, KNT-127, in the prelimbic medial prefrontal cortex attenuates glial glutamate transporter blocker-induced anxiety-like behavior in mice. Journal of pharmacological sciences 11 30322803
2022 Selective δ-Opioid Receptor Agonist, KNT-127, Facilitates Contextual Fear Extinction via Infralimbic Cortex and Amygdala in Mice. Frontiers in behavioral neuroscience 10 35264937
2021 Upregulating KTN1 promotes Hepatocellular Carcinoma progression. Journal of Cancer 10 34234850
2020 KTN1 variants and risk for attention deficit hyperactivity disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 10 32190980
2018 Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats. Psychopharmacology 10 30066134
2021 A selective delta opioid receptor agonist SNC80, but not KNT-127, induced tremor-like behaviors via hippocampal glutamatergic system in mice. Brain research 9 33516811
2020 Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence. Addiction biology 9 32115811
2020 KTN1 Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease. Frontiers in neuroscience 8 32655362
2017 Effects of the delta opioid receptor agonist KNT-127 on electroencephalographic activity in mice. Pharmacological reports : PR 8 29477045
2023 The delta opioid receptor agonist KNT-127 relieves innate anxiety-like behavior in mice by suppressing transmission from the prelimbic cortex to basolateral amygdala. Neuropsychopharmacology reports 7 38156409
2021 Long noncoding RNA KTN1 antisense RNA 1exerts an oncogenic function in lung adenocarcinoma by regulating DEP domain containing 1 expression via activating epithelial-mesenchymal transition. Anti-cancer drugs 7 33491970
2019 Systemic administration of a delta opioid receptor agonist, KNT-127, facilitates extinction learning of fear memory in rats. Journal of pharmacological sciences 7 30686587
2023 LncRNA KTN1-AS1 facilitates esophageal squamous cell carcinoma progression via miR-885-5p/STRN3 axis. Genes & genomics 6 37747640
2023 Long Non-coding RNA KTN1-AS1 Targets miR-505 to Promote Glioblastoma Progression. Behavioural neurology 5 36762036
2024 KTN1 mediated unfolded protein response protects keratinocytes from ionizing radiation-induced DNA damage. Journal of dermatological science 3 38448340
2023 Male-specific, replicable and functional roles of genetic variants and cerebral gray matter volumes in ADHD: a gene-wide association study across KTN1 and a region-wide functional validation across brain. Child and adolescent psychiatry and mental health 3 36609385
2022 Role for μ-opioid receptor in antidepressant effects of δ-opioid receptor agonist KNT-127. Journal of pharmacological sciences 3 36828615
2020 Associations of attention distractibility with attention deficit and with variation in the KTN1 gene. Neuroscience letters 3 32956741
2025 Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part II: Quinoline Ring Modifications for Enhanced G-Protein Signaling and Reduced β-Arrestin Recruitment. Chemical & pharmaceutical bulletin 2 40204491
2023 A significant, functional and replicable risk KTN1 variant block for schizophrenia. Scientific reports 2 36890161
2022 IncRNA KTN1-AS1 Silencing Inhibits Non-Small-Cell Lung Cancer Cell Proliferation and KTN1-AS1 Expression Predicts Survival. Critical reviews in eukaryotic gene expression 2 35381130
1997 Morphological and morphometric features of the deformed cervical and caudal vertebrae in a new mutant knotty-tail (knt/knt) mouse. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 2 9229083
2025 Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part I: Impact of the Morphinan Skeleton on the G-Protein-Biased DOR Agonism. Chemical & pharmaceutical bulletin 1 40159181
2026 Bioproduction of ∼10 knt single-stranded DNA for constructing large DNA origami structures. Materials today. Bio 0 42100002
2023 A genetic and transcriptomic assessment of the KTN1 gene in Parkinson's disease risk. Neurobiology of aging 0 37992546
2020 [Structural variations caused by transposons in porcine ktn1 gene and their association with production traits]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 0 32147999

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