Affinage

TMEM97

Sigma intracellular receptor 2 · UniProt Q5BJF2

Length
176 aa
Mass
20.8 kDa
Annotated
2026-04-28
57 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM97 (sigma-2 receptor) is a multifunctional integral membrane protein that regulates cholesterol trafficking, receptor-mediated endocytosis, calcium signaling, inflammatory responses, and stress pathways. It forms a ternary complex with PGRMC1 and LDLR that is required for rapid internalization of LDL, Aβ42, and apoE (PMID:30443021, PMID:32572762), and it binds NPC1 to control its protein levels post-transcriptionally, thereby governing lysosomal cholesterol egress via an ER-retention-signal-dependent mechanism (PMID:27378690). TMEM97 modulates store-operated calcium entry by reducing cholesterol association with the Orai1 channel, as demonstrated by a cholesterol-insensitive Orai1 mutant that abolishes TMEM97-dependent SOCE regulation (PMID:33618021). In retinal pigment epithelium, TMEM97 drives pro-inflammatory cytokine expression through a BAHCC1–NFκB cascade and controls partial EMT via the CTNND2–ADAM10 axis, while in nociceptors it modulates the integrated stress response to regulate neuropathic pain, as confirmed by genetic knockout (PMID:38290642, PMID:39995975, PMID:38117854).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2014 Low

    Computational analysis first predicted that TMEM97 might possess sterol isomerase activity based on a conserved EXPERA domain shared with EBP, raising the question of whether TMEM97 directly participates in sterol metabolism.

    Evidence Sequence conservation analysis of TMEM97, EBP, and TM6SF protein families

    PMID:25566323

    Open questions at the time
    • Predicted enzymatic activity has never been experimentally validated
    • No substrate or product identified for TMEM97 isomerase activity
    • Computational prediction from a single study
  2. 2016 High

    The first direct mechanistic link between TMEM97 and cholesterol trafficking was established: TMEM97 binds NPC1 and post-transcriptionally controls its protein levels, with an ER-retention signal on TMEM97 required for this function, showing that TMEM97 loss can partially rescue cholesterol egress defects in NPC1-mutant cells.

    Evidence Co-immunoprecipitation, RNAi, ER-retention-signal deletion mutant, cholesterol trafficking assays in NPC1-mutant patient fibroblasts

    PMID:27378690

    Open questions at the time
    • Mechanism by which TMEM97 controls NPC1 protein stability is undefined
    • Whether TMEM97-NPC1 regulation occurs in all tissues is untested
  3. 2018 High

    TMEM97 was identified as the molecular identity of the sigma-2 receptor and shown to form a ternary complex with PGRMC1 and LDLR required for rapid LDL internalization, establishing TMEM97's role as a key regulator of receptor-mediated lipoprotein endocytosis.

    Evidence CRISPR KO in HeLa cells, radioligand binding, proximity ligation assay, fluorescent/radiolabeled LDL uptake, epistasis analysis of double KO

    PMID:30443021

    Open questions at the time
    • Structural basis of the ternary complex is unknown
    • Whether TMEM97 directly contacts LDLR or acts through PGRMC1 is unresolved
  4. 2018 Medium

    Pharmacological evidence first linked TMEM97/sigma-2 receptor to neuropathic pain, showing that sigma-2 agonists relieve mechanical hypersensitivity and that TMEM97 is expressed in DRG nociceptors, opening the question of the downstream signaling mechanism.

    Evidence Spared nerve injury mouse model, intrathecal and systemic drug administration, pharmacological antagonism

    PMID:28644012

    Open questions at the time
    • No genetic KO validation in this study (later confirmed)
    • Molecular mechanism of antinociception not defined here
  5. 2019 High

    A critical boundary condition was established: although TMEM97/PGRMC1 mediate sigma-2 ligand internalization, they do not mediate sigma-2 ligand-induced cytotoxicity, separating the ligand uptake function from cell death pathways.

    Evidence CRISPR KO of TMEM97 and/or PGRMC1 in HeLa cells, EC50 measurements for multiple sigma-2 ligands, fluorescent ligand internalization

    PMID:30701090

    Open questions at the time
    • Identity of the cytotoxic target of sigma-2 ligands remains unknown
    • Whether TMEM97-independent cytotoxicity reflects off-target effects is unresolved
  6. 2020 Medium

    The ternary TMEM97/PGRMC1/LDLR complex was shown to extend beyond LDL to mediate internalization of Aβ42 and apoE in primary neurons, linking TMEM97 to Alzheimer's disease-relevant cargo uptake.

    Evidence CRISPR KO and pharmacological inhibition in primary neurons, fluorescence-based internalization assays for Aβ42 and apoE

    PMID:32572762

    Open questions at the time
    • In vivo relevance of TMEM97-mediated Aβ42 uptake to AD pathology is untested
    • Whether this complex mediates Aβ clearance or Aβ toxicity is unresolved
  7. 2020 Medium

    TMEM97 was linked to store-operated calcium entry regulation, with silencing impairing SOCE and reducing STIM1-Orai1 interaction in breast cancer cells, opening a new axis of TMEM97 function beyond cholesterol trafficking.

    Evidence siRNA silencing, SOCE calcium imaging, STIM1-Orai1 co-immunoprecipitation in MDA-MB-231 cells

    PMID:31973006

    Open questions at the time
    • Mechanistic link between TMEM97 and STIM1-Orai1 not fully defined in this study
  8. 2021 High

    The mechanism of TMEM97's SOCE regulation was resolved: TMEM97 facilitates SOCE by reducing cholesterol association with Orai1, as a cholesterol-insensitive Orai1 mutant (Y80E) abolished TMEM97-dependent regulation, unifying TMEM97's cholesterol-handling and calcium signaling roles.

    Evidence Loss- and gain-of-function of TMEM97, Orai1 cholesterol association assays, cholesterol-insensitive Orai1(Y80E) mutant rescue in MDA-MB-231 cells

    PMID:33618021

    Open questions at the time
    • Whether TMEM97 directly extracts cholesterol from Orai1 or acts indirectly via membrane cholesterol redistribution is unknown
    • Generalizability beyond breast cancer cells untested
  9. 2021 Medium

    TMEM97 was shown to maintain redox homeostasis and autophagy in RPE cells, with KO reducing NRF2 and SOD2 levels, elevating ROS, and impairing autophagy flux, broadening its role to stress defense.

    Evidence CRISPR KO in ARPE19 cells and TMEM97 KO mouse retina, oxidant challenge, ROS measurement, autophagy markers

    PMID:34245862

    Open questions at the time
    • Whether NRF2 regulation is direct or secondary to cholesterol/lipid perturbation is unknown
    • Specific autophagy step regulated by TMEM97 not defined
  10. 2022 Medium

    In vivo evidence established that TMEM97 normally facilitates ischemia-induced retinal ganglion cell death, with KO mice and pharmacological TMEM97 ligand treatment both conferring neuroprotection.

    Evidence TMEM97 KO mice, retinal ischemia model, RGC degeneration quantification, intravitreal selective ligand (DKR-1677) injection

    PMID:36456686

    Open questions at the time
    • Downstream death pathway engaged by TMEM97 in RGCs not identified
    • Whether protection is cell-autonomous or involves glia is unresolved
  11. 2022 Medium

    TMEM97 was shown to regulate metabolic homeostasis in vivo: fat-specific or muscle-specific overexpression causes insulin resistance, while global KO protects against diet-induced obesity, linking TMEM97 to adipogenesis repression and metabolic inflammation.

    Evidence Tissue-specific transgenic and global KO mice, metabolic phenotyping, in vitro differentiation assays

    PMID:35790353

    Open questions at the time
    • Molecular mechanism linking TMEM97 to insulin signaling is not defined
    • Whether metabolic effects depend on cholesterol trafficking or a separate pathway is unknown
  12. 2022 Medium

    YY1 was identified as a transcriptional activator of TMEM97, and TMEM97 was shown to positively regulate GSK-3β/β-catenin Wnt signaling in colorectal cancer cells, providing the first upstream transcriptional regulator and a cancer-relevant downstream pathway.

    Evidence ChIP and luciferase reporter assay for YY1 binding, TMEM97 siRNA, β-catenin pathway Western blots, xenograft model

    PMID:35907137

    Open questions at the time
    • Whether YY1-driven TMEM97 expression is context-specific or general is untested
    • Mechanism linking TMEM97 membrane protein to GSK-3β/β-catenin nuclear signaling is indirect
  13. 2023 High

    Genetic KO validated that TMEM97 mediates antinociception in neuropathic pain and revealed the integrated stress response (ISR/p-eIF2α) as the downstream signaling mechanism in DRG nociceptors, resolving the mechanism initially suggested by pharmacology.

    Evidence Tmem97 KO mice in spared nerve injury model, ISR (p-eIF2α) assays in primary mouse DRG and human sensory neurons, neurite outgrowth assay

    PMID:38117854

    Open questions at the time
    • How TMEM97 modulates eIF2α phosphorylation mechanistically is not defined
    • Whether ISR modulation is cholesterol-dependent is unknown
  14. 2023 Medium

    TMEM97 was found to physically associate with TSPO, and the TMEM97 ligand 20(S)-hydroxycholesterol modulated this interaction, suggesting a functional TMEM97-TSPO-PGRMC1 signaling platform.

    Evidence Co-immunoprecipitation and proximity ligation assay, ligand treatment with 20(S)-hydroxycholesterol

    PMID:37047353

    Open questions at the time
    • Functional consequence of TMEM97-TSPO interaction not established
    • Single lab, no reciprocal genetic validation of TSPO dependence on TMEM97
  15. 2023 Medium

    TMEM97 was linked to ERα transcriptional activity and mTOR/S6K1 signaling in ER-positive breast cancer, where its overexpression promotes tamoxifen resistance that is reversed by mTOR inhibition.

    Evidence TMEM97 overexpression and knockdown, ERα reporter, Western blot for mTOR/S6K1/p-ERα, tamoxifen resistance assays, mTOR inhibitor rescue

    PMID:38067394

    Open questions at the time
    • Whether TMEM97 directly modulates ERα or acts via mTOR-mediated phosphorylation is unresolved
    • Relevance to clinical tamoxifen resistance untested
  16. 2024 High

    A pro-inflammatory signaling cascade was elucidated: TMEM97 binds BAHCC1, which activates NFκB to drive IL-1β and CCL2 expression in RPE, validated by KO in vitro and in vivo, revealing TMEM97 as a direct upstream regulator of inflammatory transcription.

    Evidence Transcriptomics of TMEM97 KO ARPE19 cells, TMEM97-BAHCC1 co-immunoprecipitation, BAHCC1 silencing, Tmem97 KO mouse retina in degeneration model

    PMID:38290642

    Open questions at the time
    • How a membrane protein (TMEM97) controls nuclear BAHCC1/NFκB is mechanistically undefined
    • Whether BAHCC1 interaction is direct or bridged is unknown
  17. 2024 Medium

    Histatin-1 was identified as an endogenous peptide ligand that directly binds TMEM97, with critical residues mapped, and binding activates ERK/Akt signaling to drive corneal epithelial migration.

    Evidence Surface plasmon resonance with recombinant TMEM97, truncation/alanine mutagenesis of Hst1, migration and signaling assays

    PMID:39547121

    Open questions at the time
    • Whether Hst1-TMEM97 interaction occurs physiologically in corneal epithelium in vivo is untested
    • Signaling pathway downstream of Hst1-TMEM97 to ERK/Akt is not delineated
  18. 2025 High

    TMEM97 was shown to govern partial EMT in RPE by negatively regulating CTNND2, which promotes ADAM10 expression to sustain cadherins; lentiviral re-expression of TMEM97 in KO mice mitigated photoreceptor loss, providing therapeutic proof-of-concept.

    Evidence TMEM97 KO ARPE19 cells, multi-omics, lentiviral subretinal TMEM97 re-expression in KO mice, immunofluorescence

    PMID:39995975

    Open questions at the time
    • Mechanism by which TMEM97 downregulates CTNND2 protein is undefined
    • Whether partial EMT regulation is relevant outside RPE is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the structural basis of the TMEM97-PGRMC1-LDLR ternary complex, whether TMEM97 possesses intrinsic enzymatic (sterol isomerase) activity, how a membrane-embedded protein signals to nuclear transcription factors (NFκB, β-catenin, ERα), and the identity of the physiological ligand(s) that regulate TMEM97 in vivo.
  • No crystal or cryo-EM structure of TMEM97 or its complexes exists
  • Predicted sterol isomerase activity has never been experimentally tested
  • Mechanism linking membrane-localized TMEM97 to nuclear signaling cascades remains unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0038024 cargo receptor activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005764 lysosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-168256 Immune System 1
Partners
BAHCC1CTNND2LDLRNPC1PGRMC1STIM1TSPO
Complex memberships
TMEM97-PGRMC1-LDLR ternary complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 TMEM97 binds NPC1 and controls its protein levels via a post-transcriptional mechanism; TMEM97 knockdown increases NPC1 levels and restores cholesterol trafficking out of lysosomes to the ER in NPC1-mutant cells. An ER-retention signal on TMEM97 is required for this regulatory function. RNA interference knockdown, co-immunoprecipitation, rescue with WT vs. ER-retention-signal-deleted TMEM97, cholesterol trafficking assays in patient fibroblasts Human molecular genetics High 27378690
2018 TMEM97 forms a ternary complex with PGRMC1 and LDLR; this intact trimeric complex is required for the rapid internalization of LDL by LDLR. TMEM97 KO abolishes binding of the sigma-2 radioligand [125I]RHM-4 and significantly reduces LDL uptake, and knocking out both TMEM97 and PGRMC1 does not further reduce LDL uptake beyond single KO, indicating they act in the same pathway. CRISPR/Cas9 knockout in HeLa cells, radioligand binding assays ([125I]RHM-4, [3H]DTG), confocal microscopy, Proximity Ligation Assay, radiolabeled and fluorescent LDL internalization assays Scientific reports High 30443021
2020 The TMEM97/PGRMC1/LDLR ternary complex mediates cellular uptake of Aβ42 monomers and oligomers as well as apoE, via both apoE-dependent and apoE-independent mechanisms in primary neurons; loss or pharmacological inhibition of TMEM97 or PGRMC1 disrupts the complex and reduces Aβ42 and apoE internalization. CRISPR KO, pharmacological inhibition, fluorescence-based internalization assays in primary neurons Molecular neurobiology Medium 32572762
2014 Computational sequence analysis identified a conserved EXPERA domain shared among TM6SF, TMEM97/MAC30, and EBP (D8/D7 sterol isomerase) protein families, predicting that TMEM97 possesses sterol isomerase catalytic activity similar to EBP. Computational protein sequence analysis and evolutionary conservation of catalytic residues Frontiers in genetics Low 25566323
2019 TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death; CRISPR KO of TMEM97, PGRMC1, or both did not alter the EC50 of several sigma-2 ligands for cell killing. However, TMEM97 and PGRMC1 KO reduced the initial internalization rate of a sigma-2 fluorescent ligand (SW120), demonstrating TMEM97's role in ligand internalization but not cytotoxicity. CRISPR/Cas9 KO, cell viability and caspase-3 assays, fluorescent ligand internalization assays Cell death discovery High 30701090
2021 TMEM97 facilitates store-operated calcium entry (SOCE) in MDA-MB-231 breast cancer cells by reducing cholesterol association with the Orai1 calcium channel; TMEM97 silencing increases cholesterol bound to Orai1 and reduces Orai1-STIM1 co-localization, while overexpression decreases Orai1 cholesterol association and enhances SOCE. Orai1(Y80E), a cholesterol-insensitive mutant, abolishes TMEM97-dependent SOCE regulation. siRNA silencing, TMEM97 overexpression, cholesterol uptake assays, SOCE calcium imaging, co-localization of Orai1 with STIM1, cholesterol-insensitive Orai1 mutant Biochimica et biophysica acta. Molecular and cell biology of lipids High 33618021
2021 TMEM97 knockout in RPE cells results in diminished NRF2 and SOD2 abundance, elevated reactive oxygen species, increased apoptosis, and impaired autophagy flux, indicating that TMEM97 supports redox homeostasis and lysosomal/mitochondrial stability in RPE cells. CRISPR KO in ARPE19 cells, sodium iodate oxidant model, ROS measurement, Western blot for NRF2/SOD2/autophagy markers, TMEM97 KO mouse retina analysis Cellular signalling Medium 34245862
2022 TMEM97 knockout mice show resistance of retinal ganglion cells (RGCs) to ischemia-induced degeneration, establishing that TMEM97 normally facilitates RGC death following ischemic injury. Intravitreal injection of a selective TMEM97 ligand (DKR-1677) also protects RGCs in wildtype mice. TMEM97 knockout mice, ischemia model, RGC degeneration quantification, intravitreal ligand injection Scientific reports Medium 36456686
2023 The σ2R/TMEM97 ligand FEM-1689 requires the presence of the Tmem97 gene to produce antinociception in the spared nerve injury neuropathic pain model, confirming on-target action. In primary DRG neurons, FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via TMEM97-specific action; it also reduces ISR (p-eIF2α levels) in human sensory neurons. Conventional Tmem97 knockout mice (male and female), spared nerve injury model, primary DRG neuron culture, ISR assays (p-eIF2α), neurite outgrowth assay, human sensory neurons Proceedings of the National Academy of Sciences of the United States of America High 38117854
2023 TMEM97 physically associates with TSPO (translocator protein) as shown by proximity ligation assay and co-immunoprecipitation; treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduces co-immunoprecipitation of TMEM97 and PGRMC1 from TSPO immune pellets, indicating ligand binding modulates the TMEM97-TSPO interaction. Co-immunoprecipitation, proximity ligation assay, confocal microscopy, ligand treatment (20-(S)-hydroxycholesterol) International journal of molecular sciences Medium 37047353
2024 TMEM97 promotes pro-inflammatory cytokine expression (IL-1β, CCL2) in RPE cells via a TMEM97→BAHCC1→NFκB cascade; TMEM97 and BAHCC1 proteins co-immunoprecipitate, TMEM97 ablation reduces BAHCC1 and NFκB, and Tmem97 KO mice show reduced IL-1β and CCL2 in retina in a degeneration model. Transcriptomic analysis of TMEM97 KO ARPE19 cells, co-immunoprecipitation (TMEM97-BAHCC1), TMEM97 loss- and gain-of-function, BAHCC1 silencing, immunofluorescence in Tmem97 KO mouse retina Cellular signalling High 38290642
2024 The central region of histatin-1 (Hst1), specifically residues 9–19 (with loss of residues 15–19 abolishing binding), is required for Hst1 binding to TMEM97 as determined by surface plasmon resonance. Hst1 acts as an endogenous ligand for TMEM97, and binding drives ERK and Akt signaling and corneal epithelial cell migration. Surface plasmon resonance with recombinant TMEM97, truncation and alanine-substitution Hst1 mutants, migration assays, signaling (ERK, Akt) assays Biochemical and biophysical research communications Medium 39547121
2025 TMEM97 negatively regulates CTNND2 protein (catenin δ-2), which in turn promotes ADAM10 expression to sustain both E- and N-cadherin protein levels; TMEM97 knockout induces partial EMT (concurrent E- and N-cadherin expression) in RPE cells. Re-expression of TMEM97 via lentiviral subretinal delivery in TMEM97 KO mice mitigates oxidant-induced photoreceptor loss. TMEM97 KO in ARPE19 cells and mice, lentiviral TMEM97 re-expression, proteomic and transcriptomic analysis, immunoblot, immunofluorescence segmentation analysis Molecular therapy. Nucleic acids High 39995975
2022 TMEM97 is transcriptionally activated by the transcription factor YY1 binding to the TMEM97 promoter (confirmed by luciferase reporter and ChIP assays), and TMEM97 in turn positively regulates the GSK-3β/β-catenin Wnt signaling pathway in colorectal cancer cells. Luciferase reporter assay, ChIP assay, TMEM97 siRNA knockdown, Western blot for β-catenin pathway components, xenograft model Human cell Medium 35907137
2020 TMEM97 silencing in MDA-MB-231 breast cancer cells impairs SOCE; σ2R/TMEM97 positively regulates STIM1 function (detected via STIM1-Orai1 interaction assay), and the σ2R/TMEM97 ligand NO1 downregulates STIM1-Orai1 interaction, mimicking TMEM97 silencing effects on SOCE. TMEM97 silencing, SOCE calcium imaging, co-immunoprecipitation of STIM1-Orai1, Western blot Cancers Medium 31973006
2022 TMEM97 represses adipogenesis and promotes myogenesis in vitro; fat-specific TMEM97 transgenic mice develop systemic insulin resistance, as do mice overexpressing TMEM97 in skeletal muscle, while TMEM97 KO mice are protected against diet-induced obesity and insulin resistance, linked to effects on inflammation genes in adipose tissue and skeletal muscle. TMEM97 transgenic and knockout mice, fat-specific and muscle-specific overexpression, in vitro differentiation assays, metabolic phenotyping, gene expression analysis Acta medica Okayama Medium 35790353
2023 TMEM97/sigma-2 receptor enhances ERα transcriptional activity and activates mTOR/S6K1 signaling in ER-positive breast cancer cells; TMEM97 overexpression increases tamoxifen resistance and phosphorylated ERα levels, effects that are blocked by mTOR inhibition. TMEM97 knockdown reduces ERα and mTOR/S6K1 signaling and restores tamoxifen sensitivity. TMEM97 overexpression and knockdown, ERα transcriptional reporter assays, Western blot for mTOR/S6K1/p-ERα, tamoxifen resistance assays, mTOR inhibitor rescue Cancers Medium 38067394
2018 σ2R/TMEM97 agonists (DKR-1005, DKR-1051, UKH-1114) relieve neuropathic pain-induced mechanical hypersensitivity in the mouse spared nerve injury model via σ2R/TMEM97, as the effect is blocked by the putative σ2R/TMEM97 antagonist SAS-0132; TMEM97 is expressed in mouse and human DRG neurons involved in pain signaling. Spared nerve injury mouse model, intrathecal and systemic drug administration, pharmacological antagonism with SAS-0132, DRG expression analysis ACS chemical neuroscience Medium 28644012
2025 TMEM97 upregulates key lipid biosynthesis enzymes (HMGCR, SQLE, FASN, SCD) and, in the context of ZCCHC4-driven hepatocellular carcinoma, TMEM97 interacts with LCN2 to retain it in the cytoplasm, thereby relieving LCN2-mediated inhibition of Twist1 transcription factor and promoting EMT and metastasis. Co-immunoprecipitation (TMEM97-LCN2), in vitro and in vivo metastasis assays, Western blot, transcriptional analysis, xenograft models International journal of biological sciences Low 42003930
2025 Small molecule modulators of S2R/TMEM97 increase LDL uptake in RPE cells in a manner dependent on both TMEM97 and LDLR; lentiviral shRNA knockdown of TMEM97 or LDLR, or LDLR-blocking antibody, abolishes the modulator-mediated increase in LDL uptake. Fluorescent LDL uptake assay in RPE cells, lentiviral shRNA knockdown of TMEM97 and LDLR, LDLR-neutralizing antibody, S2R modulator treatment bioRxivpreprint Low bio_10.1101_2025.08.22.670986

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Scientific reports 112 30443021
2017 Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice. ACS chemical neuroscience 84 28644012
2016 Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Human molecular genetics 81 27378690
2020 The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates. Molecular neurobiology 67 32572762
2019 Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes. Frontiers in pharmacology 51 31695608
2018 Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. ACS chemical neuroscience 51 30421909
2014 TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Frontiers in genetics 51 25566323
2007 Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers. International journal of oncology 50 17143516
2007 Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC cancer 47 18070364
2018 A multiplatform approach identifies miR-152-3p as a common epigenetically regulated onco-suppressor in prostate cancer targeting TMEM97. Clinical epigenetics 46 29599847
2020 The Biological Function of Sigma-2 Receptor/TMEM97 and Its Utility in PET Imaging Studies in Cancer. Cancers 44 32668577
2019 TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. Cell death discovery 44 30701090
2004 Expression analysis of MAC30 in human pancreatic cancer and tumors of the gastrointestinal tract. Histology and histopathology 41 15375745
2015 RNA interference against TMEM97 inhibits cell proliferation, migration, and invasion in glioma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 26002575
2020 NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines. Cancers 37 31973006
2014 Down-regulated MAC30 expression inhibits proliferation and mobility of human gastric cancer cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 24853233
2018 Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 29728649
2020 The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice. Neuropharmacology 32 33221481
2023 Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response. Proceedings of the National Academy of Sciences of the United States of America 29 38117854
2018 High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model. ACS chemical neuroscience 27 29426225
2012 Expression of MAC30 protein is related to survival and clinicopathological variables in breast cancer. Journal of surgical oncology 27 22996179
2019 Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor. BMC cancer 26 31109310
2019 Down-regulated MAC30 expression inhibits breast cancer cell invasion and EMT by suppressing Wnt/β-catenin and PI3K/Akt signaling pathways. International journal of clinical and experimental pathology 25 31934012
2012 Overexpression of MAC30 is associated with poor clinical outcome in human non-small-cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 23229099
2010 Overexpression of MAC30 in the cytoplasm of oral squamous cell carcinoma predicts nodal metastasis and poor differentiation. Chemotherapy 22 21079401
2022 Neuroprotective Effects of σ2R/TMEM97 Receptor Modulators in the Neuronal Model of Huntington's Disease. ACS chemical neuroscience 20 36108101
2007 Expression of MAC30 in rectal cancers with or without preoperative radiotherapy. Oncology 19 17657172
2022 σ2R/TMEM97 in retinal ganglion cell degeneration. Scientific reports 18 36456686
2021 TMEM97 ablation aggravates oxidant-induced retinal degeneration. Cellular signalling 18 34245862
2021 TMEM97 facilitates the activation of SOCE by downregulating the association of cholesterol to Orai1 in MDA-MB-231 cells. Biochimica et biophysica acta. Molecular and cell biology of lipids 15 33618021
2021 Identification and characterization of MAM03055A: A novel bivalent sigma-2 receptor/TMEM97 ligand with cytotoxic activity. European journal of pharmacology 11 34144027
2021 The Sigma-2 Receptor/TMEM97 Agonist PB28 Suppresses Cell Proliferation and Invasion by Regulating the PI3K-AKT-mTOR Signalling Pathway in Renal Cancer. Journal of cellular and molecular medicine 11 34783163
2020 Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands. European journal of medicinal chemistry 11 33049607
2018 MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells. Biological chemistry 11 29990302
2022 TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3β/β-catenin signaling pathway. Human cell 10 35907137
2024 Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice. eNeuro 9 38866499
2023 Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97. International journal of molecular sciences 9 37047353
1999 Sigma2R, a reciprocal-space measure of the quality of macromolecular electron-density maps. Acta crystallographica. Section D, Biological crystallography 9 10329780
2023 Structure-affinity relationships of stereoisomers of norbenzomorphan-derived σ2R/TMEM97 modulators. European journal of medicinal chemistry 8 37247506
2015 Overexpression of MAC30 is Resistant to Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer. Technology in cancer research & treatment 8 26376695
2020 MAC30 Knockdown Inhibits Proliferation and Enhance Apoptosis of Gastric Cancer by Suppressing Wnt/β-Cateninsignaling Pathway. Gastroenterology research and practice 6 32904598
2024 TMEM97 knockdown inhibits 5-fluorouracil resistance by regulating epithelial-mesenchymal transition and ABC transporter expression via inactivating the Akt/mTOR pathway in 5-fluorouracil-resistant colorectal cancer cells. Chemical biology & drug design 5 38388887
2024 Structure-Affinity relationships of novel σ2R/TMEM97 ligands. Bioorganic chemistry 5 38432153
2024 Identifying the crucial binding domain of histatin-1 to recombinant TMEM97 in activating chemotactic migration in human corneal epithelial cells. Biochemical and biophysical research communications 5 39547121
2024 Mechanisms of Sigma-2/TMEM97 Involvement in Cholesterol Metabolism. Journal of cellular biochemistry 4 39300897
2022 Inhibition of MAC30 exerts antitumor effects in nasopharyngeal carcinoma via affecting the Akt/GSK-3β/β-catenin pathway. Journal of biochemical and molecular toxicology 4 35373413
2022 Targeting σ2R/TMEM97 with novel aminotetralins. European journal of medicinal chemistry 4 36088757
2024 Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine expression. Cellular signalling 3 38290642
2023 TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth. Cancers 3 38067394
2022 Roles of Transmembrane Protein 97 (TMEM97) in Adipose Tissue and Skeletal Muscle. Acta medica Okayama 3 35790353
2025 TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis. Molecular therapy. Nucleic acids 2 39995975
2025 Discovery of σ2R/TMEM97 as a Novel Biomarker for Atherosclerotic Plaques: A PET Imaging and Validation Study. Arteriosclerosis, thrombosis, and vascular biology 1 40401377
2025 Transmembrane Protein 97 (TMEM97): Molecular Target and Treatment in Age-Related Macular Degeneration (AMD). Biomolecules 1 41008535
2026 ZCCHC4 Orchestrates Hepatocellular Carcinoma Metastasis by Regulating Lipid biosynthesis and TMEM97/LCN2/Twist1 Pathway. International journal of biological sciences 0 42003930
2025 Veraguamide E, a Marine Cyanobacterial Depsipeptide Targeting σ2R/TMEM97: Chemical and Neurobiological Characterization. Journal of natural products 0 41195793
2025 Siramesine Attenuates Early Brain Injury Through the TMEM97/NPC1 Pathway After Experimental Subarachnoid Hemorrhage in Rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41277193
2023 Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response. bioRxiv : the preprint server for biology 0 37090527