Affinage

TMEM97

Sigma intracellular receptor 2 · UniProt Q5BJF2

Length
176 aa
Mass
20.8 kDa
Annotated
2026-06-10
57 papers in source corpus 23 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM97 (σ2R/MAC30) is a multi-pass ER-resident membrane protein that functions as a central regulator of cellular cholesterol handling and lipoprotein uptake (PMID:27378690, PMID:30443021). It physically interacts with NPC1 and, through a post-transcriptional mechanism dependent on its ER localization, controls NPC1 protein abundance to govern lysosomal cholesterol egress; loss of TMEM97 raises NPC1 levels and restores cholesterol trafficking in NPC disease cell models (PMID:27378690). TMEM97 also assembles into an obligate ternary complex with PGRMC1 and the LDL receptor that drives rapid LDL internalization, with TMEM97 and PGRMC1 acting epistatically in the same uptake pathway (PMID:30443021); this same complex mediates neuronal uptake of Aβ42 and apoE (PMID:32572762), and TMEM97 modulators enhance LDLR-dependent LDL uptake in RPE cells. Beyond lipoprotein trafficking, TMEM97 promotes store-operated calcium entry by reducing cholesterol association with the Orai1 channel, thereby permitting STIM1–Orai1 coupling (PMID:31973006, PMID:33618021). In tissue contexts, TMEM97 supports redox balance and NRF2/SOD2-dependent antioxidant responses in retinal pigment epithelium (PMID:34245862) and facilitates retinal ganglion cell death after ischemia (PMID:36456686). In nociceptive neurons, the gene is required for σ2R/TMEM97 ligand-mediated suppression of the integrated stress response and antinociception, validated genetically in Tmem97 knockout mice (PMID:38117854). TMEM97 additionally acts as a signaling node in RPE cells, operating upstream of a BAHCC1→NF-κB pro-inflammatory cytokine cascade (PMID:38290642) and a CTNND2→ADAM10 axis regulating partial EMT (PMID:39995975). The predicted EXPERA sterol-isomerase catalytic activity inferred from sequence conservation (PMID:25566323) has not been biochemically validated in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2014 Low

    Before any enzymatic function was assigned, sequence analysis sought to place TMEM97 in a protein family, predicting it harbors a sterol-isomerase-like EXPERA domain and tying it conceptually to sterol metabolism.

    Evidence Computational sequence and evolutionary conservation analysis

    PMID:25566323

    Open questions at the time
    • Computational prediction only; no biochemical demonstration of sterol isomerase activity
    • No substrate or product identified
    • Catalytic residues not experimentally tested
  2. 2016 High

    The first direct mechanistic role was established by showing TMEM97 binds NPC1 and post-transcriptionally limits its abundance, linking TMEM97 to lysosomal cholesterol egress and disease-relevant trafficking defects.

    Evidence RNAi knockdown, rescue with WT vs ER-retention-deleted mutant, cholesterol trafficking assays in NPC patient cell models

    PMID:27378690

    Open questions at the time
    • Molecular mechanism by which TMEM97 controls NPC1 stability is undefined
    • Binding interface not mapped
    • Does not establish whether NPC1 regulation is enzymatic or scaffolding
  3. 2018 High

    Resolved how TMEM97 acts at the plasma membrane/endosomal level by demonstrating it forms an obligate ternary complex with PGRMC1 and LDLR required for rapid LDL internalization, with epistasis placing all three in one pathway.

    Evidence CRISPR knockouts, radioligand binding, PLA, confocal, radiolabeled LDL uptake with double-KO epistasis in HeLa

    PMID:30443021

    Open questions at the time
    • Stoichiometry and structural arrangement of the trimer unknown
    • Whether TMEM97 contributes catalytic or purely structural function in the complex unresolved
  4. 2019 High

    A rigorous negative result clarified that σ2R-ligand cytotoxicity is NOT mediated through TMEM97/PGRMC1, separating the receptor's ligand-binding identity from the death-inducing effects often attributed to it.

    Evidence Multiple CRISPR KO lines, viability/caspase-3 assays, fluorescent ligand internalization

    PMID:30701090

    Open questions at the time
    • Identity of the cytotoxicity effector remains unknown
    • Does not address non-cytotoxic ligand functions
  5. 2020 Medium

    Extended the ternary-complex uptake mechanism to neurodegeneration-relevant cargo, showing the TMEM97/PGRMC1/LDLR complex internalizes Aβ42 and apoE in neurons.

    Evidence CRISPR KO, pharmacological inhibition, fluorescent ligand internalization in primary neurons

    PMID:32572762

    Open questions at the time
    • In vivo relevance to amyloid clearance not established
    • Single lab, builds on prior complex model
  6. 2021 Medium

    Defined a calcium-signaling role by showing TMEM97 enables store-operated calcium entry through lowering cholesterol association with Orai1, with the cholesterol-insensitive Orai1(Y80E) mutant placing TMEM97 upstream of the channel-lipid interaction.

    Evidence Silencing/overexpression, cholesterol-Orai1 association assay, SOCE imaging, Orai1 Y80E mutant in breast cancer cells

    PMID:31973006 PMID:33618021

    Open questions at the time
    • No direct TMEM97-Orai1 interaction detected
    • Mechanism linking TMEM97 to local cholesterol pools at the channel unclear
    • Single cell-line context
  7. 2021 Medium

    Linked TMEM97 to oxidative-stress resilience in retinal pigment epithelium, showing its loss elevates ROS and impairs NRF2/SOD2 antioxidant and autophagy/lysosomal systems.

    Evidence CRISPR KO cells and KO mice, oxidant model, ROS measurement, Western blot, apoptosis assays

    PMID:34245862

    Open questions at the time
    • Direct molecular connection between TMEM97 and NRF2 not defined
    • Whether the effect is secondary to cholesterol/lysosomal dysfunction unresolved
  8. 2022 Medium

    Genetic and pharmacological evidence established TMEM97 as a facilitator of retinal ganglion cell death after ischemia, identifying it as a neuroprotective drug target.

    Evidence Tmem97 KO mice plus intravitreal σ2R/TMEM97 ligand DKR-1677 in wildtype ischemia model

    PMID:36456686

    Open questions at the time
    • Downstream death-execution pathway not defined
    • Connection to TMEM97's cholesterol/calcium functions not established
  9. 2023 High

    Provided the strongest genetic validation of TMEM97 as a functional analgesic target by showing the gene is strictly required for ligand-induced suppression of the integrated stress response and antinociception, with human sensory-neuron confirmation.

    Evidence Conventional Tmem97 KO mice, spared nerve injury, DRG and human sensory neuron ISR/p-eIF2α assays, neurite outgrowth

    PMID:38117854

    Open questions at the time
    • Molecular mechanism connecting TMEM97 to eIF2α/ISR machinery unknown
    • Direct effector of ISR suppression not identified
  10. 2024 Medium

    Identified a new signaling output by showing TMEM97 physically associates with epigenetic reader BAHCC1 and operates upstream of a BAHCC1→NF-κB cascade driving pro-inflammatory cytokine expression in RPE cells.

    Evidence TMEM97 KO ARPE19 cells, transcriptomics, co-IP, BAHCC1 silencing, in vivo Tmem97-/- validation

    PMID:38290642

    Open questions at the time
    • How a membrane protein regulates a nuclear epigenetic reader is unexplained
    • Co-IP not reciprocally validated for direct binding
    • Single lab
  11. 2024 Medium

    Demonstrated a direct extracellular ligand interaction by showing purified recombinant TMEM97 binds the histatin-1 peptide via its central region, coupling TMEM97 to ERK/Akt-driven corneal epithelial migration.

    Evidence Surface plasmon resonance with purified protein, Hst1 truncation/alanine mutants, migration and signaling assays

    PMID:39547121

    Open questions at the time
    • Topological basis for a membrane protein binding an extracellular peptide unclear
    • Physiological role of Hst1-TMEM97 interaction beyond migration not established
  12. 2025 Medium

    Connected TMEM97 to epithelial plasticity, showing it negatively regulates CTNND2 and thereby an ADAM10 axis controlling cadherin levels and partial EMT in RPE cells.

    Evidence TMEM97 KO ARPE19 cells, in vivo lentiviral re-expression rescue, proteomics/transcriptomics, functional CTNND2/ADAM10 manipulation

    PMID:39995975

    Open questions at the time
    • Mechanism of CTNND2 protein-level regulation undefined
    • Relation to other TMEM97 functions unclear
  13. 2025 Medium

    Reinforced the cholesterol-uptake model in a new tissue, showing σ2R/TMEM97 modulators increase LDL uptake in RPE cells in a manner dependent on both TMEM97 and LDLR.

    Evidence Fluorescent LDL uptake, shRNA knockdown of TMEM97 and LDLR, LDLR-neutralizing antibody in RPE (preprint)

    Open questions at the time
    • Preprint, not peer-reviewed
    • PGRMC1 dependence in RPE not tested
    • Whether modulators act through the same trimeric complex unconfirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether TMEM97's predicted sterol-isomerase catalytic activity is real, and how a single ER membrane protein mechanistically couples cholesterol handling to such diverse outputs (calcium entry, ISR suppression, NF-κB inflammation, EMT), remains unresolved.
  • No biochemical demonstration of enzymatic activity
  • No structure of TMEM97 or its complexes
  • Unifying mechanism linking lipid function to downstream signaling outputs absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0038024 cargo receptor activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3
Partners
BAHCC1CTNND2LDLRNPC1PGRMC1STIM1TSPO
Complex memberships
TMEM97/PGRMC1/LDLR ternary complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 TMEM97 physically interacts with NPC1 (Niemann-Pick C1 protein) and acts as a cholesterol-responsive NPC1-binding protein. Reduction of TMEM97 via RNA interference increases NPC1 protein levels through a post-transcriptional mechanism, reduces lysosomal lipid storage, and restores cholesterol trafficking to the ER in NPC disease cell models. Rescue with WT TMEM97 but not an ER-retention-signal-deleted mutant restores NPC1 levels, indicating TMEM97's ER localization is required for controlling NPC1 availability. RNA interference knockdown, Western blot, confocal microscopy, cholesterol trafficking assays, rescue with WT vs. mutant TMEM97 Human molecular genetics High 27378690
2018 TMEM97 and PGRMC1 form a ternary complex with the LDL receptor (LDLR), and this intact trimeric complex is required for rapid internalization of LDL. CRISPR/Cas knockout of TMEM97 alone causes complete loss of [125I]RHM-4 binding and significant reduction in [3H]DTG binding; TMEM97 KO or PGRMC1 KO each equally reduce LDL uptake rate, and double KO produces no additive reduction, indicating they act in the same pathway. Co-localization confirmed by confocal microscopy and Proximity Ligation Assay. CRISPR/Cas9 knockout in HeLa cells, radioligand binding assays, fluorescent and radiolabeled LDL internalization assays, confocal microscopy, Proximity Ligation Assay Scientific reports High 30443021
2020 The intact TMEM97/PGRMC1/LDLR trimeric complex mediates cellular uptake of Aβ42 monomers and oligomers as well as apoE in primary neurons, both in apoE-dependent and apoE-independent manners. Loss or pharmacological inhibition of TMEM97 or PGRMC1 disrupts the complex and decreases uptake of mAβ42, oAβ42, and apoE. CRISPR/Cas9 knockout, pharmacological inhibition, fluorescent ligand internalization assays, primary neuron cultures Molecular neurobiology Medium 32572762
2019 Knockout of TMEM97 or PGRMC1 (individually or together) does not affect the EC50 of sigma-2 ligand-induced cell death, demonstrating that the cytotoxic effects of sigma-2 receptor ligands are NOT mediated by TMEM97 or PGRMC1. Knockout of TMEM97/PGRMC1 reduces the initial internalization rate of a sigma-2 fluorescent ligand (SW120) but internalized concentrations equalize later, and this initial internalization difference does not mediate cytotoxicity. CRISPR/Cas9 knockout cell lines, cell viability assays, caspase-3 assays, fluorescent ligand internalization assays Cell death discovery High 30701090
2014 Computational sequence analysis identifies that TMEM97/MAC30 contains an EXPERA domain shared with TM6SF protein family and EBP (D8/D7 sterol isomerase) family, predicting that TMEM97 likely possesses sterol isomerase catalytic activity, given conservation of residues implicated in EBP catalysis. Computational protein sequence analysis, evolutionary conservation analysis Frontiers in genetics Low 25566323
2007 TMEM97 expression is coordinately upregulated with 14 cholesterol biosynthesis enzymes, LDLR, and lipid metabolism genes in normal ovarian surface epithelial cells treated with progesterone, and TMEM97 expression is highly correlated with cholesterol biosynthesis genes across tissues, suggesting TMEM97 participates in a co-regulated cholesterol/lipid homeostasis network downstream of progesterone signaling. Oligonucleotide microarray transcriptional profiling, quantitative RT-PCR, GNF Atlas 2 database co-expression analysis BMC cancer Low 18070364
2015 RNA interference-mediated knockdown of TMEM97 in glioma cells (U87, U373) inhibits cell proliferation, G1/S transition, and reduces expression of cyclin D1, cyclin E, CDK2, and CDK4. TMEM97 knockdown also decreases cell migration and invasion and alters EMT markers (E-cadherin, β-catenin, Twist). RNA interference, cell proliferation assay, cell cycle analysis, migration/invasion assay, Western blot Tumour biology Medium 26002575
2014 Knockdown of MAC30/TMEM97 in gastric cancer cells inhibits cell proliferation, mobility (migration and invasion), reduces AKT phosphorylation, and decreases cyclin B1 and WAVE2 expression. MAC30 localizes with lamellipodia structures by immunofluorescence. RNA silencing, Western blot, cell proliferation assay, cell cycle analysis, migration/invasion assay, immunofluorescence Cellular physiology and biochemistry Medium 24853233
2020 TMEM97 promotes store-operated calcium entry (SOCE) in MDA-MB-231 breast cancer cells. TMEM97 silencing impairs SOCE and reduces STIM1-Orai1 interaction, while the NO1 σ2R/TMEM97 ligand also reduces SOCE; TMEM97 positively regulates STIM1 activity but no direct interaction with Orai1 was detected. TMEM97 silencing (siRNA), Western blot, calcium imaging (SOCE assay), co-immunoprecipitation Cancers Medium 31973006
2021 TMEM97 facilitates SOCE in MDA-MB-231 breast cancer cells by reducing cholesterol association to the SOCE channel Orai1. TMEM97 silencing increases cholesterol uptake and enhances cholesterol-Orai1 association, impairing STIM1-Orai1 co-localization and SOCE; TMEM97 overexpression decreases cholesterol-Orai1 association and increases SOCE. Effects are absent in a cholesterol-insensitive Orai1(Y80E) mutant, placing TMEM97 upstream of Orai1-cholesterol interaction. TMEM97 silencing and overexpression, cholesterol uptake assay, SOCE calcium imaging, cholesterol-Orai1 association assay, Orai1 Y80E mutant transfection Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 33618021
2021 TMEM97 knockout in retinal pigment epithelial (RPE) cells and mouse retinas leads to increased reactive oxygen species, reduced NRF2 and SOD2 (mitochondrial superoxide dismutase) abundance, elevated apoptosis markers, impaired mitochondrial and lysosomal stability, and impeded autophagy flux, demonstrating TMEM97 supports redox-balancing systems in RPE. CRISPR-mediated TMEM97 KO in RPE cells, TMEM97 KO mice, sodium iodate oxidant model, ROS measurement, Western blot (NRF2, SOD2, autophagy markers), apoptosis assays Cellular signalling Medium 34245862
2022 TMEM97 physically associates with TSPO (translocator protein) as shown by proximity ligation assay and co-immunoprecipitation in breast and pancreatic cancer cells. Treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduces co-immunoprecipitation of both TMEM97 and PGRMC1 with TSPO, indicating ligand binding modulates this protein-protein association. Proximity ligation assay, co-immunoprecipitation, confocal microscopy, ligand treatment (20-S-hydroxycholesterol) International journal of molecular sciences Medium 37047353
2022 TMEM97-knockout mice show resistance of retinal ganglion cells (RGCs) to ischemia-induced degeneration, and intravitreal injection of selective σ2R/TMEM97 ligand DKR-1677 protects RGCs from ischemia in wildtype mice. This demonstrates TMEM97 facilitates RGC death following ischemic injury. TMEM97 knockout mice, ischemia model, intravitreal ligand injection, RGC survival quantification Scientific reports Medium 36456686
2018 MAC30/TMEM97 knockdown in breast cancer cells activates the Hippo signaling pathway, as evidenced by increased phosphorylation of YAP1, MST1, and LATS1 after MAC30 siRNA transfection. siRNA knockdown, Western blot for phospho-YAP1/MST1/LATS1, soft agar assay, apoptosis assay Biological chemistry Low 29990302
2022 TMEM97 is transcriptionally activated by the oncogenic transcription factor YY1, which was shown to bind the TMEM97 promoter by luciferase reporter and ChIP assays. TMEM97 promotes colorectal cancer progression by positively regulating the β-catenin signaling pathway via modulating phosphorylated-GSK-3β and active (non-phospho) β-catenin levels. Luciferase reporter assay, ChIP assay, Western blot, TMEM97 knockdown and overexpression, xenograft model Human cell Medium 35907137
2023 σ2R/TMEM97 ligand FEM-1689 requires the presence of the Tmem97 gene to produce antinociception in the spared nerve injury model, as shown using conventional Tmem97 knockout mice. In primary DRG neurons, FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a TMEM97-specific action (absent in KO cells). FEM-1689 also reduces ISR and p-eIF2α levels in human sensory neurons. Conventional Tmem97 knockout mice, spared nerve injury model, primary DRG neuron culture, ISR/p-eIF2α assays, neurite outgrowth assay, human sensory neuron culture Proceedings of the National Academy of Sciences of the United States of America High 38117854
2024 TMEM97 and the epigenetic reader BAHCC1 constitute a novel signaling axis regulating pro-inflammatory cytokine expression (IL-1β, CCL2) in retinal pigment epithelial cells. TMEM97 ablation decreases NF-κB (p50, p52, p65) and downstream cytokines; TMEM97 overexpression increases NF-κB. BAHCC1 expression is regulated by TMEM97, and co-immunoprecipitation indicates a physical association between TMEM97 and BAHCC1 proteins. BAHCC1 silencing down-regulates NF-κB and pro-inflammatory cytokines, placing TMEM97 upstream of a TMEM97→BAHCC1→NF-κB cascade. TMEM97 KO ARPE19 cell line, transcriptomic analysis, TMEM97 loss- and gain-of-function, co-immunoprecipitation, BAHCC1 silencing, Western blot, immunofluorescence in Tmem97−/− mice Cellular signalling Medium 38290642
2025 TMEM97 negatively regulates CTNND2 (catenin δ-2) protein levels in retinal pigment epithelial cells. TMEM97 ablation induces partial EMT (pEMT), marked by co-expression of epithelial E-cadherin and mesenchymal N-cadherin, reversed by TMEM97 re-expression. CTNND2 promotes ADAM10 expression, which sustains both E- and N-cadherin protein levels, identifying a TMEM97→CTNND2→ADAM10 axis regulating pEMT in RPE cells. TMEM97 KO ARPE19 cells, subretinal lentiviral TMEM97 re-expression in KO mice, proteomics, transcriptomics, immunoblot, immunofluorescence, CTNND2 and ADAM10 functional manipulation Molecular therapy. Nucleic acids Medium 39995975
2024 TMEM97 physically binds histatin-1 (Hst1) peptide; the central region of Hst1 (residues 9–19, with residues 15–19 critical) is required for binding to purified recombinant TMEM97 as determined by surface plasmon resonance. This TMEM97-Hst1 interaction is essential for Hst1-induced corneal epithelial cell chemotactic migration and downstream ERK and Akt signaling. Surface plasmon resonance (SPR) with purified recombinant TMEM97, Hst1 truncation and alanine substitution mutants, cell migration assay, ERK/Akt signaling assay Biochemical and biophysical research communications Medium 39547121
2022 TMEM97 expression in adipose tissue and skeletal muscle regulates adipogenesis and myogenesis: TMEM97 represses adipogenesis and promotes myogenesis in vitro. Fat-specific TMEM97 transgenic mice and skeletal muscle-overexpressing mice both show systemic insulin resistance, while TMEM97 knockout mice are protected against diet-induced obesity and insulin resistance; effects are associated with altered inflammation gene expression in adipose tissue and skeletal muscle. TMEM97 transgenic mice (fat-specific, muscle-specific), TMEM97 knockout mice, in vitro differentiation assays, metabolic phenotyping Acta medica Okayama Medium 35790353
2025 TMEM97 activates TMEM97/NPC1 signaling pathway in neurons; after subarachnoid hemorrhage in rats, TMEM97 protein expression decreases. Siramesine (a reported TMEM97 activator) treatment upregulates TMEM97 and NPC1, reduces oxidative stress (Romo-1 downregulation) and neuronal apoptosis (Bax downregulation, Bcl-2 upregulation, Drp1 downregulation). The neuroprotective effect of Siramesine is significantly attenuated by TMEM97 inhibitor SM-21 or NPC1 siRNA, placing TMEM97 upstream of NPC1 in this neuroprotective pathway. Rat SAH model, Siramesine treatment, SM-21 inhibitor co-administration, NPC1 siRNA, Western blot, immunofluorescence, neurological deficit scoring FASEB journal Medium 41277193
2023 TMEM97/sigma-2 receptor increases ERα transcriptional activity and activates mTOR/S6K1 signaling in ER-positive breast cancer cells. Increased TMEM97 expression enhances ERα phosphorylation and tamoxifen resistance; these effects can be blocked by an mTOR inhibitor. TMEM97 knockdown reduces ERα and mTOR/S6K1 signaling and sensitizes cells to tamoxifen. TMEM97 overexpression and knockdown, ERα transcriptional reporter assay, Western blot (phospho-ERα, mTOR/S6K1), tamoxifen resistance assay, mTOR inhibitor treatment Cancers Medium 38067394
2019 MAC30/TMEM97 knockdown in breast cancer cells inhibits invasion and EMT by suppressing both the Wnt/β-catenin and PI3K/Akt signaling pathways, as evidenced by reduced Akt phosphorylation, β-catenin, survivin, and cyclin D1 expression. siRNA knockdown, Western blot, Transwell invasion assay, qRT-PCR International journal of clinical and experimental pathology Low 31934012
2025 In retinal pigment epithelial (RPE) cells, S2R/TMEM97 modulators increase LDL uptake; this effect requires both TMEM97 and LDLR, as demonstrated by lentiviral shRNA knockdown of either protein and LDLR-neutralizing antibody treatment, which abolish modulator-mediated LDL uptake. Fluorescent LDL uptake assay in RPE cells, lentiviral shRNA knockdown of TMEM97 and LDLR, LDLR-neutralizing antibody, S2R modulator treatment bioRxivpreprint Medium

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 85 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 70 32572762
2019 Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes. Frontiers in pharmacology 53 31695608
2018 Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. ACS chemical neuroscience 52 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
2018 A multiplatform approach identifies miR-152-3p as a common epigenetically regulated onco-suppressor in prostate cancer targeting TMEM97. Clinical epigenetics 47 29599847
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
2020 The Biological Function of Sigma-2 Receptor/TMEM97 and Its Utility in PET Imaging Studies in Cancer. Cancers 45 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 42 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 31 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 28 29426225
2019 Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor. BMC cancer 27 31109310
2012 Expression of MAC30 protein is related to survival and clinicopathological variables in breast cancer. Journal of surgical oncology 27 22996179
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
2024 Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice. eNeuro 11 38866499
2022 TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3β/β-catenin signaling pathway. Human cell 11 35907137
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
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
2024 Structure-Affinity relationships of novel σ2R/TMEM97 ligands. Bioorganic chemistry 6 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 6 39547121
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 Mechanisms of Sigma-2/TMEM97 Involvement in Cholesterol Metabolism. Journal of cellular biochemistry 5 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
2025 TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis. Molecular therapy. Nucleic acids 3 39995975
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 Discovery of σ2R/TMEM97 as a Novel Biomarker for Atherosclerotic Plaques: A PET Imaging and Validation Study. Arteriosclerosis, thrombosis, and vascular biology 2 40401377
2025 Transmembrane Protein 97 (TMEM97): Molecular Target and Treatment in Age-Related Macular Degeneration (AMD). Biomolecules 1 41008535
2023 Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response. bioRxiv : the preprint server for biology 1 37090527
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

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