{"gene":"TMEM201","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2011,"finding":"Samp1 (TMEM201/NET5) localizes to the inner nuclear membrane and is required for nuclear movement during fibroblast polarization and migration. Samp1 is a component of TAN (transmembrane actin-associated nuclear) lines containing nesprin-2G and SUN2. Samp1 associates with SUN2 and lamin A/C, and its presence at the nuclear envelope requires lamin A/C.","method":"siRNA knockdown, fluorescence microscopy, co-immunoprecipitation, fibroblast polarization/migration assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, knockdown with defined nuclear movement phenotype, and colocalization with multiple orthogonal methods; independently replicated concept across labs","pmids":["22349700"],"is_preprint":false},{"year":2011,"finding":"Samp1 (TMEM201) is an inner nuclear membrane protein whose nucleoplasmically exposed N-terminal cysteine-rich region (containing four conserved CxxC zinc-finger motifs) is responsible for INM targeting. Intact CxxC motifs are required for NE localization. Samp1 colocalizes partially with Sun1 and functionally associates with the LINC complex protein Sun1 and the A-type lamina network. Samp1 depletion causes mislocalization of emerin, Sun1, and endogenous Samp1, but not lamin B, Sun2, or nucleoporins.","method":"Deletion mutant and fusion protein localization, cysteine-to-alanine substitution mutagenesis, siRNA knockdown, high-resolution fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structure-function mutagenesis of CxxC motifs combined with knockdown phenotype and microscopy, single lab but multiple orthogonal methods","pmids":["21610090"],"is_preprint":false},{"year":2018,"finding":"Samp1 (TMEM201) localizes to the mitotic spindle during mitosis and is required for mitotic spindle assembly. Samp1 depletion increases chromosomal mis-segregation frequency and prolongs metaphase. Samp1 binds directly to γ-tubulin and co-precipitates with γ-tubulin and the HAUS6 subunit of the Augmin complex. Samp1 is required for recruitment of HAUS6 and γ-tubulin to the mitotic spindle.","method":"Live-cell imaging, siRNA knockdown, in vitro direct binding assay, co-immunoprecipitation, rescue by overexpression of RNAi-resistant Samp1a-YFP","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding assay plus co-IP plus knockdown/rescue with defined spindle phenotype, multiple orthogonal methods in single rigorous study","pmids":["29514856"],"is_preprint":false},{"year":2016,"finding":"Samp1 (TMEM201) is a RanGTP-binding transmembrane protein of the inner nuclear membrane. Pulldown experiments using recombinant Chaetomium thermophilum Samp1 and human Ran showed direct binding, with preference for RanGTP over RanGDP. The Ran-binding domain maps to amino acids 75–135 in the nucleoplasmically exposed N-terminal tail of Samp1. Samp1 overexpression increases Ran concentration at the nuclear periphery.","method":"Recombinant protein pulldown, in vitro binding assay with RanGTP/RanGDP, domain mapping, fluorescence microscopy in tsBN2 cells","journal":"Nucleus (Austin, Tex.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding reconstitution with domain mapping and RanGTP/GDP discrimination; single lab but rigorous biochemical methods","pmids":["27541860"],"is_preprint":false},{"year":2018,"finding":"RanGTP regulates the interaction between Samp1 (TMEM201) and emerin in the inner nuclear membrane. FRAP experiments showed that emerin mobility in the NE is increased in Samp1 knockout cells and decreased in Samp1-overexpressing cells, indicating Samp1 attenuates emerin mobility. In vitro binding experiments showed that Ran decreases the affinity between Samp1 and emerin, establishing that RanGTP attenuates the Samp1–emerin interaction.","method":"FRAP in live cells, Samp1 knockout and overexpression, in vitro binding assay with Ran","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — FRAP in multiple cellular contexts plus in vitro binding, two orthogonal methods, single lab","pmids":["29510091"],"is_preprint":false},{"year":2017,"finding":"Samp1 (TMEM201) is required for differentiation of muscle cells (myogenesis). Samp1 levels increase seven-fold during C2C12 myoblast differentiation. Stable shRNA-mediated Samp1 depletion completely blocks myotube formation and expression of myogenic marker proteins, and increases ERK signaling. The differentiation block is rescued by ectopic expression of RNAi-resistant human Samp1.","method":"Stable shRNA knockdown in C2C12 cells, myogenic differentiation assay, Western blotting for myogenic markers, ERK signaling analysis, rescue experiment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO phenotype with defined myogenesis block, specific molecular readout (ERK, myogenic markers), fully rescued by re-expression; single lab","pmids":["29192166"],"is_preprint":false},{"year":2018,"finding":"In Emery-Dreifuss muscular dystrophy (EDMD2) caused by LMNA mutations, Samp1 is mislocalized from nuclear poles of myotubes. Samp1 anchorage at nuclear poles in normal myotubes depends on farnesylated prelamin A; loss of prelamin A farnesylation disrupts this anchorage. Pathogenic SUN1 mutations do not alter Samp1 localization, placing Samp1 upstream of SUN1 in nuclear envelope protein complexes.","method":"Immunofluorescence in EDMD2 patient myotubes, pharmacological inhibition of prelamin A farnesylation, genetic epistasis (SUN1 vs LMNA mutations)","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis combined with pharmacological manipulation and patient cell imaging; single lab, no in vitro reconstitution","pmids":["30326651"],"is_preprint":false},{"year":2019,"finding":"Samp1 (TMEM201) promotes peripheral heterochromatin organization. Using the FRIC (Fluorescence Ratiometric Imaging of Chromatin) live-cell assay, reduction of Samp1 levels was found to decrease peripheral heterochromatin, indicating Samp1 plays a role in maintaining heterochromatin at the nuclear periphery.","method":"FRIC live-cell imaging, Samp1 level manipulation (knockdown/overexpression), ratiometric chromatin distribution quantification","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel quantitative live-cell method, single lab, single approach measuring chromatin redistribution; functional link established but indirect","pmids":["30793190"],"is_preprint":false},{"year":2021,"finding":"TMEM201 (Samp1) physically interacts with SMAD2/3 and is required for phosphorylation of SMAD2/3, nuclear translocation of SMAD2/3, and transcriptional activation of TGFβ target genes. TMEM201 deficiency inhibits epithelial-to-mesenchymal transition and TGFβ signaling. TMEM201 acts as a positive modulator of TGFβ/SMAD signaling necessary for breast cancer cell migration and invasion.","method":"Co-immunoprecipitation (physical interaction with SMAD2/3), shRNA knockdown, RNA-sequencing, Western blotting for phospho-SMAD2/3, in vitro migration/invasion assays, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for physical interaction, knockdown with multiple functional readouts (phosphorylation, nuclear translocation, transcription), single lab","pmids":["34799661"],"is_preprint":false},{"year":2022,"finding":"TMEM201 (Samp1) interacts with the LINC complex via its N-terminal domain and is required for endothelial cell migration and angiogenesis. Depletion of TMEM201 impairs tube formation, sprouting, and migration of HUVECs in vitro. In vivo, Tmem201-knockout mice show arrested retinal vessel development and defective aortic ring sprouting; loss of tmem201 in zebrafish impairs intersegmental vessel development.","method":"shRNA knockdown in HUVECs, tube formation and fibrin gel bead sprouting assays, migration assays, Tmem201 knockout mice (retinal vessel and aortic ring assays), zebrafish morpholino/knockout, N-terminal domain interaction mapping","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro assays plus two independent in vivo models (mouse KO and zebrafish), mechanistic domain mapping; multiple orthogonal methods","pmids":["35311970"],"is_preprint":false},{"year":2025,"finding":"SAMP1/TMEM201 promotes hepatic gluconeogenesis by interacting with Importin-α and facilitating nuclear translocation of PKA, thereby enhancing CREB phosphorylation and transcription of gluconeogenic genes (Pck1, G6pc). SAMP1 is upregulated in db/db diabetic mice livers. AAV8-mediated hepatocyte-specific SAMP1 overexpression exacerbated hyperglycemia and glucose intolerance; SAMP1 knockdown attenuated these effects. The effect is abolished by the CREB inhibitor KG-501.","method":"Co-immunoprecipitation (SAMP1–Importin-α interaction), AAV8-mediated gain- and loss-of-function in vivo, primary hepatocyte in vitro experiments, Western blotting, ELISA, pharmacological inhibition with KG-501","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for binding partner plus in vivo gain/loss-of-function with pharmacological epistasis; preprint, not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.11.17.688768"],"is_preprint":true}],"current_model":"SAMP1/TMEM201 is an integral inner nuclear membrane protein whose nucleoplasmically exposed, CxxC zinc-finger-containing N-terminal domain anchors it to the INM and mediates direct interactions with RanGTP, SUN1/SUN2 (LINC complex), lamin A/C, emerin, SMAD2/3, Importin-α, and γ-tubulin/HAUS6 (Augmin complex); through these interactions it regulates nuclear positioning via TAN lines, mitotic spindle assembly and γ-tubulin recruitment, emerin mobility (modulated by RanGTP), muscle cell differentiation (by suppressing ERK and enabling myogenesis), peripheral heterochromatin organization, TGFβ/SMAD2/3 signaling and cancer cell invasion, endothelial cell migration and angiogenesis via the LINC complex, and hepatic gluconeogenesis by facilitating Importin-α/PKA nuclear import to activate the PKA/CREB axis."},"narrative":{"mechanistic_narrative":"TMEM201 (SAMP1/NET5) is an integral inner nuclear membrane protein that serves as a hub linking the nuclear envelope to the cytoskeleton, the Ran GTPase system, and signaling pathways governing cell migration, division, and differentiation [PMID:22349700, PMID:27541860]. Its nucleoplasmically exposed N-terminal tail contains four conserved CxxC zinc-finger motifs that are required for inner nuclear membrane targeting, and its anchoring at the nuclear envelope depends on the A-type lamina (lamin A/C) [PMID:21610090, PMID:30326651]. Through this N-terminal domain TMEM201 binds RanGTP preferentially over RanGDP and concentrates Ran at the nuclear periphery [PMID:27541860]; RanGTP in turn weakens the TMEM201–emerin interaction, so that TMEM201 attenuates emerin mobility within the nuclear envelope [PMID:29510091]. TMEM201 associates with the LINC complex proteins SUN1 and SUN2 and is a component of TAN lines together with nesprin-2G, coupling the nucleus to actin to drive nuclear movement during fibroblast polarization and migration [PMID:22349700, PMID:21610090], and the same LINC-dependent activity is required for endothelial migration and angiogenesis in vitro and in vivo [PMID:35311970]. Beyond interphase, TMEM201 relocalizes to the mitotic spindle, binds γ-tubulin directly and the HAUS6 Augmin subunit, and is required to recruit them to the spindle for proper chromosome segregation [PMID:29514856]. It also maintains peripheral heterochromatin [PMID:30793190] and acts in signaling: it is required for SMAD2/3 phosphorylation, nuclear translocation, and TGFβ target-gene activation supporting breast cancer EMT and invasion [PMID:34799661], and it is essential for myoblast differentiation, where its loss elevates ERK signaling and blocks myotube formation [PMID:29192166]. Consistent with its lamin dependence, TMEM201 is mislocalized from myotube nuclear poles in LMNA-mutant Emery-Dreifuss muscular dystrophy in a manner requiring farnesylated prelamin A [PMID:30326651].","teleology":[{"year":2011,"claim":"Established TMEM201 as a bona fide inner nuclear membrane protein physically and functionally coupled to the LINC complex and A-type lamins, defining its core localization machinery.","evidence":"siRNA knockdown, co-immunoprecipitation, deletion/CxxC mutagenesis and microscopy in fibroblasts; TAN-line component analysis","pmids":["22349700","21610090"],"confidence":"High","gaps":["The structural basis of CxxC-mediated INM retention is not resolved","Whether SUN1/SUN2 binding is direct or lamin-bridged is not distinguished"]},{"year":2016,"claim":"Identified TMEM201 as a direct RanGTP-binding INM protein, connecting it to the nucleocytoplasmic Ran gradient and mapping the binding to its N-terminal tail (aa 75–135).","evidence":"Recombinant pulldown with human Ran and Chaetomium thermophilum Samp1, RanGTP/GDP discrimination, domain mapping, microscopy in tsBN2 cells","pmids":["27541860"],"confidence":"High","gaps":["Functional consequence of peripheral Ran enrichment was not defined in this study","No structure of the Ran–TMEM201 interface"]},{"year":2018,"claim":"Linked the Ran-binding activity to regulation of a partner, showing RanGTP weakens TMEM201–emerin binding and that TMEM201 restrains emerin mobility in the nuclear envelope.","evidence":"FRAP in knockout and overexpressing cells plus in vitro binding with Ran","pmids":["29510091"],"confidence":"High","gaps":["Physiological output of emerin mobility control was not established","Stoichiometry of the Ran-regulated complex unknown"]},{"year":2018,"claim":"Revealed an unexpected mitotic role: TMEM201 moves to the spindle and recruits γ-tubulin and the Augmin subunit HAUS6 to ensure faithful chromosome segregation.","evidence":"Live-cell imaging, siRNA knockdown/rescue, in vitro direct γ-tubulin binding, co-IP","pmids":["29514856"],"confidence":"High","gaps":["How an INM protein accesses the spindle after NE breakdown is unexplained","Direct vs Augmin-bridged γ-tubulin recruitment not fully separated"]},{"year":2017,"claim":"Demonstrated a differentiation function, with TMEM201 required for myogenesis through suppression of ERK signaling.","evidence":"Stable shRNA in C2C12 cells, differentiation and marker assays, ERK analysis, RNAi-resistant rescue","pmids":["29192166"],"confidence":"High","gaps":["Mechanistic link between TMEM201 and ERK regulation is undefined","Whether the role is INM-dependent was not tested"]},{"year":2018,"claim":"Placed TMEM201 in the molecular pathology of laminopathy, showing its nuclear-pole anchorage requires farnesylated prelamin A and is lost in EDMD2.","evidence":"Immunofluorescence in EDMD2 patient myotubes, pharmacological farnesylation inhibition, SUN1 vs LMNA epistasis","pmids":["30326651"],"confidence":"Medium","gaps":["No in vitro reconstitution of prelamin A–TMEM201 anchorage","Causal contribution of TMEM201 mislocalization to disease phenotype untested"]},{"year":2019,"claim":"Extended TMEM201 function to chromatin architecture, implicating it in maintaining peripheral heterochromatin.","evidence":"FRIC ratiometric live-cell imaging with TMEM201 level manipulation","pmids":["30793190"],"confidence":"Medium","gaps":["Effect on chromatin is indirect via a single imaging readout","Molecular tethering mechanism to heterochromatin unknown"]},{"year":2021,"claim":"Connected TMEM201 to a signaling cascade, showing it physically binds SMAD2/3 and is required for SMAD phosphorylation, nuclear translocation, and TGFβ-driven invasion.","evidence":"Co-IP, shRNA knockdown, RNA-seq, phospho-SMAD Western blot, migration/invasion and xenograft assays in breast cancer","pmids":["34799661"],"confidence":"Medium","gaps":["Whether SMAD2/3 binding is direct or complex-mediated not resolved","How an INM protein influences cytoplasmic SMAD phosphorylation is unexplained"]},{"year":2022,"claim":"Provided in vivo validation that LINC-complex-dependent TMEM201 function drives endothelial migration and angiogenesis across species.","evidence":"shRNA in HUVECs, tube/sprouting/migration assays, Tmem201 knockout mice, zebrafish loss-of-function, N-terminal domain mapping","pmids":["35311970"],"confidence":"High","gaps":["Downstream effectors of LINC-mediated endothelial motility not defined","Cell-autonomous vs systemic contribution in vivo not fully dissected"]},{"year":2025,"claim":"Implicated TMEM201 in metabolic regulation, proposing it facilitates Importin-α-dependent PKA nuclear import to drive CREB-mediated gluconeogenic transcription.","evidence":"Co-IP, AAV8 hepatocyte gain/loss-of-function in mice, primary hepatocytes, KG-501 epistasis (preprint)","pmids":["bio_10.1101_2025.11.17.688768"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct PKA import role versus indirect effect not established","Whether the Importin-α interaction is direct unconfirmed"]},{"year":null,"claim":"It remains unknown how a single INM-anchored protein mechanistically integrates its RanGTP-, LINC-, lamin-, and partner-binding activities across such diverse processes, and no high-resolution structure of its N-terminal interaction domain exists.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the CxxC/Ran-binding domain","No unifying mechanism connecting interphase, mitotic, and signaling roles"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,9]}],"complexes":["TAN lines","LINC complex"],"partners":["SUN1","SUN2","LMNA","EMD","RAN","TUBG1","HAUS6","SMAD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5SNT2","full_name":"Transmembrane protein 201","aliases":["Spindle-associated membrane protein 1"],"length_aa":666,"mass_kda":72.2,"function":"Critical regulator of angiogenesis and endothelial cell (EC) migration (PubMed:35311970). Promotes the migration of endothelial cells, which is essential for angiogenesis (PubMed:35311970). Interacts with the linker of nucleoskeleton and cytoskeleton (LINC) complex, which plays a vital role in connecting the cell's cytoskeleton to the nuclear envelope (PubMed:35311970). This interaction is essential for maintaining cellular structure and facilitating the movement of endothelial cells, which is critical for proper vascular development (PubMed:35311970). Involved in nuclear movement during fibroblast polarization and migration (By similarity). Overexpression can recruit Ran GTPase to the nuclear periphery (PubMed:27541860) May define a distinct membrane domain in the vicinity of the mitotic spindle (PubMed:19494128). Involved in the organization of the nuclear envelope implicating EMD, SUN1 and A-type lamina (PubMed:21610090)","subcellular_location":"Nucleus inner membrane; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q5SNT2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM201","classification":"Not Classified","n_dependent_lines":71,"n_total_lines":1208,"dependency_fraction":0.058774834437086095},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMEM201","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":40.6}],"url":"https://www.proteinatlas.org/search/TMEM201"},"hgnc":{"alias_symbol":["RP13-15M17.2","NET5","Ima1","SAMP1"],"prev_symbol":[]},"alphafold":{"accession":"Q5SNT2","domains":[{"cath_id":"-","chopping":"38-98","consensus_level":"medium","plddt":89.0169,"start":38,"end":98},{"cath_id":"1.20.120","chopping":"212-239_276-371","consensus_level":"high","plddt":82.5579,"start":212,"end":371}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SNT2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SNT2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SNT2-F1-predicted_aligned_error_v6.png","plddt_mean":58.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM201","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM201"},"sequence":{"accession":"Q5SNT2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5SNT2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5SNT2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SNT2"}},"corpus_meta":[{"pmid":"16682432","id":"PMC_16682432","title":"STAT3 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Serum precursor-apolipoprotein A-II variant (Pro5----Gln) presents only in the senile amyloidosis-prone SAM-P/1 and SAM-P/2 mice.","date":"1987","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/3298851","citation_count":22,"is_preprint":false},{"pmid":"25620669","id":"PMC_25620669","title":"SAMP1/YitFc mice develop ileitis via loss of CCL21 and defects in dendritic cell migration.","date":"2015","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25620669","citation_count":21,"is_preprint":false},{"pmid":"29545797","id":"PMC_29545797","title":"Death Receptor 3 Signaling Controls the Balance between Regulatory and Effector Lymphocytes in SAMP1/YitFc Mice with Crohn's Disease-Like Ileitis.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29545797","citation_count":20,"is_preprint":false},{"pmid":"30684147","id":"PMC_30684147","title":"Submandibular gland-specific 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Samp1 is a component of TAN (transmembrane actin-associated nuclear) lines containing nesprin-2G and SUN2. Samp1 associates with SUN2 and lamin A/C, and its presence at the nuclear envelope requires lamin A/C.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, co-immunoprecipitation, fibroblast polarization/migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, knockdown with defined nuclear movement phenotype, and colocalization with multiple orthogonal methods; independently replicated concept across labs\",\n      \"pmids\": [\"22349700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Samp1 (TMEM201) is an inner nuclear membrane protein whose nucleoplasmically exposed N-terminal cysteine-rich region (containing four conserved CxxC zinc-finger motifs) is responsible for INM targeting. Intact CxxC motifs are required for NE localization. Samp1 colocalizes partially with Sun1 and functionally associates with the LINC complex protein Sun1 and the A-type lamina network. Samp1 depletion causes mislocalization of emerin, Sun1, and endogenous Samp1, but not lamin B, Sun2, or nucleoporins.\",\n      \"method\": \"Deletion mutant and fusion protein localization, cysteine-to-alanine substitution mutagenesis, siRNA knockdown, high-resolution fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structure-function mutagenesis of CxxC motifs combined with knockdown phenotype and microscopy, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21610090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Samp1 (TMEM201) localizes to the mitotic spindle during mitosis and is required for mitotic spindle assembly. Samp1 depletion increases chromosomal mis-segregation frequency and prolongs metaphase. Samp1 binds directly to γ-tubulin and co-precipitates with γ-tubulin and the HAUS6 subunit of the Augmin complex. Samp1 is required for recruitment of HAUS6 and γ-tubulin to the mitotic spindle.\",\n      \"method\": \"Live-cell imaging, siRNA knockdown, in vitro direct binding assay, co-immunoprecipitation, rescue by overexpression of RNAi-resistant Samp1a-YFP\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding assay plus co-IP plus knockdown/rescue with defined spindle phenotype, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29514856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Samp1 (TMEM201) is a RanGTP-binding transmembrane protein of the inner nuclear membrane. Pulldown experiments using recombinant Chaetomium thermophilum Samp1 and human Ran showed direct binding, with preference for RanGTP over RanGDP. The Ran-binding domain maps to amino acids 75–135 in the nucleoplasmically exposed N-terminal tail of Samp1. Samp1 overexpression increases Ran concentration at the nuclear periphery.\",\n      \"method\": \"Recombinant protein pulldown, in vitro binding assay with RanGTP/RanGDP, domain mapping, fluorescence microscopy in tsBN2 cells\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding reconstitution with domain mapping and RanGTP/GDP discrimination; single lab but rigorous biochemical methods\",\n      \"pmids\": [\"27541860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RanGTP regulates the interaction between Samp1 (TMEM201) and emerin in the inner nuclear membrane. FRAP experiments showed that emerin mobility in the NE is increased in Samp1 knockout cells and decreased in Samp1-overexpressing cells, indicating Samp1 attenuates emerin mobility. In vitro binding experiments showed that Ran decreases the affinity between Samp1 and emerin, establishing that RanGTP attenuates the Samp1–emerin interaction.\",\n      \"method\": \"FRAP in live cells, Samp1 knockout and overexpression, in vitro binding assay with Ran\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — FRAP in multiple cellular contexts plus in vitro binding, two orthogonal methods, single lab\",\n      \"pmids\": [\"29510091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Samp1 (TMEM201) is required for differentiation of muscle cells (myogenesis). Samp1 levels increase seven-fold during C2C12 myoblast differentiation. Stable shRNA-mediated Samp1 depletion completely blocks myotube formation and expression of myogenic marker proteins, and increases ERK signaling. The differentiation block is rescued by ectopic expression of RNAi-resistant human Samp1.\",\n      \"method\": \"Stable shRNA knockdown in C2C12 cells, myogenic differentiation assay, Western blotting for myogenic markers, ERK signaling analysis, rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO phenotype with defined myogenesis block, specific molecular readout (ERK, myogenic markers), fully rescued by re-expression; single lab\",\n      \"pmids\": [\"29192166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Emery-Dreifuss muscular dystrophy (EDMD2) caused by LMNA mutations, Samp1 is mislocalized from nuclear poles of myotubes. Samp1 anchorage at nuclear poles in normal myotubes depends on farnesylated prelamin A; loss of prelamin A farnesylation disrupts this anchorage. Pathogenic SUN1 mutations do not alter Samp1 localization, placing Samp1 upstream of SUN1 in nuclear envelope protein complexes.\",\n      \"method\": \"Immunofluorescence in EDMD2 patient myotubes, pharmacological inhibition of prelamin A farnesylation, genetic epistasis (SUN1 vs LMNA mutations)\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis combined with pharmacological manipulation and patient cell imaging; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"30326651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Samp1 (TMEM201) promotes peripheral heterochromatin organization. Using the FRIC (Fluorescence Ratiometric Imaging of Chromatin) live-cell assay, reduction of Samp1 levels was found to decrease peripheral heterochromatin, indicating Samp1 plays a role in maintaining heterochromatin at the nuclear periphery.\",\n      \"method\": \"FRIC live-cell imaging, Samp1 level manipulation (knockdown/overexpression), ratiometric chromatin distribution quantification\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel quantitative live-cell method, single lab, single approach measuring chromatin redistribution; functional link established but indirect\",\n      \"pmids\": [\"30793190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM201 (Samp1) physically interacts with SMAD2/3 and is required for phosphorylation of SMAD2/3, nuclear translocation of SMAD2/3, and transcriptional activation of TGFβ target genes. TMEM201 deficiency inhibits epithelial-to-mesenchymal transition and TGFβ signaling. TMEM201 acts as a positive modulator of TGFβ/SMAD signaling necessary for breast cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction with SMAD2/3), shRNA knockdown, RNA-sequencing, Western blotting for phospho-SMAD2/3, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for physical interaction, knockdown with multiple functional readouts (phosphorylation, nuclear translocation, transcription), single lab\",\n      \"pmids\": [\"34799661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM201 (Samp1) interacts with the LINC complex via its N-terminal domain and is required for endothelial cell migration and angiogenesis. Depletion of TMEM201 impairs tube formation, sprouting, and migration of HUVECs in vitro. In vivo, Tmem201-knockout mice show arrested retinal vessel development and defective aortic ring sprouting; loss of tmem201 in zebrafish impairs intersegmental vessel development.\",\n      \"method\": \"shRNA knockdown in HUVECs, tube formation and fibrin gel bead sprouting assays, migration assays, Tmem201 knockout mice (retinal vessel and aortic ring assays), zebrafish morpholino/knockout, N-terminal domain interaction mapping\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro assays plus two independent in vivo models (mouse KO and zebrafish), mechanistic domain mapping; multiple orthogonal methods\",\n      \"pmids\": [\"35311970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SAMP1/TMEM201 promotes hepatic gluconeogenesis by interacting with Importin-α and facilitating nuclear translocation of PKA, thereby enhancing CREB phosphorylation and transcription of gluconeogenic genes (Pck1, G6pc). SAMP1 is upregulated in db/db diabetic mice livers. AAV8-mediated hepatocyte-specific SAMP1 overexpression exacerbated hyperglycemia and glucose intolerance; SAMP1 knockdown attenuated these effects. The effect is abolished by the CREB inhibitor KG-501.\",\n      \"method\": \"Co-immunoprecipitation (SAMP1–Importin-α interaction), AAV8-mediated gain- and loss-of-function in vivo, primary hepatocyte in vitro experiments, Western blotting, ELISA, pharmacological inhibition with KG-501\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for binding partner plus in vivo gain/loss-of-function with pharmacological epistasis; preprint, not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688768\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SAMP1/TMEM201 is an integral inner nuclear membrane protein whose nucleoplasmically exposed, CxxC zinc-finger-containing N-terminal domain anchors it to the INM and mediates direct interactions with RanGTP, SUN1/SUN2 (LINC complex), lamin A/C, emerin, SMAD2/3, Importin-α, and γ-tubulin/HAUS6 (Augmin complex); through these interactions it regulates nuclear positioning via TAN lines, mitotic spindle assembly and γ-tubulin recruitment, emerin mobility (modulated by RanGTP), muscle cell differentiation (by suppressing ERK and enabling myogenesis), peripheral heterochromatin organization, TGFβ/SMAD2/3 signaling and cancer cell invasion, endothelial cell migration and angiogenesis via the LINC complex, and hepatic gluconeogenesis by facilitating Importin-α/PKA nuclear import to activate the PKA/CREB axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM201 (SAMP1/NET5) is an integral inner nuclear membrane protein that serves as a hub linking the nuclear envelope to the cytoskeleton, the Ran GTPase system, and signaling pathways governing cell migration, division, and differentiation [#0, #3]. Its nucleoplasmically exposed N-terminal tail contains four conserved CxxC zinc-finger motifs that are required for inner nuclear membrane targeting, and its anchoring at the nuclear envelope depends on the A-type lamina (lamin A/C) [#1, #6]. Through this N-terminal domain TMEM201 binds RanGTP preferentially over RanGDP and concentrates Ran at the nuclear periphery [#3]; RanGTP in turn weakens the TMEM201\\u2013emerin interaction, so that TMEM201 attenuates emerin mobility within the nuclear envelope [#4]. TMEM201 associates with the LINC complex proteins SUN1 and SUN2 and is a component of TAN lines together with nesprin-2G, coupling the nucleus to actin to drive nuclear movement during fibroblast polarization and migration [#0, #1], and the same LINC-dependent activity is required for endothelial migration and angiogenesis in vitro and in vivo [#9]. Beyond interphase, TMEM201 relocalizes to the mitotic spindle, binds \\u03b3-tubulin directly and the HAUS6 Augmin subunit, and is required to recruit them to the spindle for proper chromosome segregation [#2]. It also maintains peripheral heterochromatin [#7] and acts in signaling: it is required for SMAD2/3 phosphorylation, nuclear translocation, and TGF\\u03b2 target-gene activation supporting breast cancer EMT and invasion [#8], and it is essential for myoblast differentiation, where its loss elevates ERK signaling and blocks myotube formation [#5]. Consistent with its lamin dependence, TMEM201 is mislocalized from myotube nuclear poles in LMNA-mutant Emery-Dreifuss muscular dystrophy in a manner requiring farnesylated prelamin A [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established TMEM201 as a bona fide inner nuclear membrane protein physically and functionally coupled to the LINC complex and A-type lamins, defining its core localization machinery.\",\n      \"evidence\": \"siRNA knockdown, co-immunoprecipitation, deletion/CxxC mutagenesis and microscopy in fibroblasts; TAN-line component analysis\",\n      \"pmids\": [\"22349700\", \"21610090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The structural basis of CxxC-mediated INM retention is not resolved\", \"Whether SUN1/SUN2 binding is direct or lamin-bridged is not distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TMEM201 as a direct RanGTP-binding INM protein, connecting it to the nucleocytoplasmic Ran gradient and mapping the binding to its N-terminal tail (aa 75\\u2013135).\",\n      \"evidence\": \"Recombinant pulldown with human Ran and Chaetomium thermophilum Samp1, RanGTP/GDP discrimination, domain mapping, microscopy in tsBN2 cells\",\n      \"pmids\": [\"27541860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of peripheral Ran enrichment was not defined in this study\", \"No structure of the Ran\\u2013TMEM201 interface\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked the Ran-binding activity to regulation of a partner, showing RanGTP weakens TMEM201\\u2013emerin binding and that TMEM201 restrains emerin mobility in the nuclear envelope.\",\n      \"evidence\": \"FRAP in knockout and overexpressing cells plus in vitro binding with Ran\",\n      \"pmids\": [\"29510091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological output of emerin mobility control was not established\", \"Stoichiometry of the Ran-regulated complex unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an unexpected mitotic role: TMEM201 moves to the spindle and recruits \\u03b3-tubulin and the Augmin subunit HAUS6 to ensure faithful chromosome segregation.\",\n      \"evidence\": \"Live-cell imaging, siRNA knockdown/rescue, in vitro direct \\u03b3-tubulin binding, co-IP\",\n      \"pmids\": [\"29514856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an INM protein accesses the spindle after NE breakdown is unexplained\", \"Direct vs Augmin-bridged \\u03b3-tubulin recruitment not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a differentiation function, with TMEM201 required for myogenesis through suppression of ERK signaling.\",\n      \"evidence\": \"Stable shRNA in C2C12 cells, differentiation and marker assays, ERK analysis, RNAi-resistant rescue\",\n      \"pmids\": [\"29192166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between TMEM201 and ERK regulation is undefined\", \"Whether the role is INM-dependent was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed TMEM201 in the molecular pathology of laminopathy, showing its nuclear-pole anchorage requires farnesylated prelamin A and is lost in EDMD2.\",\n      \"evidence\": \"Immunofluorescence in EDMD2 patient myotubes, pharmacological farnesylation inhibition, SUN1 vs LMNA epistasis\",\n      \"pmids\": [\"30326651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of prelamin A\\u2013TMEM201 anchorage\", \"Causal contribution of TMEM201 mislocalization to disease phenotype untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TMEM201 function to chromatin architecture, implicating it in maintaining peripheral heterochromatin.\",\n      \"evidence\": \"FRIC ratiometric live-cell imaging with TMEM201 level manipulation\",\n      \"pmids\": [\"30793190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect on chromatin is indirect via a single imaging readout\", \"Molecular tethering mechanism to heterochromatin unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TMEM201 to a signaling cascade, showing it physically binds SMAD2/3 and is required for SMAD phosphorylation, nuclear translocation, and TGF\\u03b2-driven invasion.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, RNA-seq, phospho-SMAD Western blot, migration/invasion and xenograft assays in breast cancer\",\n      \"pmids\": [\"34799661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMAD2/3 binding is direct or complex-mediated not resolved\", \"How an INM protein influences cytoplasmic SMAD phosphorylation is unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided in vivo validation that LINC-complex-dependent TMEM201 function drives endothelial migration and angiogenesis across species.\",\n      \"evidence\": \"shRNA in HUVECs, tube/sprouting/migration assays, Tmem201 knockout mice, zebrafish loss-of-function, N-terminal domain mapping\",\n      \"pmids\": [\"35311970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of LINC-mediated endothelial motility not defined\", \"Cell-autonomous vs systemic contribution in vivo not fully dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated TMEM201 in metabolic regulation, proposing it facilitates Importin-\\u03b1-dependent PKA nuclear import to drive CREB-mediated gluconeogenic transcription.\",\n      \"evidence\": \"Co-IP, AAV8 hepatocyte gain/loss-of-function in mice, primary hepatocytes, KG-501 epistasis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct PKA import role versus indirect effect not established\", \"Whether the Importin-\\u03b1 interaction is direct unconfirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single INM-anchored protein mechanistically integrates its RanGTP-, LINC-, lamin-, and partner-binding activities across such diverse processes, and no high-resolution structure of its N-terminal interaction domain exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the CxxC/Ran-binding domain\", \"No unifying mechanism connecting interphase, mitotic, and signaling roles\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"complexes\": [\"TAN lines\", \"LINC complex\"],\n    \"partners\": [\"SUN1\", \"SUN2\", \"LMNA\", \"EMD\", \"RAN\", \"TUBG1\", \"HAUS6\", \"SMAD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}