{"gene":"CNNM3","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2014,"finding":"PRL-2 forms a functional heterodimer with the magnesium transporter CNNM3 through a loop unique to the CBS pair domains of CNNM3, regulating intracellular magnesium levels. CNNM3 is not a phosphorylated substrate of PRL-2. PRL-2 knockdown decreases cellular magnesium influx, and the PRL-2/CNNM3 interaction is required for oncogenic/transforming activity in xenograft models.","method":"Co-immunoprecipitation, mutagenesis (CNNM3 mutant that does not associate with PRL-2), xenograft tumor assays, magnesium influx measurements, PRL-2 knockout mice","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, functional mutant, in vivo KO, xenograft), replicated in subsequent studies","pmids":["24632616"],"is_preprint":false},{"year":2016,"finding":"The crystal structure of the PRL2–CNNM3 CBS-pair domain complex reveals the molecular basis for interaction. Phosphocysteine formation at the PRL catalytic site regulates PRL-CNNM complex formation: phosphorylation of the active-site cysteine blocks PRL binding to CNNM Mg2+ transporters, and phosphocysteine levels change in response to Mg2+ levels. Mutations blocking PRL-CNNM interaction prevent regulation of Mg2+ efflux in cultured cells.","method":"Crystal structure determination, active-site mutagenesis, phosphocysteine detection, Mg2+ efflux assays in cultured cells","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional Mg2+ efflux assay in a single study","pmids":["27856537"],"is_preprint":false},{"year":2016,"finding":"A single point mutation D426A in the CBS-domain loop of CNNM3 completely disrupts PRL-2·CNNM3 complex formation. Whole-cell voltage clamping showed that CNNM3 influences surface current, while the D426A binding mutant does not, indicating PRL-2 binding is required for CNNM3 activity. The D426A mutant reduces cancer cell proliferation under Mg2+-deprived conditions and impairs anchorage-independent growth and orthotopic tumor growth.","method":"Site-directed mutagenesis, whole-cell voltage clamping, proliferation assays, anchorage-independent growth, orthotopic xenograft model, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with electrophysiology, in vitro and in vivo functional readouts","pmids":["26969161"],"is_preprint":false},{"year":2018,"finding":"The cyclic nucleotide-binding homology (CNBH) domain of CNNM3 mediates dimerization (not cyclic nucleotide binding), as determined by crystal structure at 1.9 Å resolution. CNNM3's CNBH domain was observed exclusively as a dimer (unlike active family members), and mutational analysis showed the CNBH domain is required for Mg2+ efflux activity of CNNM family members.","method":"Crystal structure (1.9 Å), analytical ultracentrifugation, mutagenesis, Mg2+ efflux assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure, biophysical dimerization assay, and functional mutagenesis","pmids":["30341174"],"is_preprint":false},{"year":2021,"finding":"CNNM3 (and CNNM4) selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Knockout of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry without affecting TRPM7 protein expression or surface levels. Whole-cell electrophysiological recordings showed that deletion of CNNM3 and CNNM4 interfered with both heterologously expressed and native TRPM7 channel function. CNNMs also possess separate TRPM7-independent Mg2+ efflux activities.","method":"Knockout cell lines, divalent cation uptake assays, whole-cell electrophysiology, TRPM7 inhibitor (NS8593), surface protein expression analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal functional readouts (electrophysiology, uptake assays, pharmacological inhibition)","pmids":["34928937"],"is_preprint":false},{"year":2021,"finding":"ARL15, a small GTP-binding protein, interacts with CNNMs including CNNM3 at their carboxyl-terminal CBS domains and is required for complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Knockdown of ARL15 in kidney cancer cell lines increases 25Mg2+ uptake, establishing ARL15 as a negative regulator of Mg2+ transport acting through CNNM glycosylation.","method":"Co-immunoprecipitation, immunocytochemistry, in silico modeling, stable isotope 25Mg2+ uptake assays, ARL15 knockdown","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional Mg2+ transport assay, single lab","pmids":["34089346"],"is_preprint":false},{"year":2023,"finding":"ARL15 increases CNNM3/TRPM7 protein complex formation to reduce TRPM7 activity, while PRL-2 overexpression counteracts ARL15 binding to CNNM3 and enhances TRPM7 function by preventing the CNNM3-TRPM7 interaction. Lowering cellular Mg2+ decreases the CNNM3-TRPM7 interaction in a PRL-dependent manner. Co-targeting TRPM7 and PRL-1/2 alters mitochondrial function and sensitizes cells to metabolic stress.","method":"Genetically encoded intracellular Mg2+ reporter, co-immunoprecipitation, overexpression/knockdown, mitochondrial function assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional reporter and metabolic readouts, single lab","pmids":["36972446"],"is_preprint":false},{"year":2014,"finding":"In the seawater pufferfish ortholog Cnnm3, expression in Xenopus laevis oocytes significantly decreased whole cellular Mg2+ content and free intracellular Mg2+ activity, demonstrating Cnnm3-mediated Mg2+ efflux. In vivo, Cnnm3 protein localizes to the lateral membrane of proximal tubule cells in marine teleost kidney, with expression upregulated in seawater conditions.","method":"Xenopus oocyte expression system, Mg2+ measurement, in situ hybridization, immunohistochemistry, RT-PCR","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 — functional expression in oocytes with Mg2+ measurement, plus in vivo localization data; fish ortholog","pmids":["24965791"],"is_preprint":false},{"year":2003,"finding":"ACDP3 (CNNM3) protein, identified by molecular cloning, showed predominant localization in the nucleus of permeabilized HeLa cells by immunofluorescence staining. The protein contains an ancient conserved domain with structural homology to cyclin molecules.","method":"Immunofluorescence staining, cDNA cloning, sequence homology analysis","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 — single localization experiment with no functional follow-up; nuclear localization contradicted by later membrane localization studies","pmids":["12657465"],"is_preprint":false},{"year":2004,"finding":"Mouse Acdp3 (Cnnm3 ortholog) shows strong amino acid homology to bacterial CorC protein involved in Mg2+ and Co2+ efflux (35% identity, 55% homology), suggesting a role in ion transport. Acdp1 (not Acdp3) immunostaining in hippocampus neurons showed predominant plasma membrane localization.","method":"Sequence homology analysis, immunostaining","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 4 — computational homology inference; immunostaining data is for Acdp1 not Acdp3","pmids":["14723793"],"is_preprint":false},{"year":2016,"finding":"In C. elegans, cnnm-1; cnnm-3 double mutants show excessive Mg2+ accumulation and defective gonadogenesis. Genetic epistasis showed that loss of aak-2 (AMPK catalytic subunit) suppresses the gonadogenesis defect, placing CNNM-dependent Mg2+ homeostasis upstream of AMPK-TORC1 signaling in germ cell proliferation.","method":"C. elegans genetic mutant analysis, genome-wide RNAi screening, epistasis with aak-2 triple mutants","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined pathway placement; C. elegans ortholog","pmids":["27564576"],"is_preprint":false},{"year":2020,"finding":"A FRET-based binding assay using purified CNNM3 CBS domain fused to YPet and PRL2 fused to CyPet quantified the CNNM3-PRL2 interaction (measurable Kd). Peptides derived from the CNNM3 CBS domain loop (PRL-binding sequences) inhibited CNNM3-PRL2 interaction in vitro.","method":"FRET assay with purified recombinant proteins, peptide inhibition assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro reconstitution with purified proteins and quantitative binding measurement","pmids":["32733084"],"is_preprint":false},{"year":2018,"finding":"PDK2 promotes cisplatin resistance in lung adenocarcinoma via transcriptional regulation of CNNM3, establishing a PDK2-CNNM3 signaling axis in drug resistance.","method":"Gene expression analysis, in vitro proliferation assays, in vivo tumor growth, mechanistic transcriptional studies","journal":"Journal of drug targeting","confidence":"Low","confidence_rationale":"Tier 3 — transcriptional regulation claim supported by single-lab study with limited mechanistic detail on CNNM3's direct role","pmids":["30457021"],"is_preprint":false}],"current_model":"CNNM3 is a magnesium transporter/regulator that mediates Mg2+ efflux and, via its CBS-pair domain, forms a complex with PRL phosphatases (particularly PRL-2) whose phosphocysteine-regulated interaction modulates CNNM3 activity; CNNM3 also selectively binds and stimulates the TRPM7 channel to promote divalent cation influx, with ARL15-dependent N-glycosylation and dimerization through its CNBH domain providing additional regulatory control of Mg2+ homeostasis and oncogenic signaling."},"narrative":{"teleology":[{"year":2004,"claim":"Sequence homology to the bacterial CorC Mg²⁺/Co²⁺ efflux system first suggested that CNNM3 functions in divalent cation transport, framing the central hypothesis for all subsequent work.","evidence":"Bioinformatic comparison of mouse Acdp3 to bacterial CorC (35% identity, 55% homology)","pmids":["14723793"],"confidence":"Low","gaps":["Purely computational inference with no functional data for CNNM3 itself","No direct transport assay performed","Immunostaining data shown only for Acdp1, not Acdp3"]},{"year":2014,"claim":"Functional studies established that CNNM3 mediates Mg²⁺ efflux and that this activity is co-opted by PRL-2 for oncogenic signaling: PRL-2 binds CNNM3's CBS-pair domain to regulate intracellular Mg²⁺ and promote tumor growth.","evidence":"Xenopus oocyte Mg²⁺ efflux assay (pufferfish ortholog); Co-IP, PRL-2 KO mice, xenograft tumor models, Mg²⁺ influx measurements (human)","pmids":["24632616","24965791"],"confidence":"High","gaps":["Structural basis of PRL-2–CNNM3 interaction not yet resolved","Oocyte efflux data from fish ortholog, not human CNNM3","Whether CNNM3 is itself the transporter or a regulator of a separate transporter was unresolved"]},{"year":2016,"claim":"Crystal structure of the PRL-2–CNNM3 CBS-pair complex revealed the molecular interface and demonstrated that phosphocysteine at the PRL active site acts as a Mg²⁺-sensitive switch controlling complex formation and Mg²⁺ efflux, while a single D426A mutation in the CBS loop completely abrogated binding and function.","evidence":"X-ray crystallography, active-site mutagenesis, phosphocysteine detection, whole-cell voltage clamping, Mg²⁺ efflux assays, orthotopic xenograft models","pmids":["27856537","26969161"],"confidence":"High","gaps":["Whether phosphocysteine regulation is the sole mechanism controlling PRL-CNNM dynamics in vivo","Electrophysiological identity of the CNNM3-associated current was undefined"]},{"year":2016,"claim":"Genetic epistasis in C. elegans placed CNNM-mediated Mg²⁺ homeostasis upstream of AMPK-TORC1 signaling in germ cell proliferation, establishing a conserved physiological role beyond cancer.","evidence":"C. elegans cnnm-1;cnnm-3 double mutants, genome-wide RNAi, aak-2 epistasis","pmids":["27564576"],"confidence":"Medium","gaps":["Genetic analysis used double mutants, so individual contribution of cnnm-3 is unclear","Whether AMPK-TORC1 link is conserved in mammals was not tested"]},{"year":2018,"claim":"Structural determination of the CNBH domain at 1.9 Å resolution showed it forms an obligate dimer (rather than binding cyclic nucleotides), and mutagenesis demonstrated this dimerization is required for Mg²⁺ efflux, defining the domain architecture essential for CNNM3 function.","evidence":"X-ray crystallography, analytical ultracentrifugation, mutagenesis, Mg²⁺ efflux assays","pmids":["30341174"],"confidence":"High","gaps":["Full-length CNNM3 structure not determined","How CNBH dimerization communicates with the transmembrane domain is unknown"]},{"year":2021,"claim":"Beyond Mg²⁺ efflux, CNNM3 was shown to selectively bind and stimulate TRPM7 channel activity to promote divalent cation influx, while ARL15 was identified as a GTPase that promotes CNNM3 N-glycosylation and negatively regulates Mg²⁺ transport.","evidence":"CNNM3/4 KO HEK-293 cells, whole-cell electrophysiology, divalent cation uptake, Co-IP, stable isotope ²⁵Mg²⁺ uptake, ARL15 knockdown","pmids":["34928937","34089346"],"confidence":"High","gaps":["Whether CNNM3 alone (without CNNM4) is sufficient for TRPM7 stimulation was not resolved","Structural basis of CNNM3–TRPM7 interaction is unknown","Whether ARL15-mediated glycosylation affects TRPM7 stimulation specifically was not tested"]},{"year":2023,"claim":"An integrated regulatory model emerged: ARL15 promotes CNNM3–TRPM7 complex formation to restrain TRPM7 activity, while PRL-2 displaces ARL15 from CNNM3 to enhance TRPM7 function, with low intracellular Mg²⁺ reducing CNNM3–TRPM7 interaction in a PRL-dependent manner.","evidence":"Genetically encoded Mg²⁺ reporter, Co-IP, overexpression/knockdown, mitochondrial function assays","pmids":["36972446"],"confidence":"Medium","gaps":["Competitive binding model inferred from overexpression; endogenous stoichiometry not established","Mitochondrial effects are correlative and downstream mechanism is unclear","In vivo validation of the ARL15–PRL-2 competition on CNNM3 is lacking"]},{"year":null,"claim":"Key open questions include: the full-length structure of CNNM3; whether CNNM3 itself conducts Mg²⁺ or acts as a regulatory subunit for another transporter; the structural basis of the CNNM3–TRPM7 interaction; and whether the PRL-2/ARL15 regulatory axis operates in specific tissues in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length CNNM3 structure or cryo-EM model","Pore-forming versus regulatory identity of CNNM3 unresolved","Tissue-specific in vivo functions in mammalian models not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3,4,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,10]}],"complexes":["PRL-2–CNNM3 heterodimer","CNNM3–TRPM7 complex"],"partners":["PRL2","TRPM7","ARL15"],"other_free_text":[]},"mechanistic_narrative":"CNNM3 is a membrane-associated magnesium transporter/regulator that mediates Mg²⁺ efflux and modulates divalent cation homeostasis through multiple regulatory interactions. Its CBS-pair domain forms a heterodimeric complex with PRL-2 phosphatase—structurally resolved and regulated by phosphocysteine at the PRL catalytic site—that is required for Mg²⁺ efflux activity and oncogenic transformation [PMID:24632616, PMID:27856537, PMID:26969161]. The C-terminal CNBH domain mediates obligate dimerization essential for Mg²⁺ efflux, while CNNM3 additionally binds and stimulates the TRPM7 channel to promote divalent cation influx, a function modulated by ARL15-dependent N-glycosylation and antagonized by PRL-2 [PMID:30341174, PMID:34928937, PMID:36972446]. In C. elegans, loss of CNNM orthologs causes Mg²⁺ accumulation and defective gonadogenesis through AMPK-TORC1 signaling, linking CNNM-dependent Mg²⁺ homeostasis to growth control [PMID:27564576]."},"prefetch_data":{"uniprot":{"accession":"Q8NE01","full_name":"Metal transporter CNNM3","aliases":["Ancient conserved domain-containing protein 3","Cyclin-M3"],"length_aa":707,"mass_kda":76.1,"function":"Probable metal transporter","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NE01/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNNM3","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CNNM3","total_profiled":1310},"omim":[{"mim_id":"607805","title":"CYCLIN M4; CNNM4","url":"https://www.omim.org/entry/607805"},{"mim_id":"607804","title":"CYCLIN M3; CNNM3","url":"https://www.omim.org/entry/607804"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CNNM3"},"hgnc":{"alias_symbol":["SLC70A3"],"prev_symbol":["ACDP3"]},"alphafold":{"accession":"Q8NE01","domains":[{"cath_id":"-","chopping":"136-294","consensus_level":"high","plddt":73.7829,"start":136,"end":294},{"cath_id":"3.10.580.10","chopping":"304-446","consensus_level":"medium","plddt":88.2303,"start":304,"end":446},{"cath_id":"2.60.120.10","chopping":"490-592_625-657","consensus_level":"high","plddt":88.9795,"start":490,"end":657}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NE01","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NE01-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NE01-F1-predicted_aligned_error_v6.png","plddt_mean":66.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNNM3","jax_strain_url":"https://www.jax.org/strain/search?query=CNNM3"},"sequence":{"accession":"Q8NE01","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NE01.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NE01/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NE01"}},"corpus_meta":[{"pmid":"24632616","id":"PMC_24632616","title":"The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24632616","citation_count":100,"is_preprint":false},{"pmid":"12657465","id":"PMC_12657465","title":"Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP).","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12657465","citation_count":91,"is_preprint":false},{"pmid":"33967835","id":"PMC_33967835","title":"Ion Transporters and Osmoregulation in the Kidney of Teleost Fishes as a Function of Salinity.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33967835","citation_count":72,"is_preprint":false},{"pmid":"27856537","id":"PMC_27856537","title":"Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.","date":"2016","source":"EMBO 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nucleotide-binding homology domain of the integral membrane protein CNNM mediates dimerization and is required for Mg2+ efflux activity.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30341174","citation_count":34,"is_preprint":false},{"pmid":"31809842","id":"PMC_31809842","title":"Overexpression of circular RNA hsa_circ_0001038 promotes cervical cancer cell progression by acting as a ceRNA for miR-337-3p to regulate cyclin-M3 and metastasis-associated in colon cancer 1 expression.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/31809842","citation_count":32,"is_preprint":false},{"pmid":"34089346","id":"PMC_34089346","title":"ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs.","date":"2021","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/34089346","citation_count":24,"is_preprint":false},{"pmid":"26371886","id":"PMC_26371886","title":"Molecular Profiling of a Rare Rosette-Forming Glioneuronal Tumor Arising in the Spinal Cord.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26371886","citation_count":24,"is_preprint":false},{"pmid":"30457021","id":"PMC_30457021","title":"PDK2 induces cisplatin-resistance in lung adenocarcinoma via transcriptional regulation of CNNM3.","date":"2018","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/30457021","citation_count":19,"is_preprint":false},{"pmid":"36972446","id":"PMC_36972446","title":"PRL-1/2 phosphatases control TRPM7 magnesium-dependent function to regulate cellular bioenergetics.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36972446","citation_count":19,"is_preprint":false},{"pmid":"27564576","id":"PMC_27564576","title":"Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27564576","citation_count":19,"is_preprint":false},{"pmid":"24174975","id":"PMC_24174975","title":"Identification of Target Genes Involved in the Antiproliferative Effect of Enzyme-Modified Ginseng Extract in HepG2 Hepatocarcinoma Cell.","date":"2013","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/24174975","citation_count":15,"is_preprint":false},{"pmid":"24965791","id":"PMC_24965791","title":"Identification and lateral membrane localization of cyclin M3, likely to be involved in renal Mg2+ handling in seawater fish.","date":"2014","source":"American journal of physiology. 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CNNM3 is not a phosphorylated substrate of PRL-2. PRL-2 knockdown decreases cellular magnesium influx, and the PRL-2/CNNM3 interaction is required for oncogenic/transforming activity in xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (CNNM3 mutant that does not associate with PRL-2), xenograft tumor assays, magnesium influx measurements, PRL-2 knockout mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, functional mutant, in vivo KO, xenograft), replicated in subsequent studies\",\n      \"pmids\": [\"24632616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The crystal structure of the PRL2–CNNM3 CBS-pair domain complex reveals the molecular basis for interaction. Phosphocysteine formation at the PRL catalytic site regulates PRL-CNNM complex formation: phosphorylation of the active-site cysteine blocks PRL binding to CNNM Mg2+ transporters, and phosphocysteine levels change in response to Mg2+ levels. Mutations blocking PRL-CNNM interaction prevent regulation of Mg2+ efflux in cultured cells.\",\n      \"method\": \"Crystal structure determination, active-site mutagenesis, phosphocysteine detection, Mg2+ efflux assays in cultured cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional Mg2+ efflux assay in a single study\",\n      \"pmids\": [\"27856537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A single point mutation D426A in the CBS-domain loop of CNNM3 completely disrupts PRL-2·CNNM3 complex formation. Whole-cell voltage clamping showed that CNNM3 influences surface current, while the D426A binding mutant does not, indicating PRL-2 binding is required for CNNM3 activity. The D426A mutant reduces cancer cell proliferation under Mg2+-deprived conditions and impairs anchorage-independent growth and orthotopic tumor growth.\",\n      \"method\": \"Site-directed mutagenesis, whole-cell voltage clamping, proliferation assays, anchorage-independent growth, orthotopic xenograft model, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with electrophysiology, in vitro and in vivo functional readouts\",\n      \"pmids\": [\"26969161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The cyclic nucleotide-binding homology (CNBH) domain of CNNM3 mediates dimerization (not cyclic nucleotide binding), as determined by crystal structure at 1.9 Å resolution. CNNM3's CNBH domain was observed exclusively as a dimer (unlike active family members), and mutational analysis showed the CNBH domain is required for Mg2+ efflux activity of CNNM family members.\",\n      \"method\": \"Crystal structure (1.9 Å), analytical ultracentrifugation, mutagenesis, Mg2+ efflux assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, biophysical dimerization assay, and functional mutagenesis\",\n      \"pmids\": [\"30341174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CNNM3 (and CNNM4) selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Knockout of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry without affecting TRPM7 protein expression or surface levels. Whole-cell electrophysiological recordings showed that deletion of CNNM3 and CNNM4 interfered with both heterologously expressed and native TRPM7 channel function. CNNMs also possess separate TRPM7-independent Mg2+ efflux activities.\",\n      \"method\": \"Knockout cell lines, divalent cation uptake assays, whole-cell electrophysiology, TRPM7 inhibitor (NS8593), surface protein expression analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal functional readouts (electrophysiology, uptake assays, pharmacological inhibition)\",\n      \"pmids\": [\"34928937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARL15, a small GTP-binding protein, interacts with CNNMs including CNNM3 at their carboxyl-terminal CBS domains and is required for complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Knockdown of ARL15 in kidney cancer cell lines increases 25Mg2+ uptake, establishing ARL15 as a negative regulator of Mg2+ transport acting through CNNM glycosylation.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, in silico modeling, stable isotope 25Mg2+ uptake assays, ARL15 knockdown\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional Mg2+ transport assay, single lab\",\n      \"pmids\": [\"34089346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ARL15 increases CNNM3/TRPM7 protein complex formation to reduce TRPM7 activity, while PRL-2 overexpression counteracts ARL15 binding to CNNM3 and enhances TRPM7 function by preventing the CNNM3-TRPM7 interaction. Lowering cellular Mg2+ decreases the CNNM3-TRPM7 interaction in a PRL-dependent manner. Co-targeting TRPM7 and PRL-1/2 alters mitochondrial function and sensitizes cells to metabolic stress.\",\n      \"method\": \"Genetically encoded intracellular Mg2+ reporter, co-immunoprecipitation, overexpression/knockdown, mitochondrial function assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional reporter and metabolic readouts, single lab\",\n      \"pmids\": [\"36972446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the seawater pufferfish ortholog Cnnm3, expression in Xenopus laevis oocytes significantly decreased whole cellular Mg2+ content and free intracellular Mg2+ activity, demonstrating Cnnm3-mediated Mg2+ efflux. In vivo, Cnnm3 protein localizes to the lateral membrane of proximal tubule cells in marine teleost kidney, with expression upregulated in seawater conditions.\",\n      \"method\": \"Xenopus oocyte expression system, Mg2+ measurement, in situ hybridization, immunohistochemistry, RT-PCR\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional expression in oocytes with Mg2+ measurement, plus in vivo localization data; fish ortholog\",\n      \"pmids\": [\"24965791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ACDP3 (CNNM3) protein, identified by molecular cloning, showed predominant localization in the nucleus of permeabilized HeLa cells by immunofluorescence staining. The protein contains an ancient conserved domain with structural homology to cyclin molecules.\",\n      \"method\": \"Immunofluorescence staining, cDNA cloning, sequence homology analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single localization experiment with no functional follow-up; nuclear localization contradicted by later membrane localization studies\",\n      \"pmids\": [\"12657465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse Acdp3 (Cnnm3 ortholog) shows strong amino acid homology to bacterial CorC protein involved in Mg2+ and Co2+ efflux (35% identity, 55% homology), suggesting a role in ion transport. Acdp1 (not Acdp3) immunostaining in hippocampus neurons showed predominant plasma membrane localization.\",\n      \"method\": \"Sequence homology analysis, immunostaining\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational homology inference; immunostaining data is for Acdp1 not Acdp3\",\n      \"pmids\": [\"14723793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans, cnnm-1; cnnm-3 double mutants show excessive Mg2+ accumulation and defective gonadogenesis. Genetic epistasis showed that loss of aak-2 (AMPK catalytic subunit) suppresses the gonadogenesis defect, placing CNNM-dependent Mg2+ homeostasis upstream of AMPK-TORC1 signaling in germ cell proliferation.\",\n      \"method\": \"C. elegans genetic mutant analysis, genome-wide RNAi screening, epistasis with aak-2 triple mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined pathway placement; C. elegans ortholog\",\n      \"pmids\": [\"27564576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A FRET-based binding assay using purified CNNM3 CBS domain fused to YPet and PRL2 fused to CyPet quantified the CNNM3-PRL2 interaction (measurable Kd). Peptides derived from the CNNM3 CBS domain loop (PRL-binding sequences) inhibited CNNM3-PRL2 interaction in vitro.\",\n      \"method\": \"FRET assay with purified recombinant proteins, peptide inhibition assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with purified proteins and quantitative binding measurement\",\n      \"pmids\": [\"32733084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDK2 promotes cisplatin resistance in lung adenocarcinoma via transcriptional regulation of CNNM3, establishing a PDK2-CNNM3 signaling axis in drug resistance.\",\n      \"method\": \"Gene expression analysis, in vitro proliferation assays, in vivo tumor growth, mechanistic transcriptional studies\",\n      \"journal\": \"Journal of drug targeting\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — transcriptional regulation claim supported by single-lab study with limited mechanistic detail on CNNM3's direct role\",\n      \"pmids\": [\"30457021\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNNM3 is a magnesium transporter/regulator that mediates Mg2+ efflux and, via its CBS-pair domain, forms a complex with PRL phosphatases (particularly PRL-2) whose phosphocysteine-regulated interaction modulates CNNM3 activity; CNNM3 also selectively binds and stimulates the TRPM7 channel to promote divalent cation influx, with ARL15-dependent N-glycosylation and dimerization through its CNBH domain providing additional regulatory control of Mg2+ homeostasis and oncogenic signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CNNM3 is a membrane-associated magnesium transporter/regulator that mediates Mg²⁺ efflux and modulates divalent cation homeostasis through multiple regulatory interactions. Its CBS-pair domain forms a heterodimeric complex with PRL-2 phosphatase—structurally resolved and regulated by phosphocysteine at the PRL catalytic site—that is required for Mg²⁺ efflux activity and oncogenic transformation [PMID:24632616, PMID:27856537, PMID:26969161]. The C-terminal CNBH domain mediates obligate dimerization essential for Mg²⁺ efflux, while CNNM3 additionally binds and stimulates the TRPM7 channel to promote divalent cation influx, a function modulated by ARL15-dependent N-glycosylation and antagonized by PRL-2 [PMID:30341174, PMID:34928937, PMID:36972446]. In C. elegans, loss of CNNM orthologs causes Mg²⁺ accumulation and defective gonadogenesis through AMPK-TORC1 signaling, linking CNNM-dependent Mg²⁺ homeostasis to growth control [PMID:27564576].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Sequence homology to the bacterial CorC Mg²⁺/Co²⁺ efflux system first suggested that CNNM3 functions in divalent cation transport, framing the central hypothesis for all subsequent work.\",\n      \"evidence\": \"Bioinformatic comparison of mouse Acdp3 to bacterial CorC (35% identity, 55% homology)\",\n      \"pmids\": [\"14723793\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational inference with no functional data for CNNM3 itself\", \"No direct transport assay performed\", \"Immunostaining data shown only for Acdp1, not Acdp3\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Functional studies established that CNNM3 mediates Mg²⁺ efflux and that this activity is co-opted by PRL-2 for oncogenic signaling: PRL-2 binds CNNM3's CBS-pair domain to regulate intracellular Mg²⁺ and promote tumor growth.\",\n      \"evidence\": \"Xenopus oocyte Mg²⁺ efflux assay (pufferfish ortholog); Co-IP, PRL-2 KO mice, xenograft tumor models, Mg²⁺ influx measurements (human)\",\n      \"pmids\": [\"24632616\", \"24965791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PRL-2–CNNM3 interaction not yet resolved\", \"Oocyte efflux data from fish ortholog, not human CNNM3\", \"Whether CNNM3 is itself the transporter or a regulator of a separate transporter was unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structure of the PRL-2–CNNM3 CBS-pair complex revealed the molecular interface and demonstrated that phosphocysteine at the PRL active site acts as a Mg²⁺-sensitive switch controlling complex formation and Mg²⁺ efflux, while a single D426A mutation in the CBS loop completely abrogated binding and function.\",\n      \"evidence\": \"X-ray crystallography, active-site mutagenesis, phosphocysteine detection, whole-cell voltage clamping, Mg²⁺ efflux assays, orthotopic xenograft models\",\n      \"pmids\": [\"27856537\", \"26969161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphocysteine regulation is the sole mechanism controlling PRL-CNNM dynamics in vivo\", \"Electrophysiological identity of the CNNM3-associated current was undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic epistasis in C. elegans placed CNNM-mediated Mg²⁺ homeostasis upstream of AMPK-TORC1 signaling in germ cell proliferation, establishing a conserved physiological role beyond cancer.\",\n      \"evidence\": \"C. elegans cnnm-1;cnnm-3 double mutants, genome-wide RNAi, aak-2 epistasis\",\n      \"pmids\": [\"27564576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic analysis used double mutants, so individual contribution of cnnm-3 is unclear\", \"Whether AMPK-TORC1 link is conserved in mammals was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural determination of the CNBH domain at 1.9 Å resolution showed it forms an obligate dimer (rather than binding cyclic nucleotides), and mutagenesis demonstrated this dimerization is required for Mg²⁺ efflux, defining the domain architecture essential for CNNM3 function.\",\n      \"evidence\": \"X-ray crystallography, analytical ultracentrifugation, mutagenesis, Mg²⁺ efflux assays\",\n      \"pmids\": [\"30341174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length CNNM3 structure not determined\", \"How CNBH dimerization communicates with the transmembrane domain is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Beyond Mg²⁺ efflux, CNNM3 was shown to selectively bind and stimulate TRPM7 channel activity to promote divalent cation influx, while ARL15 was identified as a GTPase that promotes CNNM3 N-glycosylation and negatively regulates Mg²⁺ transport.\",\n      \"evidence\": \"CNNM3/4 KO HEK-293 cells, whole-cell electrophysiology, divalent cation uptake, Co-IP, stable isotope ²⁵Mg²⁺ uptake, ARL15 knockdown\",\n      \"pmids\": [\"34928937\", \"34089346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CNNM3 alone (without CNNM4) is sufficient for TRPM7 stimulation was not resolved\", \"Structural basis of CNNM3–TRPM7 interaction is unknown\", \"Whether ARL15-mediated glycosylation affects TRPM7 stimulation specifically was not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"An integrated regulatory model emerged: ARL15 promotes CNNM3–TRPM7 complex formation to restrain TRPM7 activity, while PRL-2 displaces ARL15 from CNNM3 to enhance TRPM7 function, with low intracellular Mg²⁺ reducing CNNM3–TRPM7 interaction in a PRL-dependent manner.\",\n      \"evidence\": \"Genetically encoded Mg²⁺ reporter, Co-IP, overexpression/knockdown, mitochondrial function assays\",\n      \"pmids\": [\"36972446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competitive binding model inferred from overexpression; endogenous stoichiometry not established\", \"Mitochondrial effects are correlative and downstream mechanism is unclear\", \"In vivo validation of the ARL15–PRL-2 competition on CNNM3 is lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the full-length structure of CNNM3; whether CNNM3 itself conducts Mg²⁺ or acts as a regulatory subunit for another transporter; the structural basis of the CNNM3–TRPM7 interaction; and whether the PRL-2/ARL15 regulatory axis operates in specific tissues in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length CNNM3 structure or cryo-EM model\", \"Pore-forming versus regulatory identity of CNNM3 unresolved\", \"Tissue-specific in vivo functions in mammalian models not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3, 4, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0382551\", \"supporting_discovery_ids\": [0, 1, 3, 4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [\n      \"PRL-2–CNNM3 heterodimer\",\n      \"CNNM3–TRPM7 complex\"\n    ],\n    \"partners\": [\n      \"PRL2\",\n      \"TRPM7\",\n      \"ARL15\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}