{"gene":"PTPRM","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2020,"finding":"PTPRM directly interacts with STAT3 and dephosphorylates STAT3 at Y705. PTPRM bound wild-type STAT3 but not the STAT3 Y705F mutant. DDIAS competes with PTPRM for binding to the STAT3 transactivation domain (TAD), thereby preventing PTPRM-mediated STAT3 dephosphorylation and sustaining STAT3 activation in lung cancer cells.","method":"siRNA PTP library screening, Co-immunoprecipitation of endogenous proteins, STAT3 Y705F mutant binding assay, PTPRM knockdown/overexpression with phospho-STAT3 readout","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal endogenous Co-IP, mutagenesis (Y705F), knockdown and overexpression with phosphorylation readout, multiple orthogonal methods in one study","pmids":["31900385"],"is_preprint":false},{"year":2021,"finding":"BMI1 binds to the promoter region of the PTPRM gene and drives chromatin remodeling to silence PTPRM expression in spermatogonia. Knockdown of PTPRM rescued proliferation defects in BMI1-deficient cells, placing PTPRM downstream of BMI1 in a spermatogonia maintenance pathway.","method":"ChIP (BMI1 binding to PTPRM promoter), Bmi1-knockout mouse model, siRNA knockdown of Ptprm in GC-1 cells, proliferation and apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic rescue in KO model, single lab with two orthogonal methods","pmids":["34739857"],"is_preprint":false},{"year":2015,"finding":"PTPRM negatively regulates cell growth and colony formation in colorectal cancer cells. Loss of PTPRM function via loss of heterozygosity and promoter hypermethylation promotes oncogenic cell growth, supporting a tumor suppressor role.","method":"Genomic copy number analysis (oligonucleotide microarray), qPCR, functional overexpression/loss-of-function assays (colony formation, cell growth), promoter methylation analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss-of-function with defined cellular phenotype (colony formation), methylation mechanism defined, single lab","pmids":["25910225"],"is_preprint":false},{"year":2021,"finding":"FN1 upregulation increases PTPRM promoter methylation, reducing PTPRM expression and thereby relieving inhibition of STAT3 phosphorylation to promote glioblastoma cell proliferation. Knockdown of FN1 decreased PTPRM methylation and inhibited STAT3 phosphorylation. Treatment with the demethylating agent 5-aza restored PTPRM expression and reduced p-STAT3.","method":"Methylation-specific PCR, lentiviral overexpression/knockdown of FN1 and PTPRM, phospho-STAT3 immunoblotting, 5-aza demethylation treatment, colony formation and cell viability assays","journal":"Pharmaceutical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation-specific PCR plus functional rescue experiments, single lab with multiple methods","pmids":["34225581"],"is_preprint":false},{"year":2022,"finding":"Downregulation of PTPRM in psoriatic skin promotes keratinocyte proliferation through excessive ERK1/2 signaling, with increased DNA-binding activity of downstream NF-κB and Sp1 transcription factors observed under psoriatic conditions.","method":"Gene profiling on microarrays in 3D psoriatic skin model, electrophoretic mobility shift assay (EMSA) for NF-κB and Sp1 binding, RSK inhibition experiments","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with functional inhibitor rescue in tissue-engineered model, single lab, two orthogonal methods","pmids":["36139479"],"is_preprint":false},{"year":2022,"finding":"PTPRM is a critical gene for synapse formation regulated by zinc ions. Zinc ion availability modulates synapse formation and synaptic transmission in cultured neurons, and PTPRM mediates this effect.","method":"Cultured neuron system, zinc ion manipulation, synapse formation assays, synaptic transmission measurements, PTPRM genetic identification as key mediator","journal":"Frontiers in molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway placement via genetic identification in cultured neurons, single lab, limited methodological detail in abstract","pmids":["35386272"],"is_preprint":false},{"year":2022,"finding":"PTPRM forms head-to-tail homodimers via its extracellular domain (ECD), mediating homophilic trans cell adhesion between adjacent cell membranes. Solution SAXS revealed that the full-length ECD of PTPRM is a rigid extended molecule. A single residue difference (W351 in PTPRK vs. glycine in PTPRM) within the interaction interface is a determinant of homophilic specificity, as mutation of W351 to glycine abolishes PTPRK dimer formation in vitro.","method":"X-ray crystallography of PTPRK N-terminal domains, small-angle X-ray scattering (SAXS) of full-length ECDs of PTPRM and PTPRK, in vitro mutagenesis (W351G) with dimerization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of related family member compared to existing PTPRM structure, SAXS solution structure, in vitro mutagenesis confirming interface residue, single lab but multiple structural methods","pmids":["36436563"],"is_preprint":false},{"year":2019,"finding":"Overexpression of PTPRM in SI-NET cell lines reduced cell growth and proliferation and induced apoptosis. Notably, the tyrosine phosphatase activity of PTPRM was NOT required for cell growth inhibition in this context, suggesting a phosphatase-independent mechanism.","method":"PTPRM overexpression in CNDT2.5 and KRJ-I SI-NET cell lines, colony formation assay, cell proliferation assay, apoptosis assay; phosphatase-dead mutant experiments","journal":"Endocrine connections","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with phosphatase-dead mutant to dissect mechanism, single lab, two orthogonal phenotypic readouts","pmids":["31349215"],"is_preprint":false},{"year":1993,"finding":"The human PTPRM gene (formerly PTPRL1) was mapped to chromosomal band 18p11.2 by fluorescence in situ hybridization using a genomic clone.","method":"Fluorescence in situ hybridization (FISH) with genomic clone","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH localization, single lab, well-established cytogenetic method","pmids":["8404049"],"is_preprint":false},{"year":2024,"finding":"PTPRM hemizygosity in 18p deletion syndrome was associated with increased STAT3 phosphorylation and elevated Th17 cell fractions, consistent with PTPRM functioning as a negative regulator of STAT3 through dephosphorylation in immune cells. However, this is based on a single case series and hemizygosity rather than direct genetic manipulation.","method":"Chromosomal microarray and whole genome sequencing in monozygotic triplets, phospho-STAT3 assay, Th17 cell fraction analysis by immunophenotyping","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — observational association in three patients with hemizygous deletion, no direct functional manipulation of PTPRM, single case series","pmids":["39359478"],"is_preprint":false}],"current_model":"PTPRM is a receptor-type transmembrane protein tyrosine phosphatase that (1) directly dephosphorylates STAT3 at Y705 to suppress STAT3 signaling, an activity blocked when DDIAS competitively occupies the STAT3 transactivation domain; (2) mediates homophilic cell-cell adhesion through head-to-tail dimerization of its extracellular domain, with specificity determined by shape complementarity and discrete residue differences from paralogs; (3) negatively regulates ERK1/2 signaling in keratinocytes; (4) suppresses cell proliferation and colony formation in colorectal and neuroendocrine tumor contexts via mechanisms that can be phosphatase-activity-independent; and (5) is epigenetically silenced by BMI1 (in spermatogonia) and by FN1-induced promoter methylation (in glioblastoma), linking upstream epigenetic regulators to its tumor-suppressive phosphatase function."},"narrative":{"mechanistic_narrative":"PTPRM is a receptor-type transmembrane protein tyrosine phosphatase that couples homophilic cell-cell adhesion to negative regulation of tyrosine-phosphorylation-dependent growth signaling [PMID:31900385, PMID:36436563]. Through its extracellular domain, PTPRM forms rigid, extended head-to-tail homodimers that mediate homophilic trans adhesion between adjacent cell membranes, with binding specificity dictated by discrete interface residues that distinguish it from paralogs such as PTPRK [PMID:36436563]. Functionally, PTPRM directly binds STAT3 and dephosphorylates it at Y705 to suppress STAT3 activation, an interaction abolished by the STAT3 Y705F mutation and competitively blocked when DDIAS occupies the STAT3 transactivation domain [PMID:31900385]. PTPRM acts as a tumor suppressor that restrains cell growth and colony formation in colorectal and neuroendocrine tumor cells, and in the neuroendocrine context this growth inhibition proceeds independently of its phosphatase catalytic activity [PMID:25910225, PMID:31349215]. PTPRM additionally restrains ERK1/2 signaling in keratinocytes, where its downregulation drives proliferation [PMID:36139479]. Its expression is silenced by upstream epigenetic regulators: BMI1 binds the PTPRM promoter and drives chromatin remodeling in spermatogonia [PMID:34739857], and FN1 induces PTPRM promoter methylation in glioblastoma, relieving suppression of STAT3 phosphorylation [PMID:34225581].","teleology":[{"year":1993,"claim":"Establishing the chromosomal location of PTPRM (then PTPRL1) provided the genomic anchor needed to link the gene to subsequent functional and disease studies.","evidence":"FISH with a genomic clone mapping the gene to 18p11.2","pmids":["8404049"],"confidence":"Medium","gaps":["No functional or mechanistic information about the encoded protein","Mapping alone does not define expression pattern or activity"]},{"year":2015,"claim":"Defining PTPRM as a tumor suppressor in colorectal cancer answered whether loss of this phosphatase has oncogenic consequences and identified promoter hypermethylation as a silencing route.","evidence":"Copy number analysis, promoter methylation analysis, and colony-formation/growth assays in colorectal cancer cells","pmids":["25910225"],"confidence":"Medium","gaps":["Direct substrate or signaling pathway mediating growth suppression not defined","Single lab","Causal link between methylation and phenotype correlative"]},{"year":2019,"claim":"Testing a phosphatase-dead mutant showed that PTPRM can suppress neuroendocrine tumor cell growth without its catalytic activity, revealing a phosphatase-independent tumor-suppressive mode.","evidence":"Overexpression and phosphatase-dead mutant assays with colony-formation, proliferation, and apoptosis readouts in SI-NET cell lines","pmids":["31349215"],"confidence":"Medium","gaps":["The non-catalytic mechanism (e.g. adhesion or scaffolding) not identified","Context-specificity versus catalytic roles elsewhere unresolved"]},{"year":2020,"claim":"Identifying STAT3 Y705 as a direct PTPRM substrate, and DDIAS as a competitive blocker, defined the molecular basis by which PTPRM restrains STAT3 signaling and how tumors evade it.","evidence":"PTP siRNA library screen, reciprocal endogenous Co-IP, STAT3 Y705F binding assay, and knockdown/overexpression with phospho-STAT3 readout in lung cancer cells","pmids":["31900385"],"confidence":"High","gaps":["Whether STAT3 is the principal substrate across tissues not established","Structural basis of the PTPRM-STAT3 TAD interaction not resolved"]},{"year":2021,"claim":"Placing PTPRM downstream of BMI1 and FN1 connected upstream epigenetic regulators to its silencing in spermatogonia and glioblastoma, explaining how PTPRM tumor-suppressive function is lost.","evidence":"ChIP and Bmi1-KO rescue in spermatogonia (GC-1 cells); methylation-specific PCR, FN1/PTPRM knockdown-overexpression, and 5-aza rescue with phospho-STAT3 readout in glioblastoma","pmids":["34739857","34225581"],"confidence":"Medium","gaps":["Direct demonstration that BMI1-driven remodeling and FN1-driven methylation act on the same regulatory elements not shown","Both rely on single-lab datasets"]},{"year":2022,"claim":"Structural analysis of the extracellular domain established the molecular geometry of PTPRM homophilic adhesion and pinpointed an interface residue governing paralog specificity.","evidence":"X-ray crystallography of N-terminal domains, SAXS of full-length ECDs of PTPRM and PTPRK, and W351G mutagenesis with dimerization assay","pmids":["36436563"],"confidence":"High","gaps":["How extracellular adhesion couples to intracellular phosphatase activity not established","Functional consequence of adhesion in tissue context not measured here"]},{"year":2022,"claim":"Linking PTPRM downregulation to excessive ERK1/2 signaling in keratinocytes extended its growth-restraining role to epidermal proliferation and psoriasis biology.","evidence":"Microarray profiling, EMSA for NF-kB and Sp1 binding, and RSK inhibition in a 3D psoriatic skin model","pmids":["36139479"],"confidence":"Medium","gaps":["Direct phosphatase substrate in the ERK pathway not identified","Causality between PTPRM loss and ERK hyperactivation correlative"]},{"year":2022,"claim":"Identifying PTPRM as a zinc-regulated mediator of synapse formation raised a neuronal role distinct from its tumor-suppressive activity.","evidence":"Cultured neuron system with zinc manipulation, synapse formation and synaptic transmission assays, genetic identification of PTPRM","pmids":["35386272"],"confidence":"Low","gaps":["Single lab with limited methodological detail; mechanism of zinc regulation not defined","Direct molecular link between PTPRM and synaptic substrates absent"]},{"year":2024,"claim":"Observing elevated STAT3 phosphorylation and Th17 fractions in PTPRM-hemizygous 18p deletion patients suggested the STAT3-suppressing role operates in human immune cells.","evidence":"Chromosomal microarray, whole genome sequencing, phospho-STAT3 assay, and Th17 immunophenotyping in monozygotic triplets","pmids":["39359478"],"confidence":"Low","gaps":["Observational case series of three patients without direct PTPRM manipulation","Hemizygosity confounds attribution to PTPRM specifically"]},{"year":null,"claim":"How PTPRM extracellular homophilic adhesion is mechanistically coupled to its intracellular phosphatase activity and substrate selection across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the full receptor linking ECD engagement to catalytic state","Substrate repertoire beyond STAT3 uncharacterized","Mechanism of phosphatase-independent growth suppression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[6]}],"complexes":[],"partners":["STAT3","DDIAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P28827","full_name":"Receptor-type tyrosine-protein phosphatase mu","aliases":[],"length_aa":1452,"mass_kda":163.7,"function":"Receptor protein-tyrosine phosphatase that mediates homotypic cell-cell interactions and plays a role in adipogenic differentiation via modulation of p120 catenin/CTNND1 phosphorylation (PubMed:10753936, PubMed:17761881). Promotes CTNND1 dephosphorylation and prevents its cytoplasmic localization where it inhibits SLC2A4 membrane trafficking. In turn, SLC2A4 is directed to the plasma membrane and performs its glucose transporter function (PubMed:21998202)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P28827/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRM","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRM","total_profiled":1310},"omim":[{"mim_id":"300672","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2; DEE2","url":"https://www.omim.org/entry/300672"},{"mim_id":"176888","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, MU; PTPRM","url":"https://www.omim.org/entry/176888"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRM"},"hgnc":{"alias_symbol":["RPTPU","hR-PTPu"],"prev_symbol":["PTPRL1"]},"alphafold":{"accession":"P28827","domains":[{"cath_id":"2.60.120.200","chopping":"24-184","consensus_level":"medium","plddt":91.4824,"start":24,"end":184},{"cath_id":"2.60.40.10","chopping":"185-278","consensus_level":"medium","plddt":92.8866,"start":185,"end":278},{"cath_id":"2.60.40.10","chopping":"281-375","consensus_level":"high","plddt":88.8961,"start":281,"end":375},{"cath_id":"2.60.40.10","chopping":"385-477","consensus_level":"high","plddt":89.6849,"start":385,"end":477},{"cath_id":"2.60.40.10","chopping":"488-581","consensus_level":"high","plddt":91.2855,"start":488,"end":581},{"cath_id":"2.60.40","chopping":"599-630_644-723","consensus_level":"high","plddt":86.4597,"start":599,"end":723},{"cath_id":"3.90.190.10","chopping":"901-1160","consensus_level":"high","plddt":93.0293,"start":901,"end":1160},{"cath_id":"3.90.190.10","chopping":"1202-1435","consensus_level":"high","plddt":90.8789,"start":1202,"end":1435}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28827","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28827-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28827-F1-predicted_aligned_error_v6.png","plddt_mean":83.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRM","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRM"},"sequence":{"accession":"P28827","fasta_url":"https://rest.uniprot.org/uniprotkb/P28827.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28827/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28827"}},"corpus_meta":[{"pmid":"31900385","id":"PMC_31900385","title":"DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells.","date":"2020","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31900385","citation_count":36,"is_preprint":false},{"pmid":"34739857","id":"PMC_34739857","title":"BMI1 promotes spermatogonia proliferation through epigenetic repression of Ptprm.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34739857","citation_count":27,"is_preprint":false},{"pmid":"32663515","id":"PMC_32663515","title":"PSMD11, PTPRM and PTPRB as novel biomarkers of pancreatic cancer progression.","date":"2020","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/32663515","citation_count":24,"is_preprint":false},{"pmid":"25910225","id":"PMC_25910225","title":"Loss of PTPRM associates with the pathogenic development of colorectal adenoma-carcinoma sequence.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25910225","citation_count":21,"is_preprint":false},{"pmid":"31349215","id":"PMC_31349215","title":"PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors.","date":"2019","source":"Endocrine connections","url":"https://pubmed.ncbi.nlm.nih.gov/31349215","citation_count":17,"is_preprint":false},{"pmid":"35491723","id":"PMC_35491723","title":"CircRNA PTPRM Promotes Non-Small Cell Lung Cancer Progression by Modulating the miR-139-5p/SETD5 Axis.","date":"2022","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/35491723","citation_count":13,"is_preprint":false},{"pmid":"34225581","id":"PMC_34225581","title":"PTPRM methylation induced by FN1 promotes the development of glioblastoma by activating STAT3 signalling.","date":"2021","source":"Pharmaceutical biology","url":"https://pubmed.ncbi.nlm.nih.gov/34225581","citation_count":12,"is_preprint":false},{"pmid":"36139479","id":"PMC_36139479","title":"Gene Profiling of a 3D Psoriatic Skin Model Enriched in T Cells: Downregulation of PTPRM Promotes Keratinocyte Proliferation through Excessive ERK1/2 Signaling.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36139479","citation_count":12,"is_preprint":false},{"pmid":"35386272","id":"PMC_35386272","title":"PTPRM Is Critical for Synapse Formation Regulated by Zinc Ion.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35386272","citation_count":11,"is_preprint":false},{"pmid":"8404049","id":"PMC_8404049","title":"Fine mapping of the human receptor-like protein tyrosine phosphatase gene (PTPRM) to 18p11.2 by fluorescence in situ hybridization.","date":"1993","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8404049","citation_count":6,"is_preprint":false},{"pmid":"36436563","id":"PMC_36436563","title":"Determinants of receptor tyrosine phosphatase homophilic adhesion: Structural comparison of PTPRK and PTPRM extracellular domains.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36436563","citation_count":3,"is_preprint":false},{"pmid":"35626106","id":"PMC_35626106","title":"Characterization of Poorly Cohesive and Signet Ring Cell Carcinomas and Identification of PTPRM as a Diagnostic Marker.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35626106","citation_count":3,"is_preprint":false},{"pmid":"39359478","id":"PMC_39359478","title":"Monozygotic triplets with juvenile-onset autoimmunity and 18p microdeletion involving PTPRM.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39359478","citation_count":2,"is_preprint":false},{"pmid":"36927043","id":"PMC_36927043","title":"A quantitative trait GWAS on lens thickness identifies novel risk loci on PTPRM in the narrow angle individuals susceptible to PACG.","date":"2023","source":"European journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/36927043","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.20.25337809","title":"Rare case of Pediatric Male Secretory Breast Carcinoma: An Integrative study with Genomic and Transcriptomic analysis","date":"2025-11-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.20.25337809","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9689,"output_tokens":2624,"usd":0.034214,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9857,"output_tokens":3153,"usd":0.064055,"stage2_stop_reason":"end_turn"},"total_usd":0.098269,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRM directly interacts with STAT3 and dephosphorylates STAT3 at Y705. PTPRM bound wild-type STAT3 but not the STAT3 Y705F mutant. DDIAS competes with PTPRM for binding to the STAT3 transactivation domain (TAD), thereby preventing PTPRM-mediated STAT3 dephosphorylation and sustaining STAT3 activation in lung cancer cells.\",\n      \"method\": \"siRNA PTP library screening, Co-immunoprecipitation of endogenous proteins, STAT3 Y705F mutant binding assay, PTPRM knockdown/overexpression with phospho-STAT3 readout\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal endogenous Co-IP, mutagenesis (Y705F), knockdown and overexpression with phosphorylation readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31900385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BMI1 binds to the promoter region of the PTPRM gene and drives chromatin remodeling to silence PTPRM expression in spermatogonia. Knockdown of PTPRM rescued proliferation defects in BMI1-deficient cells, placing PTPRM downstream of BMI1 in a spermatogonia maintenance pathway.\",\n      \"method\": \"ChIP (BMI1 binding to PTPRM promoter), Bmi1-knockout mouse model, siRNA knockdown of Ptprm in GC-1 cells, proliferation and apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic rescue in KO model, single lab with two orthogonal methods\",\n      \"pmids\": [\"34739857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRM negatively regulates cell growth and colony formation in colorectal cancer cells. Loss of PTPRM function via loss of heterozygosity and promoter hypermethylation promotes oncogenic cell growth, supporting a tumor suppressor role.\",\n      \"method\": \"Genomic copy number analysis (oligonucleotide microarray), qPCR, functional overexpression/loss-of-function assays (colony formation, cell growth), promoter methylation analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss-of-function with defined cellular phenotype (colony formation), methylation mechanism defined, single lab\",\n      \"pmids\": [\"25910225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FN1 upregulation increases PTPRM promoter methylation, reducing PTPRM expression and thereby relieving inhibition of STAT3 phosphorylation to promote glioblastoma cell proliferation. Knockdown of FN1 decreased PTPRM methylation and inhibited STAT3 phosphorylation. Treatment with the demethylating agent 5-aza restored PTPRM expression and reduced p-STAT3.\",\n      \"method\": \"Methylation-specific PCR, lentiviral overexpression/knockdown of FN1 and PTPRM, phospho-STAT3 immunoblotting, 5-aza demethylation treatment, colony formation and cell viability assays\",\n      \"journal\": \"Pharmaceutical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation-specific PCR plus functional rescue experiments, single lab with multiple methods\",\n      \"pmids\": [\"34225581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Downregulation of PTPRM in psoriatic skin promotes keratinocyte proliferation through excessive ERK1/2 signaling, with increased DNA-binding activity of downstream NF-κB and Sp1 transcription factors observed under psoriatic conditions.\",\n      \"method\": \"Gene profiling on microarrays in 3D psoriatic skin model, electrophoretic mobility shift assay (EMSA) for NF-κB and Sp1 binding, RSK inhibition experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with functional inhibitor rescue in tissue-engineered model, single lab, two orthogonal methods\",\n      \"pmids\": [\"36139479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRM is a critical gene for synapse formation regulated by zinc ions. Zinc ion availability modulates synapse formation and synaptic transmission in cultured neurons, and PTPRM mediates this effect.\",\n      \"method\": \"Cultured neuron system, zinc ion manipulation, synapse formation assays, synaptic transmission measurements, PTPRM genetic identification as key mediator\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway placement via genetic identification in cultured neurons, single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"35386272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRM forms head-to-tail homodimers via its extracellular domain (ECD), mediating homophilic trans cell adhesion between adjacent cell membranes. Solution SAXS revealed that the full-length ECD of PTPRM is a rigid extended molecule. A single residue difference (W351 in PTPRK vs. glycine in PTPRM) within the interaction interface is a determinant of homophilic specificity, as mutation of W351 to glycine abolishes PTPRK dimer formation in vitro.\",\n      \"method\": \"X-ray crystallography of PTPRK N-terminal domains, small-angle X-ray scattering (SAXS) of full-length ECDs of PTPRM and PTPRK, in vitro mutagenesis (W351G) with dimerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of related family member compared to existing PTPRM structure, SAXS solution structure, in vitro mutagenesis confirming interface residue, single lab but multiple structural methods\",\n      \"pmids\": [\"36436563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Overexpression of PTPRM in SI-NET cell lines reduced cell growth and proliferation and induced apoptosis. Notably, the tyrosine phosphatase activity of PTPRM was NOT required for cell growth inhibition in this context, suggesting a phosphatase-independent mechanism.\",\n      \"method\": \"PTPRM overexpression in CNDT2.5 and KRJ-I SI-NET cell lines, colony formation assay, cell proliferation assay, apoptosis assay; phosphatase-dead mutant experiments\",\n      \"journal\": \"Endocrine connections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with phosphatase-dead mutant to dissect mechanism, single lab, two orthogonal phenotypic readouts\",\n      \"pmids\": [\"31349215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human PTPRM gene (formerly PTPRL1) was mapped to chromosomal band 18p11.2 by fluorescence in situ hybridization using a genomic clone.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) with genomic clone\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH localization, single lab, well-established cytogenetic method\",\n      \"pmids\": [\"8404049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRM hemizygosity in 18p deletion syndrome was associated with increased STAT3 phosphorylation and elevated Th17 cell fractions, consistent with PTPRM functioning as a negative regulator of STAT3 through dephosphorylation in immune cells. However, this is based on a single case series and hemizygosity rather than direct genetic manipulation.\",\n      \"method\": \"Chromosomal microarray and whole genome sequencing in monozygotic triplets, phospho-STAT3 assay, Th17 cell fraction analysis by immunophenotyping\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — observational association in three patients with hemizygous deletion, no direct functional manipulation of PTPRM, single case series\",\n      \"pmids\": [\"39359478\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRM is a receptor-type transmembrane protein tyrosine phosphatase that (1) directly dephosphorylates STAT3 at Y705 to suppress STAT3 signaling, an activity blocked when DDIAS competitively occupies the STAT3 transactivation domain; (2) mediates homophilic cell-cell adhesion through head-to-tail dimerization of its extracellular domain, with specificity determined by shape complementarity and discrete residue differences from paralogs; (3) negatively regulates ERK1/2 signaling in keratinocytes; (4) suppresses cell proliferation and colony formation in colorectal and neuroendocrine tumor contexts via mechanisms that can be phosphatase-activity-independent; and (5) is epigenetically silenced by BMI1 (in spermatogonia) and by FN1-induced promoter methylation (in glioblastoma), linking upstream epigenetic regulators to its tumor-suppressive phosphatase function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRM is a receptor-type transmembrane protein tyrosine phosphatase that couples homophilic cell-cell adhesion to negative regulation of tyrosine-phosphorylation-dependent growth signaling [#0, #6]. Through its extracellular domain, PTPRM forms rigid, extended head-to-tail homodimers that mediate homophilic trans adhesion between adjacent cell membranes, with binding specificity dictated by discrete interface residues that distinguish it from paralogs such as PTPRK [#6]. Functionally, PTPRM directly binds STAT3 and dephosphorylates it at Y705 to suppress STAT3 activation, an interaction abolished by the STAT3 Y705F mutation and competitively blocked when DDIAS occupies the STAT3 transactivation domain [#0]. PTPRM acts as a tumor suppressor that restrains cell growth and colony formation in colorectal and neuroendocrine tumor cells, and in the neuroendocrine context this growth inhibition proceeds independently of its phosphatase catalytic activity [#2, #7]. PTPRM additionally restrains ERK1/2 signaling in keratinocytes, where its downregulation drives proliferation [#4]. Its expression is silenced by upstream epigenetic regulators: BMI1 binds the PTPRM promoter and drives chromatin remodeling in spermatogonia [#1], and FN1 induces PTPRM promoter methylation in glioblastoma, relieving suppression of STAT3 phosphorylation [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the chromosomal location of PTPRM (then PTPRL1) provided the genomic anchor needed to link the gene to subsequent functional and disease studies.\",\n      \"evidence\": \"FISH with a genomic clone mapping the gene to 18p11.2\",\n      \"pmids\": [\"8404049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or mechanistic information about the encoded protein\", \"Mapping alone does not define expression pattern or activity\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining PTPRM as a tumor suppressor in colorectal cancer answered whether loss of this phosphatase has oncogenic consequences and identified promoter hypermethylation as a silencing route.\",\n      \"evidence\": \"Copy number analysis, promoter methylation analysis, and colony-formation/growth assays in colorectal cancer cells\",\n      \"pmids\": [\"25910225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate or signaling pathway mediating growth suppression not defined\", \"Single lab\", \"Causal link between methylation and phenotype correlative\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Testing a phosphatase-dead mutant showed that PTPRM can suppress neuroendocrine tumor cell growth without its catalytic activity, revealing a phosphatase-independent tumor-suppressive mode.\",\n      \"evidence\": \"Overexpression and phosphatase-dead mutant assays with colony-formation, proliferation, and apoptosis readouts in SI-NET cell lines\",\n      \"pmids\": [\"31349215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The non-catalytic mechanism (e.g. adhesion or scaffolding) not identified\", \"Context-specificity versus catalytic roles elsewhere unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying STAT3 Y705 as a direct PTPRM substrate, and DDIAS as a competitive blocker, defined the molecular basis by which PTPRM restrains STAT3 signaling and how tumors evade it.\",\n      \"evidence\": \"PTP siRNA library screen, reciprocal endogenous Co-IP, STAT3 Y705F binding assay, and knockdown/overexpression with phospho-STAT3 readout in lung cancer cells\",\n      \"pmids\": [\"31900385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 is the principal substrate across tissues not established\", \"Structural basis of the PTPRM-STAT3 TAD interaction not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing PTPRM downstream of BMI1 and FN1 connected upstream epigenetic regulators to its silencing in spermatogonia and glioblastoma, explaining how PTPRM tumor-suppressive function is lost.\",\n      \"evidence\": \"ChIP and Bmi1-KO rescue in spermatogonia (GC-1 cells); methylation-specific PCR, FN1/PTPRM knockdown-overexpression, and 5-aza rescue with phospho-STAT3 readout in glioblastoma\",\n      \"pmids\": [\"34739857\", \"34225581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that BMI1-driven remodeling and FN1-driven methylation act on the same regulatory elements not shown\", \"Both rely on single-lab datasets\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural analysis of the extracellular domain established the molecular geometry of PTPRM homophilic adhesion and pinpointed an interface residue governing paralog specificity.\",\n      \"evidence\": \"X-ray crystallography of N-terminal domains, SAXS of full-length ECDs of PTPRM and PTPRK, and W351G mutagenesis with dimerization assay\",\n      \"pmids\": [\"36436563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How extracellular adhesion couples to intracellular phosphatase activity not established\", \"Functional consequence of adhesion in tissue context not measured here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking PTPRM downregulation to excessive ERK1/2 signaling in keratinocytes extended its growth-restraining role to epidermal proliferation and psoriasis biology.\",\n      \"evidence\": \"Microarray profiling, EMSA for NF-kB and Sp1 binding, and RSK inhibition in a 3D psoriatic skin model\",\n      \"pmids\": [\"36139479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase substrate in the ERK pathway not identified\", \"Causality between PTPRM loss and ERK hyperactivation correlative\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PTPRM as a zinc-regulated mediator of synapse formation raised a neuronal role distinct from its tumor-suppressive activity.\",\n      \"evidence\": \"Cultured neuron system with zinc manipulation, synapse formation and synaptic transmission assays, genetic identification of PTPRM\",\n      \"pmids\": [\"35386272\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab with limited methodological detail; mechanism of zinc regulation not defined\", \"Direct molecular link between PTPRM and synaptic substrates absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Observing elevated STAT3 phosphorylation and Th17 fractions in PTPRM-hemizygous 18p deletion patients suggested the STAT3-suppressing role operates in human immune cells.\",\n      \"evidence\": \"Chromosomal microarray, whole genome sequencing, phospho-STAT3 assay, and Th17 immunophenotyping in monozygotic triplets\",\n      \"pmids\": [\"39359478\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Observational case series of three patients without direct PTPRM manipulation\", \"Hemizygosity confounds attribution to PTPRM specifically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPRM extracellular homophilic adhesion is mechanistically coupled to its intracellular phosphatase activity and substrate selection across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the full receptor linking ECD engagement to catalytic state\", \"Substrate repertoire beyond STAT3 uncharacterized\", \"Mechanism of phosphatase-independent growth suppression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT3\", \"DDIAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}