{"gene":"PTPRH","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"SAP-1 (PTPRH), using a substrate-trapping approach, was shown to dephosphorylate p130cas (a major focal adhesion-associated phosphotyrosyl protein) as a likely physiological substrate. Expression of recombinant SAP-1 induced dephosphorylation of p130cas, FAK, and p62dok in intact cells; a substrate-trapping mutant caused hyperphosphorylation (dominant negative effect). SAP-1 enzymatic activity was increased by cell-cell adhesion, and overexpression disrupted the actin cytoskeleton and inhibited cell spreading on fibronectin, ERK2 activation, and colony formation.","method":"Substrate-trapping mutagenesis, overexpression in intact cells, immunocomplex phosphatase assay, cell spreading/colony formation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate-trapping mutagenesis plus immunocomplex phosphatase assay plus multiple orthogonal cellular readouts in a single focused study","pmids":["11278335"],"is_preprint":false},{"year":2003,"finding":"The cytoplasmic region of SAP-1 (PTPRH) directly binds and dephosphorylates the tyrosine kinase Lck in vitro. Overexpression of wild-type (but not catalytically inactive) SAP-1 inhibited basal and TCR-stimulated Lck activity in Jurkat T cells, reduced ZAP-70 and LAT tyrosine phosphorylation, attenuated MAP kinase activation, CD69 upregulation, p62dok phosphorylation, and cell migration.","method":"Direct binding assay, in vitro dephosphorylation assay, catalytically inactive mutant overexpression, TCR stimulation assays in Jurkat cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro dephosphorylation assay plus catalytic-dead mutant control plus multiple cellular readouts, single lab","pmids":["12837766"],"is_preprint":false},{"year":2005,"finding":"SAP-1/PTPRH forms a stable homodimer mediated by its extracellular and transmembrane domains (not the catalytic domain). Dimer formation/stabilization involves cysteine bonds, as reducing conditions reversibly disrupt the dimer. Monomerization is accompanied by increased catalytic activity; monomeric SAP-1 dephosphorylates and activates c-Src, identified as a novel substrate.","method":"Chemical cross-linking, co-immunoprecipitation, reducing agent treatment, catalytic activity assay toward c-Src","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and cross-linking plus functional activity assay, single lab with two orthogonal methods","pmids":["15850787"],"is_preprint":false},{"year":2009,"finding":"SAP-1 (PTPRH) protein localizes specifically to the microvilli of the brush border in gastrointestinal epithelial cells. SAP-1 ablation in mice with heterozygous APC mutation inhibited intestinal tumorigenesis, establishing SAP-1 as a microvillus-specific RPTP that modulates intestinal tumor development.","method":"Immunofluorescence/subcellular fractionation for localization; SAP-1-deficient mouse crossed with APC heterozygous mouse for tumorigenesis readout","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment plus genetic loss-of-function with clear tumor phenotype, single lab","pmids":["19170756"],"is_preprint":false},{"year":2015,"finding":"SAP-1 (PTPRH) dephosphorylates CEACAM20 (a microvillus-specific transmembrane Ig superfamily protein) as a substrate; SAP-1 and CEACAM20 form a complex through interaction of their ectodomains. Tyrosine phosphorylation of CEACAM20 by c-Src, unopposed by SAP-1, promotes CEACAM20 association with Syk, activating NF-κB and IL-8 production. SAP-1-deficient mice on an IL-10-deficient background showed markedly increased colitis severity.","method":"Tyrosine phosphorylation analysis in SAP-1-deficient intestinal epithelium, co-immunoprecipitation of SAP-1 and CEACAM20, overexpression of c-Src and Syk in cultured cells, NF-κB reporter assay, SAP-1/IL-10 double-knockout mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function mouse model, in vitro phosphorylation assays, and NF-κB pathway assay providing multiple orthogonal lines of evidence","pmids":["26195794"],"is_preprint":false},{"year":2004,"finding":"SAP-1 (ELK4) is required for ERK-mediated thymocyte positive selection. SAP-1-deficient mice showed severely reduced (80–90%) positive selection and impaired TCR-induced activation of target genes including Egr1 in double-positive thymocytes, despite normal ERK activation, positioning SAP-1 as a transcriptional effector directly downstream of ERK in the positive selection pathway. Negative selection was unimpaired.","method":"SAP-1 knockout mouse, TCR transgene analysis, RT-PCR/gene expression, ERK activation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout (positive vs negative selection dissected), replicated with TCR transgenes and target gene analysis","pmids":["14770179"],"is_preprint":false},{"year":2010,"finding":"SAP-1 and Elk-1 are functionally equivalent for thymocyte positive selection (Elk-1 ectopic expression rescues SAP-1-null positive selection defect; Net does not). Ectopic expression of the SAP-1/Elk-1 target gene Egr-1 alone restored positive selection in SAP-1-null thymocytes, establishing Egr-1 (and possibly other Egr family members) as the primary transcriptional effectors of the ERK–SAP-1 signaling axis in positive selection.","method":"SAP-1/Elk-1/Net genetic knockout mice, ectopic TCF expression rescue experiments, Egr-1 transgenic rescue, chromatin immunoprecipitation, array gene expression analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO combinations, rescue experiments, and ChIP providing converging evidence","pmids":["20554967"],"is_preprint":false},{"year":2007,"finding":"SAP-1 (ELK4) is NOT required for regulatory T cell (Treg) development or suppressive function; SAP-1-deficient CD4+CD25+ Tregs still suppress T cell proliferation in vitro and in a colitis model in vivo, despite impaired Egr-1 induction after TCR crosslinking.","method":"SAP-1 knockout mouse, Foxp3/CD25/GITR/CTLA4 expression analysis, in vitro suppression assay, in vivo colitis model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple Treg markers and functional suppression assays, single lab; this is a negative/dissociation finding","pmids":["17982074"],"is_preprint":false},{"year":2018,"finding":"ELK4 (SAP-1) and ELK1 act cell-autonomously in the thymus to suppress the generation of innate-like αβ CD8+ T cells. In ELK4/ELK1 double-knockout mice, increased innate-like CD8+ T cell numbers were associated with reduced ERK-mediated activation of ELK4-SRF target genes, and ectopic EGR2 expression partially suppressed this phenotype.","method":"ELK4 and ELK1 single and double knockout mice, flow cytometry of CD8+ T cell populations, ectopic EGR2 expression rescue, ERK inhibition in peripheral CD8+ T cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double KO and rescue experiments, single lab","pmids":["30068599"],"is_preprint":false},{"year":2022,"finding":"PTPRH directly dephosphorylates EGFR at tyrosine Y1197 (Y1173). PTPRH knockout in NSCLC cells increased Y1197 EGFR phosphorylation; rescue with wild-type PTPRH restored basal phosphorylation levels, while rescue with catalytically dead PTPRH did not. PTPRH mutations found in NSCLC tumors (V483M) are inhibitory to PTPRH function, resulting in aberrant EGFR activity.","method":"PTPRH knockout NSCLC cell line, wild-type vs catalytically dead PTPRH rescue expression, Western blot for pEGFR Y1197, whole genome sequencing, TCGA data analysis, immunohistochemistry","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus catalytic-dead mutant rescue provides clean mechanistic evidence for EGFR as substrate, single lab","pmids":["36054194"],"is_preprint":false},{"year":2017,"finding":"PTPRH expression in colorectal tumors is regulated epigenetically: DNA methylation of PTPRH promoter regions correlates with reduced PTPRH expression in CRC, and treatment with 5-aza-deoxycytidine restored PTPRH expression in methylated cell lines. H3K27 trimethylation in promoter/gene body and reduced RNA Pol II occupancy were also associated with silenced PTPRH.","method":"Pyrosequencing of promoter methylation, 5-aza-deoxycytidine demethylation treatment, chromatin immunoprecipitation (RNA Pol II, H3K27me3), qRT-PCR, immunohistochemistry","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological demethylation rescue plus ChIP, single lab with two orthogonal methods","pmids":["28713969"],"is_preprint":false},{"year":2017,"finding":"SAP-1 (PTPRH) deficiency in mice increases paracellular transport of macromolecules (dextrans FD-4 and FD-10) across the intestinal epithelium, as measured in everted ileal sacs and colonic loop absorption assays, indicating SAP-1 contributes to regulation of tight junction permeability for macromolecules.","method":"SAP-1-deficient mouse, everted ileal sac transport assay, colonic loop absorption assay","journal":"Journal of pharmaceutical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single KO study with a functional readout but no direct molecular mechanism identified for tight junction regulation","pmids":["28431964"],"is_preprint":false},{"year":2023,"finding":"PTPRH promotes glycolysis in NSCLC cells via the PI3K/AKT/mTOR signaling pathway. Altering PTPRH expression changed 18F-FDG uptake, lactate production, and expression of glycolysis-related proteins; PI3K inhibitor (LY294002) or agonist (740Y-P) modulated these effects, consistent with PTPRH acting upstream of PI3K/AKT/mTOR in this context.","method":"PTPRH overexpression/knockdown in NSCLC cells, 18F-FDG uptake assay, lactate production assay, Western blot for glycolysis proteins and PI3K/AKT pathway, PI3K inhibitor/agonist treatment, xenograft tumor model","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological pathway modulation without direct substrate identification; single lab","pmids":["37974250"],"is_preprint":false},{"year":2025,"finding":"PTPRH does not directly interact with EGFR in NSCLC cells; instead PTPRH interacts with NF-κB (a transcription factor downstream of EGFR), as demonstrated by Co-IP and proximity-dependent biotinylation (BioID). BioID also identified 48 novel PTPRH interactors including HELZ2 and RFC2. Disruption of either extracellular or intracellular PTPRH domains leads to EGFR dephosphorylation, suggesting an indirect mechanism. PTPRH overexpression downregulates multiple oncogenic signature pathways and modulates expression of 34 protein tyrosine phosphatases and 45 tyrosine kinases.","method":"Co-immunoprecipitation, proximity-dependent biotinylation (BioID), PTPRH domain deletion mutants, RNA sequencing, PTPRH overexpression/knockout in NSCLC cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint; Co-IP/BioID in single lab, indirect EGFR mechanism not fully resolved","pmids":["41383754"],"is_preprint":true}],"current_model":"PTPRH (SAP-1) is a receptor-type protein tyrosine phosphatase localized to intestinal microvillus brush borders that negatively regulates integrin- and adhesion-mediated signaling by dephosphorylating p130cas, FAK, and p62dok; directly binds and inactivates Lck to suppress T cell signaling; dephosphorylates CEACAM20 (forming an ectodomain complex) to restrain c-Src/Syk/NF-κB-driven intestinal inflammation; dephosphorylates EGFR at Y1197 to suppress EGFR pathway activity; undergoes redox-regulated homodimerization via its extracellular/transmembrane domains that controls catalytic activity (monomer is more active); and in the nucleus acts as an ETS/TCF transcription factor (ELK4/SAP-1) that is phosphorylated and activated by ERK2 and selective p38 MAPKs via D-domain and FXF motif docking, cooperates with SRF on serum response elements, and is required for thymocyte positive selection through transcriptional activation of immediate-early genes such as Egr1."},"narrative":{"mechanistic_narrative":"PTPRH (SAP-1) is a microvillus-specific receptor-type protein tyrosine phosphatase that negatively regulates adhesion- and growth-factor signaling in epithelial and immune cells by dephosphorylating key tyrosine-phosphorylated substrates [PMID:11278335, PMID:19170756]. Using substrate trapping, it was established to dephosphorylate the focal-adhesion proteins p130cas, FAK, and p62dok, with its catalytic activity stimulated by cell-cell adhesion and its overexpression disrupting the actin cytoskeleton, cell spreading on fibronectin, and ERK2 activation [PMID:11278335]. Its substrate repertoire extends to the T-cell kinase Lck, which it directly binds and inactivates to suppress TCR-proximal signaling [PMID:12837766], to c-Src [PMID:15850787], to the microvillus protein CEACAM20 — where loss of PTPRH-mediated dephosphorylation permits c-Src-driven CEACAM20–Syk association, NF-κB activation, and IL-8 production, and PTPRH deficiency aggravates colitis [PMID:26195794] — and to EGFR at Y1197, where catalytically intact PTPRH restrains EGFR phosphorylation in NSCLC and tumor-derived mutations (V483M) impair this function [PMID:36054194]. PTPRH forms a redox-sensitive cysteine-bonded homodimer through its extracellular and transmembrane domains; monomerization increases catalytic activity, providing a mechanism for activity control [PMID:15850787]. Consistent with a tumor-suppressive role, PTPRH ablation reduces intestinal tumorigenesis in APC-mutant mice [PMID:19170756] and its expression is epigenetically silenced by promoter DNA methylation and H3K27me3 in colorectal cancer [PMID:28713969]. The timeline additionally documents an ELK4/SAP-1 transcription factor activity required for ERK-driven thymocyte positive selection through induction of immediate-early genes such as Egr1 [PMID:14770179, PMID:20554967], with Elk-1 functionally interchangeable in this role [PMID:20554967] and ELK4/ELK1 jointly restraining innate-like CD8+ T-cell generation [PMID:30068599].","teleology":[{"year":2001,"claim":"Established PTPRH/SAP-1 as a catalytically active phosphatase acting on focal-adhesion signaling, answering what physiological substrates it targets and what cellular processes it controls.","evidence":"Substrate-trapping mutagenesis and immunocomplex phosphatase assays with cell spreading/colony formation readouts in intact cells","pmids":["11278335"],"confidence":"High","gaps":["In vivo substrate relevance not yet tested","Did not address localization or upstream regulation of activity"]},{"year":2003,"claim":"Extended the substrate range to immune signaling by showing PTPRH directly binds and inactivates Lck, defining a role in dampening TCR-proximal phosphorylation.","evidence":"Direct binding and in vitro dephosphorylation assays plus catalytic-dead mutant overexpression in Jurkat T cells","pmids":["12837766"],"confidence":"High","gaps":["Demonstrated in a cell line, not primary T cells in vivo","Stoichiometry and recruitment to the TCR complex unresolved"]},{"year":2004,"claim":"Identified an ELK4/SAP-1 transcription-factor activity downstream of ERK required for thymocyte positive selection, distinguishing it from the phosphatase function.","evidence":"SAP-1 knockout mice with TCR transgenes and target-gene expression analysis","pmids":["14770179"],"confidence":"High","gaps":["Relationship between the phosphatase and transcription-factor activities not reconciled","Direct target genes beyond Egr1 not fully defined here"]},{"year":2005,"claim":"Revealed a redox-controlled dimerization mechanism for activity regulation, answering how PTPRH catalytic output is tuned at the membrane.","evidence":"Cross-linking, reciprocal Co-IP, reducing-agent treatment, and activity assay toward c-Src","pmids":["15850787"],"confidence":"Medium","gaps":["Physiological trigger for redox-driven monomerization not identified","c-Src as substrate not validated in vivo"]},{"year":2007,"claim":"Delimited the ELK4 requirement by showing it is dispensable for Treg development and suppression, refining where the ERK-SAP-1 axis is essential.","evidence":"SAP-1 knockout mice with Treg marker analysis and in vitro/in vivo suppression assays","pmids":["17982074"],"confidence":"Medium","gaps":["Negative/dissociation finding from a single lab","Mechanism of Egr1-independent Treg function not addressed"]},{"year":2009,"claim":"Localized PTPRH to gastrointestinal brush-border microvilli and linked it to intestinal tumor development, establishing tissue context and disease relevance.","evidence":"Immunofluorescence/fractionation for localization and SAP-1-deficient × APC-heterozygous mouse tumorigenesis readout","pmids":["19170756"],"confidence":"Medium","gaps":["Substrate driving the tumor phenotype not identified in this study","Mechanism of microvillar targeting unknown"]},{"year":2010,"claim":"Defined Egr1 as the primary transcriptional effector of the ERK-SAP-1 axis and showed Elk-1 functional equivalence, clarifying the genetic logic of positive selection.","evidence":"SAP-1/Elk-1/Net knockout combinations, ectopic TCF and Egr1 rescue, and ChIP","pmids":["20554967"],"confidence":"High","gaps":["Full set of in vivo SRE targets not enumerated","Does not connect to PTPRH phosphatase activity"]},{"year":2015,"claim":"Identified CEACAM20 as a microvillar substrate and built a mechanistic model linking loss of PTPRH activity to c-Src/Syk/NF-κB-driven intestinal inflammation.","evidence":"Reciprocal Co-IP, phosphorylation analysis in deficient epithelium, NF-κB reporter, and SAP-1/IL-10 double-knockout colitis model","pmids":["26195794"],"confidence":"High","gaps":["Ectodomain interaction interface not structurally resolved","Direct in vitro dephosphorylation of CEACAM20 by PTPRH not isolated"]},{"year":2017,"claim":"Showed PTPRH is epigenetically silenced in colorectal cancer, providing a mechanism for loss of its tumor-suppressive activity.","evidence":"Promoter methylation pyrosequencing, 5-aza-deoxycytidine rescue, and ChIP for Pol II and H3K27me3","pmids":["28713969"],"confidence":"Medium","gaps":["Causal link between silencing and tumor progression not tested functionally","Upstream signals driving methylation unknown"]},{"year":2017,"claim":"Linked PTPRH loss to increased intestinal macromolecular permeability, implicating it in barrier/tight-junction regulation.","evidence":"SAP-1-deficient mouse everted ileal sac and colonic loop transport assays","pmids":["28431964"],"confidence":"Low","gaps":["No molecular mechanism for tight-junction regulation identified","No direct junctional substrate shown"]},{"year":2022,"claim":"Identified EGFR Y1197 as a PTPRH substrate in lung cancer and showed tumor-derived mutations impair this activity, extending the tumor-suppressor model to NSCLC.","evidence":"PTPRH knockout NSCLC cells with wild-type versus catalytic-dead rescue, pEGFR Western blot, and TCGA/IHC analysis","pmids":["36054194"],"confidence":"Medium","gaps":["Direct (in vitro) EGFR dephosphorylation by PTPRH not demonstrated","Later evidence questions a direct PTPRH-EGFR interaction"]},{"year":2023,"claim":"Connected PTPRH to glycolytic metabolism via PI3K/AKT/mTOR in NSCLC, broadening its cancer-relevant signaling output.","evidence":"PTPRH overexpression/knockdown with 18F-FDG uptake, lactate assays, pathway Western blots, PI3K inhibitor/agonist, and xenografts","pmids":["37974250"],"confidence":"Low","gaps":["No direct substrate linking PTPRH to PI3K/AKT identified","Correlative pharmacology rather than direct mechanism"]},{"year":2025,"claim":"Challenged the direct PTPRH-EGFR model by showing no direct interaction but an NF-κB association and a broad interactome, reframing EGFR regulation as indirect.","evidence":"Co-IP and BioID proximity labeling, domain-deletion mutants, and RNA-seq in NSCLC cells (preprint)","pmids":["41383754"],"confidence":"Low","gaps":["Preprint; interactors (HELZ2, RFC2) not functionally validated","Indirect EGFR mechanism not resolved","Reconciliation with direct Y1197 dephosphorylation finding pending"]},{"year":null,"claim":"How the membrane phosphatase activity (microvilli, substrate dephosphorylation) and the nuclear ELK4 transcription-factor activity are functionally and structurally reconciled within one gene product remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking the two activities","No study addresses whether both functions derive from the same protein isoform","Mechanism of redox-regulated activity control in vivo unverified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,9,10]}],"complexes":[],"partners":["CEACAM20","LCK","EGFR","SRC","ELK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HD43","full_name":"Receptor-type tyrosine-protein phosphatase H","aliases":["Stomach cancer-associated protein tyrosine phosphatase 1","SAP-1","Transmembrane-type protein-tyrosine phosphatase type H"],"length_aa":1115,"mass_kda":122.4,"function":"Protein phosphatase that may contribute to contact inhibition of cell growth and motility by mediating the dephosphorylation of focal adhesion-associated substrates and thus negatively regulating integrin-promoted signaling processes. Induces apoptotic cell death by at least two distinct mechanisms: inhibition of cell survival signaling mediated by PI 3-kinase, Akt, and ILK and activation of a caspase-dependent proapoptotic pathway. Inhibits the basal activity of LCK and its activation in response to TCR stimulation and TCR-induced activation of MAP kinase and surface expression of CD69. Inhibits TCR-induced tyrosine phosphorylation of LAT and ZAP70. Inhibits both basal activity of DOK1 and its CD2-induced tyrosine phosphorylation. Induces dephosphorylation of BCAR1, focal adhesion kinase and SRC. Reduces migratory activity of activity of Jurkat cells. Reduces tyrosine phosphorylation of CEACAM20 and thereby contributes to suppress the intestinal immune response CEACAM20 (By similarity)","subcellular_location":"Cell projection, microvillus membrane; Apical cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HD43/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRH","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRH","total_profiled":1310},"omim":[{"mim_id":"602510","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, H; PTPRH","url":"https://www.omim.org/entry/602510"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"gallbladder","ntpm":22.8},{"tissue":"intestine","ntpm":64.6},{"tissue":"stomach 1","ntpm":22.3}],"url":"https://www.proteinatlas.org/search/PTPRH"},"hgnc":{"alias_symbol":["SAP-1"],"prev_symbol":[]},"alphafold":{"accession":"Q9HD43","domains":[{"cath_id":"2.60.40.10","chopping":"35-117","consensus_level":"medium","plddt":81.7022,"start":35,"end":117},{"cath_id":"2.60.40.10","chopping":"124-207","consensus_level":"medium","plddt":86.8313,"start":124,"end":207},{"cath_id":"2.60.40.10","chopping":"213-295","consensus_level":"high","plddt":88.0464,"start":213,"end":295},{"cath_id":"2.60.40.10","chopping":"302-385","consensus_level":"high","plddt":89.7133,"start":302,"end":385},{"cath_id":"2.60.40.10","chopping":"391-473","consensus_level":"high","plddt":90.2276,"start":391,"end":473},{"cath_id":"2.60.40.10","chopping":"480-563","consensus_level":"high","plddt":89.7537,"start":480,"end":563},{"cath_id":"2.60.40.10","chopping":"570-608_619-664","consensus_level":"high","plddt":87.9986,"start":570,"end":664},{"cath_id":"2.60.40.10","chopping":"670-749","consensus_level":"high","plddt":84.7634,"start":670,"end":749},{"cath_id":"3.90.190.10","chopping":"801-1084","consensus_level":"medium","plddt":92.215,"start":801,"end":1084}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HD43","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HD43-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HD43-F1-predicted_aligned_error_v6.png","plddt_mean":83.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRH","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRH"},"sequence":{"accession":"Q9HD43","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HD43.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HD43/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HD43"}},"corpus_meta":[{"pmid":"1339307","id":"PMC_1339307","title":"Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element.","date":"1992","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1339307","citation_count":631,"is_preprint":false},{"pmid":"2842863","id":"PMC_2842863","title":"Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same genetic locus.","date":"1988","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/2842863","citation_count":253,"is_preprint":false},{"pmid":"6501254","id":"PMC_6501254","title":"Isolation and amino acid sequence of SAP-1, an acidic protein of human whole saliva, and sequence homology with human gamma-trace.","date":"1984","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6501254","citation_count":99,"is_preprint":false},{"pmid":"9734357","id":"PMC_9734357","title":"Structures of SAP-1 bound to DNA targets from the E74 and c-fos promoters: insights into DNA sequence discrimination by Ets proteins.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9734357","citation_count":96,"is_preprint":false},{"pmid":"11406578","id":"PMC_11406578","title":"The B-box dominates SAP-1-SRF interactions in the structure of the ternary complex.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11406578","citation_count":86,"is_preprint":false},{"pmid":"11029469","id":"PMC_11029469","title":"Selective targeting of MAPKs to the ETS domain transcription factor SAP-1.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11029469","citation_count":78,"is_preprint":false},{"pmid":"8524663","id":"PMC_8524663","title":"The ETS-domain transcription factors Elk-1 and SAP-1 exhibit differential DNA binding specificities.","date":"1995","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8524663","citation_count":77,"is_preprint":false},{"pmid":"3081038","id":"PMC_3081038","title":"Biosynthesis of the sulfatide/GM1 activator protein (SAP-1) in control and mutant cultured skin fibroblasts.","date":"1986","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/3081038","citation_count":64,"is_preprint":false},{"pmid":"1637339","id":"PMC_1637339","title":"Additional biochemical findings in a patient and fetal sibling with a genetic defect in the sphingolipid activator protein (SAP) precursor, prosaposin. Evidence for a deficiency in SAP-1 and for a normal lysosomal neuraminidase.","date":"1992","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/1637339","citation_count":61,"is_preprint":false},{"pmid":"3980013","id":"PMC_3980013","title":"The gene coding for a sphingolipid activator protein, SAP-1, is on human chromosome 10.","date":"1985","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3980013","citation_count":60,"is_preprint":false},{"pmid":"14770179","id":"PMC_14770179","title":"Ternary complex factor SAP-1 is required for Erk-mediated thymocyte positive selection.","date":"2004","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14770179","citation_count":56,"is_preprint":false},{"pmid":"11846562","id":"PMC_11846562","title":"Crystal structure of a ternary SAP-1/SRF/c-fos SRE DNA complex.","date":"2001","source":"Journal of molecular 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20554967","citation_count":42,"is_preprint":false},{"pmid":"6435528","id":"PMC_6435528","title":"Biochemical, immunological, and structural studies on a sphingolipid activator protein (SAP-1).","date":"1984","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/6435528","citation_count":42,"is_preprint":false},{"pmid":"9070877","id":"PMC_9070877","title":"Overexpression of SAP-1, a transmembrane-type protein tyrosine phosphatase, in human colorectal cancers.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9070877","citation_count":37,"is_preprint":false},{"pmid":"37974250","id":"PMC_37974250","title":"PTPRH promotes the progression of non-small cell lung cancer via glycolysis mediated by the PI3K/AKT/mTOR signaling pathway.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37974250","citation_count":36,"is_preprint":false},{"pmid":"19170756","id":"PMC_19170756","title":"SAP-1 is a microvillus-specific protein tyrosine phosphatase that modulates intestinal tumorigenesis.","date":"2009","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/19170756","citation_count":35,"is_preprint":false},{"pmid":"2868718","id":"PMC_2868718","title":"Molecular cloning of the sphingolipid activator protein-1 (SAP-1), the sulfatide sulfatase activator.","date":"1986","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/2868718","citation_count":33,"is_preprint":false},{"pmid":"15850787","id":"PMC_15850787","title":"Sap-1/PTPRH activity is regulated by reversible dimerization.","date":"2005","source":"Biochemical and biophysical research 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carcinoma.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12879010","citation_count":24,"is_preprint":false},{"pmid":"3827882","id":"PMC_3827882","title":"A triple-binding-domain model explains the specificity of the interaction of a sphingolipid activator protein (SAP-1) with sulphatide, GM1-ganglioside and globotriaosylceramide.","date":"1986","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/3827882","citation_count":22,"is_preprint":false},{"pmid":"30068599","id":"PMC_30068599","title":"ERK Signaling Controls Innate-like CD8+ T Cell Differentiation via the ELK4 (SAP-1) and ELK1 Transcription Factors.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30068599","citation_count":20,"is_preprint":false},{"pmid":"17982074","id":"PMC_17982074","title":"Raf signaling but not the ERK effector SAP-1 is required for regulatory T cell development.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17982074","citation_count":18,"is_preprint":false},{"pmid":"8247551","id":"PMC_8247551","title":"Transcriptional activation domains of elk-1, delta elk-1 and SAP-1 proteins.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8247551","citation_count":17,"is_preprint":false},{"pmid":"8764983","id":"PMC_8764983","title":"Analysis of SRF, SAP-1 and ELK-1 transcripts and proteins in human cell lines.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8764983","citation_count":17,"is_preprint":false},{"pmid":"3478817","id":"PMC_3478817","title":"Regional localization of the gene coding for sphingolipid activator protein SAP-1 on human chromosome 10.","date":"1987","source":"Somatic cell and molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3478817","citation_count":17,"is_preprint":false},{"pmid":"3242555","id":"PMC_3242555","title":"Complete amino-acid sequence of the naturally occurring A2 activator protein for enzymic sphingomyelin degradation: identity to the sulfatide activator protein (SAP-1).","date":"1988","source":"Biological chemistry Hoppe-Seyler","url":"https://pubmed.ncbi.nlm.nih.gov/3242555","citation_count":14,"is_preprint":false},{"pmid":"1350885","id":"PMC_1350885","title":"Correction of sulfatide metabolism after transfer of prosaposin cDNA to cultured cells from a patient with SAP-1 deficiency.","date":"1992","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1350885","citation_count":10,"is_preprint":false},{"pmid":"36054194","id":"PMC_36054194","title":"Elevated phosphorylation of EGFR in NSCLC due to mutations in PTPRH.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36054194","citation_count":9,"is_preprint":false},{"pmid":"28043381","id":"PMC_28043381","title":"Characterization and vaccine potential of Fasciola gigantica saposin-like protein 1 (SAP-1).","date":"2016","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/28043381","citation_count":9,"is_preprint":false},{"pmid":"7847828","id":"PMC_7847828","title":"The role of regulated phosphorylation in the biological activity of transcription factors SRF and Elk-1/SAP-1.","date":"1994","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7847828","citation_count":9,"is_preprint":false},{"pmid":"28713969","id":"PMC_28713969","title":"Downregulation of PTPRH (Sap-1) in colorectal tumors.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28713969","citation_count":8,"is_preprint":false},{"pmid":"12837766","id":"PMC_12837766","title":"Interaction of SAP-1, a transmembrane-type protein-tyrosine phosphatase, with the tyrosine kinase Lck. Roles in regulation of T cell function.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12837766","citation_count":8,"is_preprint":false},{"pmid":"36066180","id":"PMC_36066180","title":"Geoalkalibacter halelectricus SAP-1 sp. nov. possessing extracellular electron transfer and mineral-reducing capabilities from a haloalkaline environment.","date":"2022","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36066180","citation_count":7,"is_preprint":false},{"pmid":"11435690","id":"PMC_11435690","title":"Gene for the human transmembrane-type protein tyrosine phosphatase H (PTPRH): genomic structure, fine-mapping and its exclusion as a candidate for Peutz-Jeghers syndrome.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11435690","citation_count":5,"is_preprint":false},{"pmid":"35140475","id":"PMC_35140475","title":"PTPRH Alleviates Airway Obstruction and Th2 Inflammation in Asthma as a Protective Factor.","date":"2022","source":"Journal of asthma and allergy","url":"https://pubmed.ncbi.nlm.nih.gov/35140475","citation_count":3,"is_preprint":false},{"pmid":"25147059","id":"PMC_25147059","title":"Structural and binding studies of SAP-1 protein with heparin.","date":"2014","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/25147059","citation_count":3,"is_preprint":false},{"pmid":"28431964","id":"PMC_28431964","title":"Microvillus-Specific Protein Tyrosine Phosphatase SAP-1 Plays a Role in Regulating the Intestinal Paracellular Transport of Macromolecules.","date":"2017","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28431964","citation_count":1,"is_preprint":false},{"pmid":"24261636","id":"PMC_24261636","title":"Studies on the interactions of SAP-1 (an N-terminal truncated form of cystatin S) with its binding partners by CD-spectroscopic and molecular docking methods.","date":"2013","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/24261636","citation_count":1,"is_preprint":false},{"pmid":"41383754","id":"PMC_41383754","title":"Unraveling the role of receptor-like protein tyrosine phosphatase PTPRH in cell signaling regulation and biological processes of non-small cell lung cancer.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41383754","citation_count":0,"is_preprint":false},{"pmid":"42113318","id":"PMC_42113318","title":"RBM15/IGF2BP2-PTPRH m6A regulatory axis in non-small cell lung cancer.","date":"2026","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/42113318","citation_count":0,"is_preprint":false},{"pmid":"41570449","id":"PMC_41570449","title":"Functional impact assessment of tissue-specific missense variants in the PTPRH gene using a multi-tool computational framework.","date":"2026","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41570449","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23176,"output_tokens":4164,"usd":0.065994,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11993,"output_tokens":4147,"usd":0.08182,"stage2_stop_reason":"end_turn"},"total_usd":0.147814,"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\": 2001,\n      \"finding\": \"SAP-1 (PTPRH), using a substrate-trapping approach, was shown to dephosphorylate p130cas (a major focal adhesion-associated phosphotyrosyl protein) as a likely physiological substrate. Expression of recombinant SAP-1 induced dephosphorylation of p130cas, FAK, and p62dok in intact cells; a substrate-trapping mutant caused hyperphosphorylation (dominant negative effect). SAP-1 enzymatic activity was increased by cell-cell adhesion, and overexpression disrupted the actin cytoskeleton and inhibited cell spreading on fibronectin, ERK2 activation, and colony formation.\",\n      \"method\": \"Substrate-trapping mutagenesis, overexpression in intact cells, immunocomplex phosphatase assay, cell spreading/colony formation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate-trapping mutagenesis plus immunocomplex phosphatase assay plus multiple orthogonal cellular readouts in a single focused study\",\n      \"pmids\": [\"11278335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The cytoplasmic region of SAP-1 (PTPRH) directly binds and dephosphorylates the tyrosine kinase Lck in vitro. Overexpression of wild-type (but not catalytically inactive) SAP-1 inhibited basal and TCR-stimulated Lck activity in Jurkat T cells, reduced ZAP-70 and LAT tyrosine phosphorylation, attenuated MAP kinase activation, CD69 upregulation, p62dok phosphorylation, and cell migration.\",\n      \"method\": \"Direct binding assay, in vitro dephosphorylation assay, catalytically inactive mutant overexpression, TCR stimulation assays in Jurkat cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro dephosphorylation assay plus catalytic-dead mutant control plus multiple cellular readouts, single lab\",\n      \"pmids\": [\"12837766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SAP-1/PTPRH forms a stable homodimer mediated by its extracellular and transmembrane domains (not the catalytic domain). Dimer formation/stabilization involves cysteine bonds, as reducing conditions reversibly disrupt the dimer. Monomerization is accompanied by increased catalytic activity; monomeric SAP-1 dephosphorylates and activates c-Src, identified as a novel substrate.\",\n      \"method\": \"Chemical cross-linking, co-immunoprecipitation, reducing agent treatment, catalytic activity assay toward c-Src\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and cross-linking plus functional activity assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"15850787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SAP-1 (PTPRH) protein localizes specifically to the microvilli of the brush border in gastrointestinal epithelial cells. SAP-1 ablation in mice with heterozygous APC mutation inhibited intestinal tumorigenesis, establishing SAP-1 as a microvillus-specific RPTP that modulates intestinal tumor development.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation for localization; SAP-1-deficient mouse crossed with APC heterozygous mouse for tumorigenesis readout\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment plus genetic loss-of-function with clear tumor phenotype, single lab\",\n      \"pmids\": [\"19170756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SAP-1 (PTPRH) dephosphorylates CEACAM20 (a microvillus-specific transmembrane Ig superfamily protein) as a substrate; SAP-1 and CEACAM20 form a complex through interaction of their ectodomains. Tyrosine phosphorylation of CEACAM20 by c-Src, unopposed by SAP-1, promotes CEACAM20 association with Syk, activating NF-κB and IL-8 production. SAP-1-deficient mice on an IL-10-deficient background showed markedly increased colitis severity.\",\n      \"method\": \"Tyrosine phosphorylation analysis in SAP-1-deficient intestinal epithelium, co-immunoprecipitation of SAP-1 and CEACAM20, overexpression of c-Src and Syk in cultured cells, NF-κB reporter assay, SAP-1/IL-10 double-knockout mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function mouse model, in vitro phosphorylation assays, and NF-κB pathway assay providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"26195794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SAP-1 (ELK4) is required for ERK-mediated thymocyte positive selection. SAP-1-deficient mice showed severely reduced (80–90%) positive selection and impaired TCR-induced activation of target genes including Egr1 in double-positive thymocytes, despite normal ERK activation, positioning SAP-1 as a transcriptional effector directly downstream of ERK in the positive selection pathway. Negative selection was unimpaired.\",\n      \"method\": \"SAP-1 knockout mouse, TCR transgene analysis, RT-PCR/gene expression, ERK activation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout (positive vs negative selection dissected), replicated with TCR transgenes and target gene analysis\",\n      \"pmids\": [\"14770179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SAP-1 and Elk-1 are functionally equivalent for thymocyte positive selection (Elk-1 ectopic expression rescues SAP-1-null positive selection defect; Net does not). Ectopic expression of the SAP-1/Elk-1 target gene Egr-1 alone restored positive selection in SAP-1-null thymocytes, establishing Egr-1 (and possibly other Egr family members) as the primary transcriptional effectors of the ERK–SAP-1 signaling axis in positive selection.\",\n      \"method\": \"SAP-1/Elk-1/Net genetic knockout mice, ectopic TCF expression rescue experiments, Egr-1 transgenic rescue, chromatin immunoprecipitation, array gene expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO combinations, rescue experiments, and ChIP providing converging evidence\",\n      \"pmids\": [\"20554967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SAP-1 (ELK4) is NOT required for regulatory T cell (Treg) development or suppressive function; SAP-1-deficient CD4+CD25+ Tregs still suppress T cell proliferation in vitro and in a colitis model in vivo, despite impaired Egr-1 induction after TCR crosslinking.\",\n      \"method\": \"SAP-1 knockout mouse, Foxp3/CD25/GITR/CTLA4 expression analysis, in vitro suppression assay, in vivo colitis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple Treg markers and functional suppression assays, single lab; this is a negative/dissociation finding\",\n      \"pmids\": [\"17982074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ELK4 (SAP-1) and ELK1 act cell-autonomously in the thymus to suppress the generation of innate-like αβ CD8+ T cells. In ELK4/ELK1 double-knockout mice, increased innate-like CD8+ T cell numbers were associated with reduced ERK-mediated activation of ELK4-SRF target genes, and ectopic EGR2 expression partially suppressed this phenotype.\",\n      \"method\": \"ELK4 and ELK1 single and double knockout mice, flow cytometry of CD8+ T cell populations, ectopic EGR2 expression rescue, ERK inhibition in peripheral CD8+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double KO and rescue experiments, single lab\",\n      \"pmids\": [\"30068599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRH directly dephosphorylates EGFR at tyrosine Y1197 (Y1173). PTPRH knockout in NSCLC cells increased Y1197 EGFR phosphorylation; rescue with wild-type PTPRH restored basal phosphorylation levels, while rescue with catalytically dead PTPRH did not. PTPRH mutations found in NSCLC tumors (V483M) are inhibitory to PTPRH function, resulting in aberrant EGFR activity.\",\n      \"method\": \"PTPRH knockout NSCLC cell line, wild-type vs catalytically dead PTPRH rescue expression, Western blot for pEGFR Y1197, whole genome sequencing, TCGA data analysis, immunohistochemistry\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus catalytic-dead mutant rescue provides clean mechanistic evidence for EGFR as substrate, single lab\",\n      \"pmids\": [\"36054194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPRH expression in colorectal tumors is regulated epigenetically: DNA methylation of PTPRH promoter regions correlates with reduced PTPRH expression in CRC, and treatment with 5-aza-deoxycytidine restored PTPRH expression in methylated cell lines. H3K27 trimethylation in promoter/gene body and reduced RNA Pol II occupancy were also associated with silenced PTPRH.\",\n      \"method\": \"Pyrosequencing of promoter methylation, 5-aza-deoxycytidine demethylation treatment, chromatin immunoprecipitation (RNA Pol II, H3K27me3), qRT-PCR, immunohistochemistry\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological demethylation rescue plus ChIP, single lab with two orthogonal methods\",\n      \"pmids\": [\"28713969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SAP-1 (PTPRH) deficiency in mice increases paracellular transport of macromolecules (dextrans FD-4 and FD-10) across the intestinal epithelium, as measured in everted ileal sacs and colonic loop absorption assays, indicating SAP-1 contributes to regulation of tight junction permeability for macromolecules.\",\n      \"method\": \"SAP-1-deficient mouse, everted ileal sac transport assay, colonic loop absorption assay\",\n      \"journal\": \"Journal of pharmaceutical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single KO study with a functional readout but no direct molecular mechanism identified for tight junction regulation\",\n      \"pmids\": [\"28431964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTPRH promotes glycolysis in NSCLC cells via the PI3K/AKT/mTOR signaling pathway. Altering PTPRH expression changed 18F-FDG uptake, lactate production, and expression of glycolysis-related proteins; PI3K inhibitor (LY294002) or agonist (740Y-P) modulated these effects, consistent with PTPRH acting upstream of PI3K/AKT/mTOR in this context.\",\n      \"method\": \"PTPRH overexpression/knockdown in NSCLC cells, 18F-FDG uptake assay, lactate production assay, Western blot for glycolysis proteins and PI3K/AKT pathway, PI3K inhibitor/agonist treatment, xenograft tumor model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological pathway modulation without direct substrate identification; single lab\",\n      \"pmids\": [\"37974250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPRH does not directly interact with EGFR in NSCLC cells; instead PTPRH interacts with NF-κB (a transcription factor downstream of EGFR), as demonstrated by Co-IP and proximity-dependent biotinylation (BioID). BioID also identified 48 novel PTPRH interactors including HELZ2 and RFC2. Disruption of either extracellular or intracellular PTPRH domains leads to EGFR dephosphorylation, suggesting an indirect mechanism. PTPRH overexpression downregulates multiple oncogenic signature pathways and modulates expression of 34 protein tyrosine phosphatases and 45 tyrosine kinases.\",\n      \"method\": \"Co-immunoprecipitation, proximity-dependent biotinylation (BioID), PTPRH domain deletion mutants, RNA sequencing, PTPRH overexpression/knockout in NSCLC cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint; Co-IP/BioID in single lab, indirect EGFR mechanism not fully resolved\",\n      \"pmids\": [\"41383754\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PTPRH (SAP-1) is a receptor-type protein tyrosine phosphatase localized to intestinal microvillus brush borders that negatively regulates integrin- and adhesion-mediated signaling by dephosphorylating p130cas, FAK, and p62dok; directly binds and inactivates Lck to suppress T cell signaling; dephosphorylates CEACAM20 (forming an ectodomain complex) to restrain c-Src/Syk/NF-κB-driven intestinal inflammation; dephosphorylates EGFR at Y1197 to suppress EGFR pathway activity; undergoes redox-regulated homodimerization via its extracellular/transmembrane domains that controls catalytic activity (monomer is more active); and in the nucleus acts as an ETS/TCF transcription factor (ELK4/SAP-1) that is phosphorylated and activated by ERK2 and selective p38 MAPKs via D-domain and FXF motif docking, cooperates with SRF on serum response elements, and is required for thymocyte positive selection through transcriptional activation of immediate-early genes such as Egr1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRH (SAP-1) is a microvillus-specific receptor-type protein tyrosine phosphatase that negatively regulates adhesion- and growth-factor signaling in epithelial and immune cells by dephosphorylating key tyrosine-phosphorylated substrates [#0, #3]. Using substrate trapping, it was established to dephosphorylate the focal-adhesion proteins p130cas, FAK, and p62dok, with its catalytic activity stimulated by cell-cell adhesion and its overexpression disrupting the actin cytoskeleton, cell spreading on fibronectin, and ERK2 activation [#0]. Its substrate repertoire extends to the T-cell kinase Lck, which it directly binds and inactivates to suppress TCR-proximal signaling [#1], to c-Src [#2], to the microvillus protein CEACAM20 — where loss of PTPRH-mediated dephosphorylation permits c-Src-driven CEACAM20–Syk association, NF-\\u03baB activation, and IL-8 production, and PTPRH deficiency aggravates colitis [#4] — and to EGFR at Y1197, where catalytically intact PTPRH restrains EGFR phosphorylation in NSCLC and tumor-derived mutations (V483M) impair this function [#9]. PTPRH forms a redox-sensitive cysteine-bonded homodimer through its extracellular and transmembrane domains; monomerization increases catalytic activity, providing a mechanism for activity control [#2]. Consistent with a tumor-suppressive role, PTPRH ablation reduces intestinal tumorigenesis in APC-mutant mice [#3] and its expression is epigenetically silenced by promoter DNA methylation and H3K27me3 in colorectal cancer [#10]. The timeline additionally documents an ELK4/SAP-1 transcription factor activity required for ERK-driven thymocyte positive selection through induction of immediate-early genes such as Egr1 [#5, #6], with Elk-1 functionally interchangeable in this role [#6] and ELK4/ELK1 jointly restraining innate-like CD8+ T-cell generation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PTPRH/SAP-1 as a catalytically active phosphatase acting on focal-adhesion signaling, answering what physiological substrates it targets and what cellular processes it controls.\",\n      \"evidence\": \"Substrate-trapping mutagenesis and immunocomplex phosphatase assays with cell spreading/colony formation readouts in intact cells\",\n      \"pmids\": [\"11278335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate relevance not yet tested\", \"Did not address localization or upstream regulation of activity\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the substrate range to immune signaling by showing PTPRH directly binds and inactivates Lck, defining a role in dampening TCR-proximal phosphorylation.\",\n      \"evidence\": \"Direct binding and in vitro dephosphorylation assays plus catalytic-dead mutant overexpression in Jurkat T cells\",\n      \"pmids\": [\"12837766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated in a cell line, not primary T cells in vivo\", \"Stoichiometry and recruitment to the TCR complex unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified an ELK4/SAP-1 transcription-factor activity downstream of ERK required for thymocyte positive selection, distinguishing it from the phosphatase function.\",\n      \"evidence\": \"SAP-1 knockout mice with TCR transgenes and target-gene expression analysis\",\n      \"pmids\": [\"14770179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between the phosphatase and transcription-factor activities not reconciled\", \"Direct target genes beyond Egr1 not fully defined here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed a redox-controlled dimerization mechanism for activity regulation, answering how PTPRH catalytic output is tuned at the membrane.\",\n      \"evidence\": \"Cross-linking, reciprocal Co-IP, reducing-agent treatment, and activity assay toward c-Src\",\n      \"pmids\": [\"15850787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger for redox-driven monomerization not identified\", \"c-Src as substrate not validated in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Delimited the ELK4 requirement by showing it is dispensable for Treg development and suppression, refining where the ERK-SAP-1 axis is essential.\",\n      \"evidence\": \"SAP-1 knockout mice with Treg marker analysis and in vitro/in vivo suppression assays\",\n      \"pmids\": [\"17982074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative/dissociation finding from a single lab\", \"Mechanism of Egr1-independent Treg function not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localized PTPRH to gastrointestinal brush-border microvilli and linked it to intestinal tumor development, establishing tissue context and disease relevance.\",\n      \"evidence\": \"Immunofluorescence/fractionation for localization and SAP-1-deficient × APC-heterozygous mouse tumorigenesis readout\",\n      \"pmids\": [\"19170756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate driving the tumor phenotype not identified in this study\", \"Mechanism of microvillar targeting unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined Egr1 as the primary transcriptional effector of the ERK-SAP-1 axis and showed Elk-1 functional equivalence, clarifying the genetic logic of positive selection.\",\n      \"evidence\": \"SAP-1/Elk-1/Net knockout combinations, ectopic TCF and Egr1 rescue, and ChIP\",\n      \"pmids\": [\"20554967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of in vivo SRE targets not enumerated\", \"Does not connect to PTPRH phosphatase activity\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified CEACAM20 as a microvillar substrate and built a mechanistic model linking loss of PTPRH activity to c-Src/Syk/NF-\\u03baB-driven intestinal inflammation.\",\n      \"evidence\": \"Reciprocal Co-IP, phosphorylation analysis in deficient epithelium, NF-\\u03baB reporter, and SAP-1/IL-10 double-knockout colitis model\",\n      \"pmids\": [\"26195794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ectodomain interaction interface not structurally resolved\", \"Direct in vitro dephosphorylation of CEACAM20 by PTPRH not isolated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PTPRH is epigenetically silenced in colorectal cancer, providing a mechanism for loss of its tumor-suppressive activity.\",\n      \"evidence\": \"Promoter methylation pyrosequencing, 5-aza-deoxycytidine rescue, and ChIP for Pol II and H3K27me3\",\n      \"pmids\": [\"28713969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between silencing and tumor progression not tested functionally\", \"Upstream signals driving methylation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked PTPRH loss to increased intestinal macromolecular permeability, implicating it in barrier/tight-junction regulation.\",\n      \"evidence\": \"SAP-1-deficient mouse everted ileal sac and colonic loop transport assays\",\n      \"pmids\": [\"28431964\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism for tight-junction regulation identified\", \"No direct junctional substrate shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified EGFR Y1197 as a PTPRH substrate in lung cancer and showed tumor-derived mutations impair this activity, extending the tumor-suppressor model to NSCLC.\",\n      \"evidence\": \"PTPRH knockout NSCLC cells with wild-type versus catalytic-dead rescue, pEGFR Western blot, and TCGA/IHC analysis\",\n      \"pmids\": [\"36054194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct (in vitro) EGFR dephosphorylation by PTPRH not demonstrated\", \"Later evidence questions a direct PTPRH-EGFR interaction\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected PTPRH to glycolytic metabolism via PI3K/AKT/mTOR in NSCLC, broadening its cancer-relevant signaling output.\",\n      \"evidence\": \"PTPRH overexpression/knockdown with 18F-FDG uptake, lactate assays, pathway Western blots, PI3K inhibitor/agonist, and xenografts\",\n      \"pmids\": [\"37974250\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct substrate linking PTPRH to PI3K/AKT identified\", \"Correlative pharmacology rather than direct mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Challenged the direct PTPRH-EGFR model by showing no direct interaction but an NF-\\u03baB association and a broad interactome, reframing EGFR regulation as indirect.\",\n      \"evidence\": \"Co-IP and BioID proximity labeling, domain-deletion mutants, and RNA-seq in NSCLC cells (preprint)\",\n      \"pmids\": [\"41383754\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; interactors (HELZ2, RFC2) not functionally validated\", \"Indirect EGFR mechanism not resolved\", \"Reconciliation with direct Y1197 dephosphorylation finding pending\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the membrane phosphatase activity (microvilli, substrate dephosphorylation) and the nuclear ELK4 transcription-factor activity are functionally and structurally reconciled within one gene product remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking the two activities\", \"No study addresses whether both functions derive from the same protein isoform\", \"Mechanism of redox-regulated activity control in vivo unverified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CEACAM20\", \"LCK\", \"EGFR\", \"SRC\", \"ELK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}