{"gene":"PTPRH","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2001,"finding":"SAP-1 (PTPRH) dephosphorylates p130cas, a major focal adhesion-associated phosphotyrosyl protein, identified via a substrate-trapping approach. Expression of SAP-1 also induced dephosphorylation of focal adhesion kinase and p62(dok), disrupted the actin-based cytoskeleton, inhibited cell spreading on fibronectin, and inhibited colony formation. SAP-1 enzymatic activity was increased by cell-cell adhesion, suggesting a role in contact inhibition.","method":"Substrate-trapping mutant, overexpression, immunocomplex phosphatase assay, cell spreading assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including substrate-trapping, dominant-negative overexpression, and functional assays in intact cells","pmids":["11278335"],"is_preprint":false},{"year":2005,"finding":"SAP-1/PTPRH forms a stable homodimer mediated by its extracellular and transmembrane domains (not the catalytic domain). Dimerization is stabilized by disulfide bonds and is reversible under reducing conditions. Disruption of the dimer increases catalytic activity; c-Src was identified as a novel substrate dephosphorylated by SAP-1 monomers.","method":"Chemical cross-linking, co-immunoprecipitation, catalytic activity assay, reducing agent treatment","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — two orthogonal methods (crosslinking + co-IP) plus functional activity measurement with identified substrate","pmids":["15850787"],"is_preprint":false},{"year":2003,"finding":"The cytoplasmic region of SAP-1 (PTPRH) directly binds the tyrosine kinase Lck. SAP-1 dephosphorylates Lck in vitro and inhibits its kinase activity in cells. Overexpression of wild-type (but not catalytically inactive) SAP-1 inhibited TCR-stimulated MAPK activation, CD69 upregulation, ZAP-70 and LAT phosphorylation, and cell migration in Jurkat T cells.","method":"Direct binding assay, in vitro phosphatase assay with catalytically inactive mutant, overexpression in Jurkat cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro dephosphorylation assay plus catalytic mutant controls and multiple downstream readouts","pmids":["12837766"],"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-deficient mice show inhibited intestinal tumorigenesis in mice with heterozygous APC mutation, establishing SAP-1 as a microvillus-specific RPTP that regulates intestinal tumorigenesis.","method":"Immunofluorescence localization, SAP-1 knockout mice crossed with APC heterozygous mice, tumor quantification","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 — direct localization by imaging plus genetic loss-of-function with clear tumor phenotype","pmids":["19170756"],"is_preprint":false},{"year":2015,"finding":"SAP-1 (PTPRH) dephosphorylates CEACAM20, an intestinal microvillus-specific transmembrane protein. SAP-1 and CEACAM20 form a complex via their ectodomains. c-Src phosphorylates CEACAM20, and the resulting phosphorylation promotes Syk association with CEACAM20, activating NF-κB and IL-8 production. SAP-1 ablation in IL-10-deficient mice worsened colitis.","method":"Substrate identification in SAP-1-deficient mice, co-immunoprecipitation of SAP-1/CEACAM20 complex, in vitro phosphorylation by c-Src, NF-κB reporter assay, IL-10 KO mouse colitis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches including substrate identification in vivo, co-IP, in vitro kinase assay, and genetic model with defined phenotype","pmids":["26195794"],"is_preprint":false},{"year":2022,"finding":"PTPRH dephosphorylates EGFR at tyrosine 1197 (Y1197) in NSCLC cells. Knockout of PTPRH resulted in increased Y1197 phosphorylation; rescue with wild-type PTPRH restored normal phosphorylation levels, while catalytically dead PTPRH did not. PTPRH mutations in NSCLC are mutually exclusive with EGFR mutations and confer sensitivity to EGFR tyrosine kinase inhibitors.","method":"PTPRH knockout cell line, wild-type vs. catalytically dead rescue expression, phospho-EGFR immunoblot, osimertinib dose-response, xenograft tumor model","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — KO plus wild-type and catalytic-dead rescue with specific phosphosite readout, validated in vivo","pmids":["36054194"],"is_preprint":false},{"year":2022,"finding":"PTPRH overexpression in human bronchial epithelial cells inhibits phosphorylation of EGFR, ERK1/2, and AKT, and suppresses MUC5AC secretion. Knockdown of PTPRH leads to dephosphorylation of EGFR, ERK1/2, and AKT. In a house dust mite asthma mouse model, PTPRH treatment suppressed Th2 airway inflammation and Muc5ac expression.","method":"PTPRH overexpression and knockdown in HBECs, Western blot for phospho-EGFR/ERK/AKT, in vivo HDM asthma mouse model","journal":"Journal of asthma and allergy","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression/knockdown with phospho-readouts but no direct substrate trapping or in vitro phosphatase assay","pmids":["35140475"],"is_preprint":false},{"year":2023,"finding":"PTPRH promotes glycolysis and tumor cell proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC. Altering PTPRH expression changed 18F-FDG uptake, lactate production, and glycolysis-related protein levels. PI3K inhibition (LY294002) reversed PTPRH-driven effects, placing PTPRH upstream of PI3K/AKT/mTOR.","method":"Colony assay, EdU, Transwell, wound healing, 18F-FDG uptake, Western blot, PI3K inhibitor/agonist, xenograft mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 — genetic epistasis using pharmacological inhibitor plus multiple cellular assays, but no direct substrate identification","pmids":["37974250"],"is_preprint":false},{"year":2017,"finding":"PTPRH expression in colorectal tumors is regulated by promoter DNA methylation and histone H3K27 trimethylation. Cell lines with highly methylated PTPRH promoters showed lower expression, lower RNA Pol II occupancy, and treatment with 5-aza-deoxycytidine restored PTPRH expression.","method":"Pyrosequencing of promoter methylation, chromatin immunoprecipitation (H3K27me3 and RNA Pol II), 5-aza-dC treatment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and demethylation rescue establish epigenetic mechanism for PTPRH regulation, though functional downstream consequence not directly linked","pmids":["28713969"],"is_preprint":false},{"year":2017,"finding":"SAP-1 (PTPRH) deficiency increases paracellular transport of hydrophilic macromolecules (FD-4, FD-10 dextrans) through intestinal tight junctions in SAP-1 knockout mice, without affecting transporter-mediated absorption, indicating SAP-1 contributes to regulation of intestinal paracellular permeability.","method":"SAP-1 knockout mice, everted ileal sac transport assay, colonic loop absorption assay","journal":"Journal of pharmaceutical sciences","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific macromolecular transport phenotype, though molecular substrate not identified","pmids":["28431964"],"is_preprint":false},{"year":2025,"finding":"Co-immunoprecipitation and proximity-dependent biotinylation (BioID) in NSCLC cells showed that PTPRH does not directly interact with EGFR but interacts with NF-κB, a downstream EGFR pathway transcription factor. BioID identified 48 novel PTPRH interactors including HELZ2 and RFC2. PTPRH overexpression downregulated oncogenic pathways and modulated expression of protein tyrosine phosphatases and kinases including EGFR.","method":"Co-immunoprecipitation, BioID proximity labeling, RNA sequencing","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 — BioID plus co-IP with multiple interactors identified, but preprint without peer review","pmids":["41383754"],"is_preprint":true},{"year":2003,"finding":"SAP-1 (PTPRH) expression is downregulated in moderately and poorly differentiated hepatocellular carcinoma. Re-expression of recombinant SAP-1 in two highly motile HCC cell lines reduced migratory activity and growth rate, establishing a functional role for SAP-1 in suppressing HCC cell motility.","method":"Immunohistochemical and immunoblot analysis, recombinant SAP-1 re-expression, migration and growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — re-expression with defined migratory and growth phenotype but without substrate identification","pmids":["12879010"],"is_preprint":false}],"current_model":"PTPRH (SAP-1) is a receptor-type protein tyrosine phosphatase localized to intestinal epithelial microvilli that negatively regulates integrin and growth factor signaling by dephosphorylating substrates including p130cas, FAK, p62(dok), Lck, CEACAM20, and EGFR-Y1197; it forms redox-sensitive homodimers through its extracellular/transmembrane domains that regulate its catalytic activity, and controls intestinal immunity, tumorigenesis, and cell motility through dephosphorylation-mediated suppression of downstream pathways including PI3K/AKT/mTOR and NF-κB."},"narrative":{"teleology":[{"year":2001,"claim":"Identifying the first substrates of PTPRH established it as a phosphatase that targets focal adhesion signaling components and mediates contact inhibition of cell growth.","evidence":"Substrate-trapping mutant approach in cultured cells identified p130cas, FAK, and p62(dok) as substrates; functional assays showed inhibited cell spreading and colony formation","pmids":["11278335"],"confidence":"High","gaps":["No in vivo validation of substrate dephosphorylation","Mechanism by which cell-cell adhesion increases SAP-1 activity not defined","Structural basis for substrate recognition unknown"]},{"year":2003,"claim":"Demonstrating that PTPRH directly binds and dephosphorylates Lck extended its functional scope beyond focal adhesion signaling to T cell receptor signaling, showing it suppresses TCR-triggered MAPK activation and T cell migration.","evidence":"Direct binding assay, in vitro phosphatase assay with catalytic-dead control, and overexpression in Jurkat T cells measuring ZAP-70/LAT phosphorylation and CD69 upregulation","pmids":["12837766"],"confidence":"High","gaps":["Endogenous relevance in primary T cells not demonstrated","Whether PTPRH is physiologically expressed in T cells in vivo unclear"]},{"year":2003,"claim":"Showing that PTPRH is downregulated in hepatocellular carcinoma and that its re-expression suppresses cell motility and growth suggested a tumor-suppressive function in liver.","evidence":"Immunohistochemistry and immunoblot of HCC tissue, recombinant SAP-1 re-expression with migration and growth assays","pmids":["12879010"],"confidence":"Medium","gaps":["No substrate identified in HCC context","Lack of in vivo tumor model confirmation"]},{"year":2005,"claim":"Revealing that PTPRH forms redox-sensitive homodimers through its extracellular/transmembrane domains, with dimerization inhibiting catalytic activity, provided a regulatory mechanism and identified c-Src as an additional substrate.","evidence":"Chemical cross-linking, co-immunoprecipitation, reducing agent treatment, and catalytic activity assays","pmids":["15850787"],"confidence":"High","gaps":["Structural details of dimer interface unresolved","Physiological redox conditions that regulate dimerization not defined","Whether dimerization is regulated by ligand binding unknown"]},{"year":2009,"claim":"Localizing PTPRH specifically to intestinal epithelial microvilli and showing that its knockout inhibits APC-driven intestinal tumorigenesis established an unexpected pro-tumorigenic role in the gut, contrasting with its anti-proliferative effects in vitro.","evidence":"Immunofluorescence in gastrointestinal tissue and genetic cross of SAP-1 knockout with APC heterozygous mice with tumor quantification","pmids":["19170756"],"confidence":"High","gaps":["Molecular mechanism by which PTPRH promotes intestinal tumorigenesis not identified","Apparent contradiction with tumor-suppressive in vitro data not resolved"]},{"year":2015,"claim":"Identifying CEACAM20 as a microvillar substrate of PTPRH and linking its dephosphorylation to suppression of NF-κB/IL-8 signaling connected PTPRH to intestinal innate immune regulation, with loss-of-function worsening colitis in IL-10-deficient mice.","evidence":"Substrate identification in SAP-1 knockout mice, co-IP of SAP-1/CEACAM20 complex, in vitro c-Src phosphorylation, NF-κB reporter assay, colitis phenotype in IL-10 KO mice","pmids":["26195794"],"confidence":"High","gaps":["Whether CEACAM20 dephosphorylation fully accounts for colitis phenotype not tested","PTPRH regulation of other NF-κB pathway components not explored"]},{"year":2017,"claim":"Two studies filled distinct gaps: one showed PTPRH expression in colorectal tumors is silenced by promoter DNA methylation and H3K27me3, and the other demonstrated that PTPRH deficiency increases intestinal paracellular permeability, broadening its role to epithelial barrier function.","evidence":"Pyrosequencing, ChIP for H3K27me3/Pol II, and 5-aza-dC rescue (epigenetic); SAP-1 knockout mice with everted ileal sac and colonic loop transport assays (permeability)","pmids":["28713969","28431964"],"confidence":"Medium","gaps":["Tight junction substrate(s) of PTPRH not identified","Whether epigenetic silencing causally drives tumor progression not tested in vivo"]},{"year":2022,"claim":"Pinpointing EGFR Y1197 as a direct dephosphorylation target of PTPRH in NSCLC, using knockout and catalytic-dead rescue, established a specific phosphosite-level mechanism and revealed mutual exclusivity of PTPRH and EGFR mutations with therapeutic implications for TKI sensitivity.","evidence":"PTPRH knockout cells, wild-type vs. catalytic-dead rescue, phospho-EGFR Y1197 immunoblot, osimertinib dose-response, xenograft model","pmids":["36054194"],"confidence":"High","gaps":["Whether PTPRH dephosphorylates other EGFR tyrosine sites not addressed","Physical interaction between PTPRH and EGFR not confirmed by co-IP"]},{"year":2023,"claim":"Placing PTPRH upstream of PI3K/AKT/mTOR in NSCLC and showing it promotes glycolysis and proliferation via this pathway addressed the downstream signaling cascade but did not identify the direct substrate.","evidence":"Colony, EdU, Transwell, wound healing assays, 18F-FDG uptake, PI3K inhibitor epistasis, xenograft model","pmids":["37974250"],"confidence":"Medium","gaps":["Direct phosphatase substrate in PI3K/AKT/mTOR axis not identified","Context-dependent tumor-promoting vs. tumor-suppressive roles unresolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis for PTPRH substrate selectivity, the identity of any extracellular ligand, the mechanistic explanation for context-dependent tumor-promoting versus tumor-suppressive activities, and the direct substrates mediating its effects on tight junction permeability and PI3K/AKT/mTOR signaling.","evidence":"","pmids":[],"confidence":"High","gaps":["No extracellular ligand identified","No crystal structure of full-length PTPRH or its dimer","Conflicting tumor-promoting (intestinal) versus tumor-suppressive (HCC, NSCLC) roles not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5]}],"complexes":[],"partners":["CEACAM20","LCK","SRC","BCAR1","PTK2","EGFR","DOK1"],"other_free_text":[]},"mechanistic_narrative":"PTPRH (SAP-1) is a receptor-type protein tyrosine phosphatase that localizes to intestinal epithelial microvilli and functions as a negative regulator of integrin signaling, growth factor receptor signaling, and T cell activation through dephosphorylation of key signaling intermediates. Its identified substrates include the focal adhesion proteins p130cas and FAK, the adaptor p62(dok), the kinases Lck and c-Src, the microvillar transmembrane protein CEACAM20, and EGFR at tyrosine 1197, through which it suppresses downstream PI3K/AKT/mTOR and NF-κB signaling, cell motility, and proliferation [PMID:11278335, PMID:12837766, PMID:26195794, PMID:36054194]. PTPRH forms redox-sensitive homodimers via its extracellular and transmembrane domains, and dimerization inhibits catalytic activity, providing a mechanism for regulation by the cellular redox environment [PMID:15850787]. In vivo, PTPRH deficiency increases intestinal paracellular permeability and modulates intestinal tumorigenesis in an APC-mutant background, while loss of PTPRH in the IL-10-deficient setting worsens colitis, establishing roles in epithelial barrier integrity and mucosal immune homeostasis [PMID:19170756, PMID:26195794, PMID:28431964]."},"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 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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":"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21733,"output_tokens":3185,"usd":0.056487},"stage2":{"model":"claude-opus-4-6","input_tokens":6540,"output_tokens":2635,"usd":0.147863},"total_usd":0.20435,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SAP-1 (PTPRH) dephosphorylates p130cas, a major focal adhesion-associated phosphotyrosyl protein, identified via a substrate-trapping approach. Expression of SAP-1 also induced dephosphorylation of focal adhesion kinase and p62(dok), disrupted the actin-based cytoskeleton, inhibited cell spreading on fibronectin, and inhibited colony formation. SAP-1 enzymatic activity was increased by cell-cell adhesion, suggesting a role in contact inhibition.\",\n      \"method\": \"Substrate-trapping mutant, overexpression, immunocomplex phosphatase assay, cell spreading assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including substrate-trapping, dominant-negative overexpression, and functional assays in intact cells\",\n      \"pmids\": [\"11278335\"],\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). Dimerization is stabilized by disulfide bonds and is reversible under reducing conditions. Disruption of the dimer increases catalytic activity; c-Src was identified as a novel substrate dephosphorylated by SAP-1 monomers.\",\n      \"method\": \"Chemical cross-linking, co-immunoprecipitation, catalytic activity assay, reducing agent treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal methods (crosslinking + co-IP) plus functional activity measurement with identified substrate\",\n      \"pmids\": [\"15850787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The cytoplasmic region of SAP-1 (PTPRH) directly binds the tyrosine kinase Lck. SAP-1 dephosphorylates Lck in vitro and inhibits its kinase activity in cells. Overexpression of wild-type (but not catalytically inactive) SAP-1 inhibited TCR-stimulated MAPK activation, CD69 upregulation, ZAP-70 and LAT phosphorylation, and cell migration in Jurkat T cells.\",\n      \"method\": \"Direct binding assay, in vitro phosphatase assay with catalytically inactive mutant, overexpression in Jurkat cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro dephosphorylation assay plus catalytic mutant controls and multiple downstream readouts\",\n      \"pmids\": [\"12837766\"],\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-deficient mice show inhibited intestinal tumorigenesis in mice with heterozygous APC mutation, establishing SAP-1 as a microvillus-specific RPTP that regulates intestinal tumorigenesis.\",\n      \"method\": \"Immunofluorescence localization, SAP-1 knockout mice crossed with APC heterozygous mice, tumor quantification\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by imaging plus genetic loss-of-function with clear tumor phenotype\",\n      \"pmids\": [\"19170756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SAP-1 (PTPRH) dephosphorylates CEACAM20, an intestinal microvillus-specific transmembrane protein. SAP-1 and CEACAM20 form a complex via their ectodomains. c-Src phosphorylates CEACAM20, and the resulting phosphorylation promotes Syk association with CEACAM20, activating NF-κB and IL-8 production. SAP-1 ablation in IL-10-deficient mice worsened colitis.\",\n      \"method\": \"Substrate identification in SAP-1-deficient mice, co-immunoprecipitation of SAP-1/CEACAM20 complex, in vitro phosphorylation by c-Src, NF-κB reporter assay, IL-10 KO mouse colitis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including substrate identification in vivo, co-IP, in vitro kinase assay, and genetic model with defined phenotype\",\n      \"pmids\": [\"26195794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRH dephosphorylates EGFR at tyrosine 1197 (Y1197) in NSCLC cells. Knockout of PTPRH resulted in increased Y1197 phosphorylation; rescue with wild-type PTPRH restored normal phosphorylation levels, while catalytically dead PTPRH did not. PTPRH mutations in NSCLC are mutually exclusive with EGFR mutations and confer sensitivity to EGFR tyrosine kinase inhibitors.\",\n      \"method\": \"PTPRH knockout cell line, wild-type vs. catalytically dead rescue expression, phospho-EGFR immunoblot, osimertinib dose-response, xenograft tumor model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO plus wild-type and catalytic-dead rescue with specific phosphosite readout, validated in vivo\",\n      \"pmids\": [\"36054194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRH overexpression in human bronchial epithelial cells inhibits phosphorylation of EGFR, ERK1/2, and AKT, and suppresses MUC5AC secretion. Knockdown of PTPRH leads to dephosphorylation of EGFR, ERK1/2, and AKT. In a house dust mite asthma mouse model, PTPRH treatment suppressed Th2 airway inflammation and Muc5ac expression.\",\n      \"method\": \"PTPRH overexpression and knockdown in HBECs, Western blot for phospho-EGFR/ERK/AKT, in vivo HDM asthma mouse model\",\n      \"journal\": \"Journal of asthma and allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression/knockdown with phospho-readouts but no direct substrate trapping or in vitro phosphatase assay\",\n      \"pmids\": [\"35140475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTPRH promotes glycolysis and tumor cell proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC. Altering PTPRH expression changed 18F-FDG uptake, lactate production, and glycolysis-related protein levels. PI3K inhibition (LY294002) reversed PTPRH-driven effects, placing PTPRH upstream of PI3K/AKT/mTOR.\",\n      \"method\": \"Colony assay, EdU, Transwell, wound healing, 18F-FDG uptake, Western blot, PI3K inhibitor/agonist, xenograft mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic epistasis using pharmacological inhibitor plus multiple cellular assays, but no direct substrate identification\",\n      \"pmids\": [\"37974250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPRH expression in colorectal tumors is regulated by promoter DNA methylation and histone H3K27 trimethylation. Cell lines with highly methylated PTPRH promoters showed lower expression, lower RNA Pol II occupancy, and treatment with 5-aza-deoxycytidine restored PTPRH expression.\",\n      \"method\": \"Pyrosequencing of promoter methylation, chromatin immunoprecipitation (H3K27me3 and RNA Pol II), 5-aza-dC treatment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and demethylation rescue establish epigenetic mechanism for PTPRH regulation, though functional downstream consequence not directly linked\",\n      \"pmids\": [\"28713969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SAP-1 (PTPRH) deficiency increases paracellular transport of hydrophilic macromolecules (FD-4, FD-10 dextrans) through intestinal tight junctions in SAP-1 knockout mice, without affecting transporter-mediated absorption, indicating SAP-1 contributes to regulation of intestinal paracellular permeability.\",\n      \"method\": \"SAP-1 knockout mice, everted ileal sac transport assay, colonic loop absorption assay\",\n      \"journal\": \"Journal of pharmaceutical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific macromolecular transport phenotype, though molecular substrate not identified\",\n      \"pmids\": [\"28431964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Co-immunoprecipitation and proximity-dependent biotinylation (BioID) in NSCLC cells showed that PTPRH does not directly interact with EGFR but interacts with NF-κB, a downstream EGFR pathway transcription factor. BioID identified 48 novel PTPRH interactors including HELZ2 and RFC2. PTPRH overexpression downregulated oncogenic pathways and modulated expression of protein tyrosine phosphatases and kinases including EGFR.\",\n      \"method\": \"Co-immunoprecipitation, BioID proximity labeling, RNA sequencing\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — BioID plus co-IP with multiple interactors identified, but preprint without peer review\",\n      \"pmids\": [\"41383754\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SAP-1 (PTPRH) expression is downregulated in moderately and poorly differentiated hepatocellular carcinoma. Re-expression of recombinant SAP-1 in two highly motile HCC cell lines reduced migratory activity and growth rate, establishing a functional role for SAP-1 in suppressing HCC cell motility.\",\n      \"method\": \"Immunohistochemical and immunoblot analysis, recombinant SAP-1 re-expression, migration and growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — re-expression with defined migratory and growth phenotype but without substrate identification\",\n      \"pmids\": [\"12879010\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRH (SAP-1) is a receptor-type protein tyrosine phosphatase localized to intestinal epithelial microvilli that negatively regulates integrin and growth factor signaling by dephosphorylating substrates including p130cas, FAK, p62(dok), Lck, CEACAM20, and EGFR-Y1197; it forms redox-sensitive homodimers through its extracellular/transmembrane domains that regulate its catalytic activity, and controls intestinal immunity, tumorigenesis, and cell motility through dephosphorylation-mediated suppression of downstream pathways including PI3K/AKT/mTOR and NF-κB.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTPRH (SAP-1) is a receptor-type protein tyrosine phosphatase that localizes to intestinal epithelial microvilli and functions as a negative regulator of integrin signaling, growth factor receptor signaling, and T cell activation through dephosphorylation of key signaling intermediates. Its identified substrates include the focal adhesion proteins p130cas and FAK, the adaptor p62(dok), the kinases Lck and c-Src, the microvillar transmembrane protein CEACAM20, and EGFR at tyrosine 1197, through which it suppresses downstream PI3K/AKT/mTOR and NF-κB signaling, cell motility, and proliferation [PMID:11278335, PMID:12837766, PMID:26195794, PMID:36054194]. PTPRH forms redox-sensitive homodimers via its extracellular and transmembrane domains, and dimerization inhibits catalytic activity, providing a mechanism for regulation by the cellular redox environment [PMID:15850787]. In vivo, PTPRH deficiency increases intestinal paracellular permeability and modulates intestinal tumorigenesis in an APC-mutant background, while loss of PTPRH in the IL-10-deficient setting worsens colitis, establishing roles in epithelial barrier integrity and mucosal immune homeostasis [PMID:19170756, PMID:26195794, PMID:28431964].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying the first substrates of PTPRH established it as a phosphatase that targets focal adhesion signaling components and mediates contact inhibition of cell growth.\",\n      \"evidence\": \"Substrate-trapping mutant approach in cultured cells identified p130cas, FAK, and p62(dok) as substrates; functional assays showed inhibited cell spreading and colony formation\",\n      \"pmids\": [\"11278335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo validation of substrate dephosphorylation\",\n        \"Mechanism by which cell-cell adhesion increases SAP-1 activity not defined\",\n        \"Structural basis for substrate recognition unknown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that PTPRH directly binds and dephosphorylates Lck extended its functional scope beyond focal adhesion signaling to T cell receptor signaling, showing it suppresses TCR-triggered MAPK activation and T cell migration.\",\n      \"evidence\": \"Direct binding assay, in vitro phosphatase assay with catalytic-dead control, and overexpression in Jurkat T cells measuring ZAP-70/LAT phosphorylation and CD69 upregulation\",\n      \"pmids\": [\"12837766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous relevance in primary T cells not demonstrated\",\n        \"Whether PTPRH is physiologically expressed in T cells in vivo unclear\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that PTPRH is downregulated in hepatocellular carcinoma and that its re-expression suppresses cell motility and growth suggested a tumor-suppressive function in liver.\",\n      \"evidence\": \"Immunohistochemistry and immunoblot of HCC tissue, recombinant SAP-1 re-expression with migration and growth assays\",\n      \"pmids\": [\"12879010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No substrate identified in HCC context\",\n        \"Lack of in vivo tumor model confirmation\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealing that PTPRH forms redox-sensitive homodimers through its extracellular/transmembrane domains, with dimerization inhibiting catalytic activity, provided a regulatory mechanism and identified c-Src as an additional substrate.\",\n      \"evidence\": \"Chemical cross-linking, co-immunoprecipitation, reducing agent treatment, and catalytic activity assays\",\n      \"pmids\": [\"15850787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural details of dimer interface unresolved\",\n        \"Physiological redox conditions that regulate dimerization not defined\",\n        \"Whether dimerization is regulated by ligand binding unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localizing PTPRH specifically to intestinal epithelial microvilli and showing that its knockout inhibits APC-driven intestinal tumorigenesis established an unexpected pro-tumorigenic role in the gut, contrasting with its anti-proliferative effects in vitro.\",\n      \"evidence\": \"Immunofluorescence in gastrointestinal tissue and genetic cross of SAP-1 knockout with APC heterozygous mice with tumor quantification\",\n      \"pmids\": [\"19170756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which PTPRH promotes intestinal tumorigenesis not identified\",\n        \"Apparent contradiction with tumor-suppressive in vitro data not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying CEACAM20 as a microvillar substrate of PTPRH and linking its dephosphorylation to suppression of NF-κB/IL-8 signaling connected PTPRH to intestinal innate immune regulation, with loss-of-function worsening colitis in IL-10-deficient mice.\",\n      \"evidence\": \"Substrate identification in SAP-1 knockout mice, co-IP of SAP-1/CEACAM20 complex, in vitro c-Src phosphorylation, NF-κB reporter assay, colitis phenotype in IL-10 KO mice\",\n      \"pmids\": [\"26195794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CEACAM20 dephosphorylation fully accounts for colitis phenotype not tested\",\n        \"PTPRH regulation of other NF-κB pathway components not explored\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies filled distinct gaps: one showed PTPRH expression in colorectal tumors is silenced by promoter DNA methylation and H3K27me3, and the other demonstrated that PTPRH deficiency increases intestinal paracellular permeability, broadening its role to epithelial barrier function.\",\n      \"evidence\": \"Pyrosequencing, ChIP for H3K27me3/Pol II, and 5-aza-dC rescue (epigenetic); SAP-1 knockout mice with everted ileal sac and colonic loop transport assays (permeability)\",\n      \"pmids\": [\"28713969\", \"28431964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Tight junction substrate(s) of PTPRH not identified\",\n        \"Whether epigenetic silencing causally drives tumor progression not tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pinpointing EGFR Y1197 as a direct dephosphorylation target of PTPRH in NSCLC, using knockout and catalytic-dead rescue, established a specific phosphosite-level mechanism and revealed mutual exclusivity of PTPRH and EGFR mutations with therapeutic implications for TKI sensitivity.\",\n      \"evidence\": \"PTPRH knockout cells, wild-type vs. catalytic-dead rescue, phospho-EGFR Y1197 immunoblot, osimertinib dose-response, xenograft model\",\n      \"pmids\": [\"36054194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PTPRH dephosphorylates other EGFR tyrosine sites not addressed\",\n        \"Physical interaction between PTPRH and EGFR not confirmed by co-IP\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing PTPRH upstream of PI3K/AKT/mTOR in NSCLC and showing it promotes glycolysis and proliferation via this pathway addressed the downstream signaling cascade but did not identify the direct substrate.\",\n      \"evidence\": \"Colony, EdU, Transwell, wound healing assays, 18F-FDG uptake, PI3K inhibitor epistasis, xenograft model\",\n      \"pmids\": [\"37974250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct phosphatase substrate in PI3K/AKT/mTOR axis not identified\",\n        \"Context-dependent tumor-promoting vs. tumor-suppressive roles unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for PTPRH substrate selectivity, the identity of any extracellular ligand, the mechanistic explanation for context-dependent tumor-promoting versus tumor-suppressive activities, and the direct substrates mediating its effects on tight junction permeability and PI3K/AKT/mTOR signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No extracellular ligand identified\",\n        \"No crystal structure of full-length PTPRH or its dimer\",\n        \"Conflicting tumor-promoting (intestinal) versus tumor-suppressive (HCC, NSCLC) roles not mechanistically reconciled\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CEACAM20\",\n      \"LCK\",\n      \"SRC\",\n      \"BCAR1\",\n      \"PTK2\",\n      \"EGFR\",\n      \"DOK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}