{"gene":"PIP","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1983,"finding":"GCDFP-15 (PIP) protein was localized by immunoperoxidase technique to apocrine glandular epithelium (breast cysts, axillary/vulval/eyelid/ear canal apocrine glands) and to serous cells of submandibular salivary gland and bronchial submucosal glands, establishing it as a tissue marker of apocrine differentiation.","method":"Immunoperoxidase immunohistochemistry on normal and tumor tissues","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by IHC across multiple tissue types, single lab, single method but broad survey with consistent results","pmids":["6130702"],"is_preprint":false},{"year":1984,"finding":"Ultrastructural localization of GCDFP-15 (PIP) in metaplastic apocrine epithelium of the breast showed the protein is stored in Golgi vesicles and cytoplasmic granules, packaged into apical vacuoles, and secreted by exocytosis into cyst fluid lumens.","method":"Low-temperature embedding colloidal gold immunoelectron microscopy","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct ultrastructural localization with colloidal gold EM, single lab but rigorous method definitively establishing secretory pathway","pmids":["6205595"],"is_preprint":false},{"year":1991,"finding":"The human PIP gene (7 kb, 4 exons) is transcriptionally upregulated by both androgen and prolactin; neither hormone affected stability of PIP precursor RNA or mature mRNA, establishing that hormonal regulation occurs at the level of transcription.","method":"Gene cloning, nuclear run-on transcription assays with PIP genomic fragments","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — nuclear run-on assay directly measuring nascent transcription, distinguishing transcriptional from post-transcriptional regulation; single lab with two orthogonal hormone conditions","pmids":["1955075"],"is_preprint":false},{"year":1989,"finding":"Estradiol (E2) inhibits GCDFP-15 mRNA accumulation and secretion in ZR-75-1 breast cancer cells, an effect reversed by the antiestrogen LY156758; dihydrotestosterone (DHT) and dexamethasone (DEX) stimulate GCDFP-15 expression, and E2 antagonizes DHT- and DEX-induced stimulation.","method":"Northern blot for mRNA levels; ELISA/RIA for secreted protein; competition with antiestrogen","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (mRNA measurement, secretion assay, competitive antagonism with antiestrogen), single lab","pmids":["2725533"],"is_preprint":false},{"year":1994,"finding":"EP-GP (extra-parotid glycoprotein), shown to be identical to SABP/GCDFP-15/PIP by immunochemical and biochemical analysis, binds actin and fibrinogen in vitro; additionally, PIP/SABP binds to the cell wall of Streptococcus salivarius, suggesting a role in innate mucosal immunity.","method":"Immunochemical identity assays; biochemical binding assays (actin, fibrinogen); electron microscopy for bacterial cell-wall localization","journal":"Biological chemistry Hoppe-Seyler","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding assays demonstrated actin/fibrinogen and bacterial interactions, electron microscopy for ultrastructural localization; authors note physiological relevance of actin/fibrinogen binding is unclear","pmids":["7840903"],"is_preprint":false},{"year":1996,"finding":"IL-4 and IL-13 stimulate GCDFP-15 mRNA expression (5.5- to 6-fold) and protein secretion in ZR-75-1 and T-47D breast cancer cells; this stimulation is additive to that of DHT and dexamethasone but IL-13 is not additive to IL-4, suggesting shared signaling pathway between IL-4 and IL-13 for PIP regulation.","method":"Northern blot for mRNA; RIA/ELISA for secreted protein; dose-response analysis","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cytokine conditions, mRNA and protein secretion measured, additivity experiments; single lab","pmids":["8865161"],"is_preprint":false},{"year":1999,"finding":"Recombinant gp17/GCDFP-15 (PIP) produced in Pichia pastoris retains the ability to bind CD4 and blocks CD4-mediated T lymphocyte programmed death; expression with incorrect signal peptide in HeLa cells resulted in misfolded insoluble protein, demonstrating the requirement for proper secretory processing.","method":"Recombinant expression in HeLa cells and P. pastoris; CD4 binding assay; functional apoptosis inhibition assay","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein with functional validation (CD4 binding and T cell apoptosis inhibition), single lab, two systems tested","pmids":["10504398"],"is_preprint":false},{"year":1999,"finding":"Androgen receptor (AR)-mediated regulation of GCDFP-15 was confirmed in AR-positive breast cancer cell lines: DHT stimulated GCDFP-15 mRNA and secretion, and this was blocked by pure antiandrogens (hydroxyflutamide, casodex), which also suppressed basal expression, establishing AR as a direct transcriptional regulator of PIP.","method":"RT-PCR/Northern blot for mRNA; secretion measurement; antiandrogen competition assays in MFM-223 and ZR-75-1 cells","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive pharmacological antagonism confirming AR involvement, two cell lines tested, mRNA and secretion measured; single lab","pmids":["10402478"],"is_preprint":false},{"year":2021,"finding":"PIP directly interacts with the aquaporin AQP5, with the interaction involving the AQP5 C-terminus and the N-terminal region of PIP (one PIP molecule per AQP5 tetramer); PIP misexpression or knockout in mice and in Sjögren's syndrome patient salivary glands correlates with altered AQP5 apical membrane localization, indicating PIP controls AQP5 trafficking to the apical membrane.","method":"Co-immunoprecipitation, pulldown assays in vitro and in mouse tissues; immunohistochemistry in PIP knockout mice and human minor salivary gland biopsies; domain mapping","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction shown in vitro and in vivo, domain mapping, functional consequence (AQP5 mislocalization) demonstrated in KO mice and patient tissue; single lab","pmids":["34440877"],"is_preprint":false},{"year":2019,"finding":"The transcription factor Slug drives PIP (prolactin-induced protein) expression in macrophages in pulmonary fibrosis-associated pulmonary hypertension (PF-PH); PIP in turn acts as an extracellular matrix protein that induces pulmonary arterial smooth muscle cell (PASMC) proliferation, and Slug inhibition decreased PH severity in a rat model.","method":"Immunohistochemistry in human PF-PH tissue and rat model; Slug inhibition in vivo; PASMC proliferation assays","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/pharmacological epistasis (Slug inhibition reduces PIP and PH severity), functional assay (PASMC proliferation), validated in both human tissue and animal model; single lab","pmids":["31468711"],"is_preprint":false}],"current_model":"PIP (GCDFP-15/prolactin-inducible protein) is a small secreted glycoprotein whose transcription is upregulated by androgen receptor (via DHT), prolactin, glucocorticoids, IL-4, and IL-13, and repressed by estrogens; it is synthesized in the Golgi, packaged into cytoplasmic granules, and secreted by exocytosis from apocrine-type epithelial cells; extracellularly, PIP binds CD4 on lymphocytes and spermatozoa (inhibiting CD4-mediated T cell apoptosis), binds actin and fibrinogen, and interacts with bacterial cell walls; PIP also directly binds the water channel AQP5 (one PIP per tetramer, via AQP5 C-terminus) to promote AQP5 apical membrane localization in salivary glands, and in a pathological context acts downstream of the transcription factor Slug to stimulate pulmonary arterial smooth muscle cell proliferation."},"narrative":{"mechanistic_narrative":"PIP (GCDFP-15/prolactin-inducible protein) is a small secreted glycoprotein that serves as a marker of apocrine epithelial differentiation and functions extracellularly as a multivalent binding protein with roles in secretion, immune modulation, and aquaporin trafficking [PMID:6130702, PMID:7840903, PMID:34440877]. It is synthesized through the secretory pathway, stored in Golgi vesicles and cytoplasmic granules, packaged into apical vacuoles, and released by exocytosis from apocrine-type epithelial cells; correct secretory processing via its signal peptide is required for proper folding and solubility [PMID:6205595, PMID:10504398]. Its expression is controlled at the level of transcription: androgen receptor signaling (DHT), prolactin, glucocorticoids, and the cytokines IL-4 and IL-13 each upregulate PIP, whereas estradiol represses it and antagonizes androgen- and glucocorticoid-driven induction [PMID:1955075, PMID:2725533, PMID:8865161, PMID:10402478]. Extracellularly PIP binds actin, fibrinogen, and bacterial cell walls, and binds CD4 on lymphocytes where it blocks CD4-mediated T-cell programmed death [PMID:7840903, PMID:10504398]. PIP also directly binds the water channel AQP5 through the AQP5 C-terminus and its own N-terminal region (one PIP per AQP5 tetramer), controlling AQP5 trafficking to the apical membrane in salivary glands [PMID:34440877]. In a pathological context, PIP acts downstream of the transcription factor Slug as an extracellular matrix protein that drives pulmonary arterial smooth muscle cell proliferation in pulmonary hypertension [PMID:31468711].","teleology":[{"year":1983,"claim":"Established where PIP/GCDFP-15 is expressed, defining it as a marker of apocrine differentiation across diverse epithelia.","evidence":"Immunoperoxidase IHC across normal and tumor tissues","pmids":["6130702"],"confidence":"Medium","gaps":["Localization alone did not define molecular function","No mechanism for tissue-restricted expression"]},{"year":1984,"claim":"Resolved the subcellular route of PIP, showing it traverses the regulated secretory pathway rather than acting intracellularly.","evidence":"Colloidal gold immunoelectron microscopy in metaplastic apocrine breast epithelium","pmids":["6205595"],"confidence":"High","gaps":["Did not identify extracellular binding partners or function of secreted protein"]},{"year":1989,"claim":"Defined the hormonal logic of PIP regulation, showing androgens and glucocorticoids induce while estrogens repress and antagonize that induction.","evidence":"Northern blot, ELISA/RIA, and antiestrogen competition in ZR-75-1 breast cancer cells","pmids":["2725533"],"confidence":"High","gaps":["Did not map cis-regulatory elements or confirm direct receptor binding to the promoter"]},{"year":1991,"claim":"Determined that hormonal control of PIP operates at transcription rather than RNA stability, localizing regulation to the gene level.","evidence":"Gene cloning and nuclear run-on transcription assays with PIP genomic fragments","pmids":["1955075"],"confidence":"High","gaps":["Specific promoter elements and bound factors not identified"]},{"year":1994,"claim":"Identified PIP as a multivalent extracellular binding protein, linking it to cytoskeletal/coagulation ligands and mucosal bacteria.","evidence":"Immunochemical identity assays and in vitro binding to actin, fibrinogen, and Streptococcus salivarius cell walls","pmids":["7840903"],"confidence":"Medium","gaps":["Physiological relevance of actin/fibrinogen binding noted as unclear by authors","No structural basis for the interactions"]},{"year":1996,"claim":"Extended PIP regulation to cytokine signaling, showing IL-4 and IL-13 induce PIP via an apparently shared pathway additive to steroid hormone induction.","evidence":"Northern blot, RIA/ELISA, and additivity/dose-response in ZR-75-1 and T-47D cells","pmids":["8865161"],"confidence":"Medium","gaps":["Shared IL-4/IL-13 signaling pathway inferred from additivity, not directly mapped"]},{"year":1999,"claim":"Provided functional evidence that secreted PIP binds CD4 and inhibits CD4-mediated T-cell apoptosis, and that secretory processing is required for proper folding.","evidence":"Recombinant expression in HeLa and P. pastoris; CD4 binding and apoptosis inhibition assays","pmids":["10504398"],"confidence":"Medium","gaps":["CD4-binding interface not mapped","In vivo relevance of T-cell apoptosis inhibition not established"]},{"year":1999,"claim":"Confirmed the androgen receptor as a regulator of PIP using antiandrogen antagonism in AR-positive cells.","evidence":"RT-PCR/Northern blot, secretion measurement, and antiandrogen competition in MFM-223 and ZR-75-1 cells","pmids":["10402478"],"confidence":"Medium","gaps":["Direct AR binding to PIP regulatory DNA not demonstrated"]},{"year":2019,"claim":"Placed PIP in a pathological signaling axis, acting downstream of Slug as an extracellular matrix protein driving smooth muscle proliferation in pulmonary hypertension.","evidence":"IHC in human PF-PH tissue and rat model, Slug inhibition in vivo, PASMC proliferation assays","pmids":["31468711"],"confidence":"Medium","gaps":["Receptor/signaling mechanism for PASMC proliferation not identified","Single lab, one disease context"]},{"year":2021,"claim":"Defined a direct molecular function for PIP as an AQP5 trafficking regulator, mapping the interaction and showing functional consequences for apical membrane localization.","evidence":"Co-IP/pulldown in vitro and in mouse tissue, domain mapping, IHC in PIP-knockout mice and Sjögren's patient salivary glands","pmids":["34440877"],"confidence":"Medium","gaps":["Mechanism by which PIP promotes AQP5 trafficking unresolved","Stoichiometry-to-function relationship not fully defined"]},{"year":null,"claim":"How PIP's diverse extracellular binding activities (CD4, actin, fibrinogen, AQP5, ECM) integrate into a unified physiological role, and the structural basis for its multivalent binding, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking distinct binding partners","No single in vivo phenotype unifying its secretory, immune, and trafficking roles"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8]}],"complexes":[],"partners":["CD4","AQP5","ACTB","FGB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P12273","full_name":"Prolactin-inducible protein","aliases":["Gross cystic disease fluid protein 15","GCDFP-15","Prolactin-induced protein","Secretory actin-binding protein","SABP","gp17"],"length_aa":146,"mass_kda":16.6,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P12273/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PIP","total_profiled":1310},"omim":[{"mim_id":"620743","title":"SDE2 TELOMERE MAINTENANCE HOMOLOG; SDE2","url":"https://www.omim.org/entry/620743"},{"mim_id":"618288","title":"5-@HYDROXYMETHYLCYTOSINE-BINDING PROTEIN, EMBRYONIC STEM CELL-SPECIFIC; HMCES","url":"https://www.omim.org/entry/618288"},{"mim_id":"618175","title":"WARBURG-CINOTTI SYNDROME; WRCN","url":"https://www.omim.org/entry/618175"},{"mim_id":"616955","title":"RRAD- AND GEM-LIKE GTPase 2; REM2","url":"https://www.omim.org/entry/616955"},{"mim_id":"616086","title":"SprT-LIKE N-TERMINAL DOMAIN PROTEIN; SPRTN","url":"https://www.omim.org/entry/616086"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"salivary gland","ntpm":17175.0}],"url":"https://www.proteinatlas.org/search/PIP"},"hgnc":{"alias_symbol":["GCDFP-15","GCDFP15","GPIP4","SABP","BRST-2"],"prev_symbol":[]},"alphafold":{"accession":"P12273","domains":[{"cath_id":"2.60.40.10","chopping":"38-146","consensus_level":"high","plddt":96.946,"start":38,"end":146}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12273","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12273-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12273-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIP","jax_strain_url":"https://www.jax.org/strain/search?query=PIP"},"sequence":{"accession":"P12273","fasta_url":"https://rest.uniprot.org/uniprotkb/P12273.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12273/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12273"}},"corpus_meta":[{"pmid":"11988466","id":"PMC_11988466","title":"PIP(2) and proteins: interactions, organization, and information flow.","date":"2001","source":"Annual review of biophysics and biomolecular structure","url":"https://pubmed.ncbi.nlm.nih.gov/11988466","citation_count":704,"is_preprint":false},{"pmid":"12670425","id":"PMC_12670425","title":"PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.","date":"2003","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/12670425","citation_count":454,"is_preprint":false},{"pmid":"10995437","id":"PMC_10995437","title":"Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex.","date":"2000","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10995437","citation_count":424,"is_preprint":false},{"pmid":"6130702","id":"PMC_6130702","title":"Immunohistochemistry of a gross cystic disease fluid protein (GCDFP-15) of the breast. A marker of apocrine epithelium and breast carcinomas with apocrine features.","date":"1983","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/6130702","citation_count":304,"is_preprint":false},{"pmid":"10898977","id":"PMC_10898977","title":"Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability.","date":"2000","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/10898977","citation_count":191,"is_preprint":false},{"pmid":"17145637","id":"PMC_17145637","title":"Mammaglobin vs GCDFP-15: an immunohistologic validation survey for sensitivity and specificity.","date":"2007","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17145637","citation_count":167,"is_preprint":false},{"pmid":"12086619","id":"PMC_12086619","title":"PIP(2)-PDZ domain binding controls the association of syntenin with the plasma membrane.","date":"2002","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/12086619","citation_count":167,"is_preprint":false},{"pmid":"30421640","id":"PMC_30421640","title":"Accurate delineation of cell cycle phase transitions in living cells with PIP-FUCCI.","date":"2018","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30421640","citation_count":102,"is_preprint":false},{"pmid":"16224215","id":"PMC_16224215","title":"Expression of WT1, CA 125, and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary.","date":"2005","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16224215","citation_count":98,"is_preprint":false},{"pmid":"2459984","id":"PMC_2459984","title":"Immunohistochemistry of gross cystic disease fluid protein (GCDFP-15) in 65 benign sweat gland tumors of the skin.","date":"1988","source":"The American Journal of dermatopathology","url":"https://pubmed.ncbi.nlm.nih.gov/2459984","citation_count":98,"is_preprint":false},{"pmid":"2655863","id":"PMC_2655863","title":"Expression of GCDFP-15 in breast carcinomas. Relationship to pathologic and clinical factors.","date":"1989","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/2655863","citation_count":97,"is_preprint":false},{"pmid":"17412762","id":"PMC_17412762","title":"Target-specific PIP(2) signalling: how might it work?","date":"2007","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17412762","citation_count":97,"is_preprint":false},{"pmid":"31134302","id":"PMC_31134302","title":"The PCNA interaction motifs revisited: thinking outside the PIP-box.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31134302","citation_count":92,"is_preprint":false},{"pmid":"17534652","id":"PMC_17534652","title":"Local PIP(2) signals: when, where, and how?","date":"2007","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17534652","citation_count":90,"is_preprint":false},{"pmid":"29581272","id":"PMC_29581272","title":"Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29581272","citation_count":85,"is_preprint":false},{"pmid":"23663520","id":"PMC_23663520","title":"Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.","date":"2013","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/23663520","citation_count":83,"is_preprint":false},{"pmid":"23602387","id":"PMC_23602387","title":"Endosomal type Iγ PIP 5-kinase controls EGF receptor lysosomal sorting.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23602387","citation_count":78,"is_preprint":false},{"pmid":"17031667","id":"PMC_17031667","title":"Regulation of TRP channels by PIP(2).","date":"2006","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17031667","citation_count":73,"is_preprint":false},{"pmid":"34385319","id":"PMC_34385319","title":"Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34385319","citation_count":72,"is_preprint":false},{"pmid":"36227998","id":"PMC_36227998","title":"Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36227998","citation_count":71,"is_preprint":false},{"pmid":"25617736","id":"PMC_25617736","title":"PIP kinases define PI4,5P₂signaling specificity by association with effectors.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25617736","citation_count":70,"is_preprint":false},{"pmid":"32844743","id":"PMC_32844743","title":"Cryo-EM analysis of PIP2 regulation in mammalian GIRK channels.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32844743","citation_count":69,"is_preprint":false},{"pmid":"1955075","id":"PMC_1955075","title":"The prolactin-inducible protein (PIP/GCDFP-15) gene: cloning, structure and regulation.","date":"1991","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/1955075","citation_count":69,"is_preprint":false},{"pmid":"32764146","id":"PMC_32764146","title":"PIP2: A critical regulator of vascular ion channels hiding in plain sight.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32764146","citation_count":67,"is_preprint":false},{"pmid":"25070172","id":"PMC_25070172","title":"Gross cystic disease fluid protein 15 (GCDFP-15) expression in breast cancer subtypes.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25070172","citation_count":66,"is_preprint":false},{"pmid":"29211993","id":"PMC_29211993","title":"Single-Molecule Study Reveals How Receptor and Ras Synergistically Activate PI3Kα and PIP3 Signaling.","date":"2017","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/29211993","citation_count":63,"is_preprint":false},{"pmid":"33763649","id":"PMC_33763649","title":"PIP2 Improves Cerebral Blood Flow in a Mouse Model of Alzheimer's Disease.","date":"2021","source":"Function (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33763649","citation_count":62,"is_preprint":false},{"pmid":"2725533","id":"PMC_2725533","title":"Inhibitory effect of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells.","date":"1989","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/2725533","citation_count":61,"is_preprint":false},{"pmid":"31776383","id":"PMC_31776383","title":"Quantification of phosphoinositides reveals strong enrichment of PIP2 in HIV-1 compared to producer cell membranes.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31776383","citation_count":61,"is_preprint":false},{"pmid":"8751328","id":"PMC_8751328","title":"Estrogen and progesterone receptors and anti-gross cystic disease fluid protein 15 (BRST-2) fail to distinguish metastatic breast carcinoma from eccrine neoplasms.","date":"1995","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/8751328","citation_count":59,"is_preprint":false},{"pmid":"29340880","id":"PMC_29340880","title":"GATA-3 is superior to GCDFP-15 and mammaglobin to identify primary and metastatic breast cancer.","date":"2018","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/29340880","citation_count":58,"is_preprint":false},{"pmid":"27539869","id":"PMC_27539869","title":"R.I.P. to the PIP: PCNA-binding motif no longer considered specific: PIP motifs and other related sequences are not distinct entities and can bind multiple proteins involved in genome maintenance.","date":"2016","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27539869","citation_count":58,"is_preprint":false},{"pmid":"23012232","id":"PMC_23012232","title":"Phosphoinositides and cytokinesis: the \"PIP\" of the iceberg.","date":"2012","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/23012232","citation_count":57,"is_preprint":false},{"pmid":"8865161","id":"PMC_8865161","title":"Interleukin-4 and interleukin-13 inhibit estrogen-induced breast cancer cell proliferation and stimulate GCDFP-15 expression in human breast cancer cells.","date":"1996","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/8865161","citation_count":55,"is_preprint":false},{"pmid":"16428437","id":"PMC_16428437","title":"E2A and IRF-4/Pip promote chromatin modification and transcription of the immunoglobulin kappa locus in pre-B cells.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16428437","citation_count":53,"is_preprint":false},{"pmid":"35588786","id":"PMC_35588786","title":"PKC regulation of ion channels: The involvement of PIP2.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35588786","citation_count":52,"is_preprint":false},{"pmid":"25906123","id":"PMC_25906123","title":"The Novel Marker GATA3 is Significantly More Sensitive Than Traditional Markers Mammaglobin and GCDFP15 for Identifying Breast Cancer in Surgical and Cytology Specimens of Metastatic and Matched Primary Tumors.","date":"2016","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/25906123","citation_count":51,"is_preprint":false},{"pmid":"16045781","id":"PMC_16045781","title":"Expression of GCDFP-15 and AR decreases in larger or node-positive apocrine carcinomas of the breast.","date":"2005","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/16045781","citation_count":51,"is_preprint":false},{"pmid":"33933453","id":"PMC_33933453","title":"PIP2 regulation of TRPC5 channel activation and desensitization.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33933453","citation_count":49,"is_preprint":false},{"pmid":"28574338","id":"PMC_28574338","title":"Synchronized HIV assembly by tunable PIP2 changes reveals PIP2 requirement for stable Gag anchoring.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28574338","citation_count":44,"is_preprint":false},{"pmid":"32558386","id":"PMC_32558386","title":"PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS.","date":"2020","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32558386","citation_count":44,"is_preprint":false},{"pmid":"30628926","id":"PMC_30628926","title":"SOX10, GATA3, GCDFP15, Androgen Receptor, and Mammaglobin for the Differential Diagnosis Between Triple-negative Breast Cancer and TTF1-negative Lung Adenocarcinoma.","date":"2019","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30628926","citation_count":43,"is_preprint":false},{"pmid":"9532005","id":"PMC_9532005","title":"Spectrum of GCDFP-15 expression in human fetal and adult normal tissues.","date":"1998","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9532005","citation_count":42,"is_preprint":false},{"pmid":"7840903","id":"PMC_7840903","title":"Identity of human extra parotid glycoprotein (EP-GP) with secretory actin binding protein (SABP) and its biological properties.","date":"1994","source":"Biological chemistry Hoppe-Seyler","url":"https://pubmed.ncbi.nlm.nih.gov/7840903","citation_count":42,"is_preprint":false},{"pmid":"29521261","id":"PMC_29521261","title":"Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29521261","citation_count":42,"is_preprint":false},{"pmid":"35079141","id":"PMC_35079141","title":"PIP2 determines length and stability of primary cilia by balancing membrane turnovers.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35079141","citation_count":41,"is_preprint":false},{"pmid":"18339419","id":"PMC_18339419","title":"Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast. Are WT1, CA125, and GCDFP-15 useful in differential diagnosis?","date":"2008","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18339419","citation_count":41,"is_preprint":false},{"pmid":"30555735","id":"PMC_30555735","title":"Prolactin-induced protein (PIP)-characterization and role in breast cancer progression.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30555735","citation_count":40,"is_preprint":false},{"pmid":"33637964","id":"PMC_33637964","title":"Specific PIP2 binding promotes calcium activation of TMEM16A chloride channels.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33637964","citation_count":39,"is_preprint":false},{"pmid":"30784597","id":"PMC_30784597","title":"ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLCβ3 Catalysis: Targeting It Eradicates Leukemia Stem Cells.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30784597","citation_count":39,"is_preprint":false},{"pmid":"28934471","id":"PMC_28934471","title":"A novel non-canonical PIP-box mediates PARG interaction with PCNA.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28934471","citation_count":39,"is_preprint":false},{"pmid":"34433062","id":"PMC_34433062","title":"Structural insights into GIRK2 channel modulation by cholesterol and PIP2.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34433062","citation_count":36,"is_preprint":false},{"pmid":"31091438","id":"PMC_31091438","title":"Phosphatidylinositol 5 Phosphate 4-Kinase Regulates Plasma-Membrane PIP3 Turnover and Insulin Signaling.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31091438","citation_count":36,"is_preprint":false},{"pmid":"18300807","id":"PMC_18300807","title":"Gross cystic disease fluid protein-(GCDFP-15): expression in primary lung adenocarcinoma.","date":"2008","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18300807","citation_count":35,"is_preprint":false},{"pmid":"26447897","id":"PMC_26447897","title":"Comparative Sensitivities and Specificities of Antibodies to Breast Markers GCDFP-15, Mammaglobin A, and Different Clones of Antibodies to GATA-3: A Study of 338 Tumors Using Whole Sections.","date":"2016","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/26447897","citation_count":35,"is_preprint":false},{"pmid":"8693878","id":"PMC_8693878","title":"Value of GCDFP-15 (BRST-2) as a specific immunocytochemical marker for breast carcinoma in cytologic specimens.","date":"1996","source":"Acta cytologica","url":"https://pubmed.ncbi.nlm.nih.gov/8693878","citation_count":34,"is_preprint":false},{"pmid":"30244966","id":"PMC_30244966","title":"Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2.","date":"2018","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30244966","citation_count":34,"is_preprint":false},{"pmid":"33277361","id":"PMC_33277361","title":"PIP2 promotes conformation-specific dimerization of the EphA2 membrane region.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33277361","citation_count":33,"is_preprint":false},{"pmid":"19262752","id":"PMC_19262752","title":"A functional and regulatory network associated with PIP expression in human breast cancer.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19262752","citation_count":33,"is_preprint":false},{"pmid":"32332165","id":"PMC_32332165","title":"Palmitoylation of the KATP channel Kir6.2 subunit promotes channel opening by regulating PIP2 sensitivity.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32332165","citation_count":33,"is_preprint":false},{"pmid":"24434580","id":"PMC_24434580","title":"PIP-box-mediated degradation prohibits re-accumulation of Cdc6 during S phase.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24434580","citation_count":32,"is_preprint":false},{"pmid":"27028641","id":"PMC_27028641","title":"PIP Water Transport and Its pH Dependence Are Regulated by Tetramer Stoichiometry.","date":"2016","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27028641","citation_count":31,"is_preprint":false},{"pmid":"28390076","id":"PMC_28390076","title":"Sugar and hexokinase suppress expression of PIP aquaporins and reduce leaf hydraulics that preserves leaf water potential.","date":"2017","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28390076","citation_count":29,"is_preprint":false},{"pmid":"11029771","id":"PMC_11029771","title":"Immunohistochemical analysis of GCDFP-15 and GCDFP-24 in mammary and non-mammary tissue.","date":"2000","source":"Breast cancer (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/11029771","citation_count":28,"is_preprint":false},{"pmid":"19620839","id":"PMC_19620839","title":"GCDFP-15 positive and TTF-1 negative primary lung neoplasms: a tissue microarray study of 381 primary lung tumors.","date":"2009","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/19620839","citation_count":28,"is_preprint":false},{"pmid":"19217055","id":"PMC_19217055","title":"Diagnostic utility of mammaglobin and GCDFP-15 in the identification of metastatic breast carcinoma in fluid specimens.","date":"2009","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/19217055","citation_count":28,"is_preprint":false},{"pmid":"18330597","id":"PMC_18330597","title":"Barley plasma membrane intrinsic proteins (PIP Aquaporins) as water and CO2 transporters.","date":"2008","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18330597","citation_count":28,"is_preprint":false},{"pmid":"15182429","id":"PMC_15182429","title":"Expression of the prolactin-inducible protein (PIP/GCDFP15) gene in benign epithelium and adenocarcinoma of the prostate.","date":"2004","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/15182429","citation_count":27,"is_preprint":false},{"pmid":"38509107","id":"PMC_38509107","title":"Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38509107","citation_count":27,"is_preprint":false},{"pmid":"28038704","id":"PMC_28038704","title":"GATA3 expression in clinically useful groups of breast carcinoma: a comparison with GCDFP15 and mammaglobin for identifying paired primary and metastatic tumors.","date":"2016","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28038704","citation_count":26,"is_preprint":false},{"pmid":"38480730","id":"PMC_38480730","title":"Thunder-DDA-PASEF enables high-coverage immunopeptidomics and is boosted by MS2Rescore with MS2PIP timsTOF fragmentation prediction model.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38480730","citation_count":26,"is_preprint":false},{"pmid":"32992595","id":"PMC_32992595","title":"A Survey of Barley PIP Aquaporin Ionic Conductance Reveals Ca2+-Sensitive HvPIP2;8 Na+ and K+ Conductance.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32992595","citation_count":26,"is_preprint":false},{"pmid":"35646908","id":"PMC_35646908","title":"When PIP2 Meets p53: Nuclear Phosphoinositide Signaling in the DNA Damage Response.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35646908","citation_count":25,"is_preprint":false},{"pmid":"22403073","id":"PMC_22403073","title":"PIP kinases from the cell membrane to the nucleus.","date":"2012","source":"Sub-cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22403073","citation_count":24,"is_preprint":false},{"pmid":"25966627","id":"PMC_25966627","title":"Regulation of Sperm Capacitation and the Acrosome Reaction by PIP 2 and Actin Modulation.","date":"2015","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/25966627","citation_count":24,"is_preprint":false},{"pmid":"20045432","id":"PMC_20045432","title":"Venom neutralization by purified bioactive molecules: Synthetic peptide derivatives of the endogenous PLA(2) inhibitory protein PIP (a mini-review).","date":"2010","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/20045432","citation_count":24,"is_preprint":false},{"pmid":"34440877","id":"PMC_34440877","title":"Unraveling Human AQP5-PIP Molecular Interaction and Effect on AQP5 Salivary Glands Localization in SS Patients.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34440877","citation_count":24,"is_preprint":false},{"pmid":"6205595","id":"PMC_6205595","title":"The ultrastructural localization of gross cystic disease fluid protein (GCDFP-15) in breast epithelium.","date":"1984","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/6205595","citation_count":24,"is_preprint":false},{"pmid":"10504398","id":"PMC_10504398","title":"Biosynthesis and immunobiochemical characterization of gp17/GCDFP-15. A glycoprotein from seminal vesicles and from breast tumors, in HeLa cells and in Pichia pastoris yeast.","date":"1999","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10504398","citation_count":23,"is_preprint":false},{"pmid":"32434869","id":"PMC_32434869","title":"Bidirectional transfer of homeoprotein EN2 across the plasma membrane requires PIP2.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32434869","citation_count":23,"is_preprint":false},{"pmid":"31468711","id":"PMC_31468711","title":"Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.","date":"2019","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31468711","citation_count":22,"is_preprint":false},{"pmid":"31898884","id":"PMC_31898884","title":"Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition.","date":"2020","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31898884","citation_count":21,"is_preprint":false},{"pmid":"37788993","id":"PMC_37788993","title":"Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37788993","citation_count":21,"is_preprint":false},{"pmid":"8982381","id":"PMC_8982381","title":"Expression of the PIP/GCDFP-15 gene and survival in breast cancer.","date":"1996","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8982381","citation_count":21,"is_preprint":false},{"pmid":"25252779","id":"PMC_25252779","title":"PIP-DB: the Protein Isoelectric Point database.","date":"2014","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25252779","citation_count":20,"is_preprint":false},{"pmid":"24416635","id":"PMC_24416635","title":"Gross Cystic Disease Fluid Protein-15(GCDFP-15)/Prolactin-Inducible Protein (PIP) as Functional Salivary Biomarker for Primary Sjögren's Syndrome.","date":"2013","source":"Journal of genetic syndromes & gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24416635","citation_count":20,"is_preprint":false},{"pmid":"34601312","id":"PMC_34601312","title":"PIP2 and septin control STIM1/Orai1 assembly by regulating cytoskeletal remodeling via a CDC42-WASP/WAVE-ARP2/3 protein complex.","date":"2021","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/34601312","citation_count":20,"is_preprint":false},{"pmid":"27723083","id":"PMC_27723083","title":"Protein Interaction Profile Sequencing (PIP-seq).","date":"2016","source":"Current protocols in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27723083","citation_count":19,"is_preprint":false},{"pmid":"35020418","id":"PMC_35020418","title":"Nir1 constitutively localizes at ER-PM junctions and promotes Nir2 recruitment for PIP2 homeostasis.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35020418","citation_count":19,"is_preprint":false},{"pmid":"39366376","id":"PMC_39366376","title":"Dual regulation of IP3 receptors by IP3 and PIP2 controls the transition from local to global Ca2+ signals.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39366376","citation_count":19,"is_preprint":false},{"pmid":"19331818","id":"PMC_19331818","title":"Contribution of PIP-5 kinase Ialpha to raft-based FcgammaRIIA signaling.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19331818","citation_count":19,"is_preprint":false},{"pmid":"33984330","id":"PMC_33984330","title":"Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33984330","citation_count":19,"is_preprint":false},{"pmid":"36396757","id":"PMC_36396757","title":"Phosphatidylinositol 4,5-bisphosphate (PIP2) facilitates norepinephrine transporter dimerization and modulates substrate efflux.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36396757","citation_count":18,"is_preprint":false},{"pmid":"29150438","id":"PMC_29150438","title":"A PIP2-derived amplification loop fuels the sustained initiation of B cell activation.","date":"2017","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29150438","citation_count":18,"is_preprint":false},{"pmid":"34270937","id":"PMC_34270937","title":"Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions.","date":"2021","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/34270937","citation_count":18,"is_preprint":false},{"pmid":"32420483","id":"PMC_32420483","title":"ACLY is the novel signaling target of PIP2/PIP3 and Lyn in acute myeloid leukemia.","date":"2020","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/32420483","citation_count":17,"is_preprint":false},{"pmid":"36633397","id":"PMC_36633397","title":"Inhibition of the proton-activated chloride channel PAC by PIP2.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36633397","citation_count":16,"is_preprint":false},{"pmid":"30911644","id":"PMC_30911644","title":"Comparison of GATA-3, mammaglobin, GCDFP-15 expression in breast carcinoma in serous effusions: A cell-block micro-array study.","date":"2017","source":"Pleura and peritoneum","url":"https://pubmed.ncbi.nlm.nih.gov/30911644","citation_count":16,"is_preprint":false},{"pmid":"29393635","id":"PMC_29393635","title":"Pip-HoGu: An Artificial Assembly with Cooperative DNA Recognition Capable of Mimicking Transcription Factor Pairs.","date":"2018","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/29393635","citation_count":16,"is_preprint":false},{"pmid":"10402478","id":"PMC_10402478","title":"Regulation of GCDFP-15 expression in human mammary cancer cells.","date":"1999","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10402478","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48646,"output_tokens":3254,"usd":0.097374,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9867,"output_tokens":3089,"usd":0.06328,"stage2_stop_reason":"end_turn"},"total_usd":0.160654,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through these abstracts, I need to identify papers about the canonical PIP gene (GCDFP-15, GCDFP15, GPIP4, SABP, BRST-2 = Prolactin-Inducible Protein). I'll exclude papers about phosphatidylinositol phosphates (PIP2/PIP3), PCNA-interacting PIP-box motifs, plant aquaporin PIPs, and other unrelated uses of \"PIP.\"\n\nRelevant papers about the canonical PIP/GCDFP-15/prolactin-inducible protein gene:\n- PMID 6130702, 2459984, 2655863, 1955075, 2725533, 8865161, 7840903, 10504398, 10995437 (no - that's WASp/actin), 19262752, 8982381, 10402478, 15182429, 34440877, 24416635, 81 (Slug/PIP axis)\n\nLet me carefully review each:\n\n- PMID 1955075: PIP gene cloning, structure, regulation by androgen and prolactin - CANONICAL PIP\n- PMID 2725533: Estrogen inhibits GCDFP-15 mRNA - CANONICAL PIP\n- PMID 8865161: IL-4/IL-13 stimulate GCDFP-15 - CANONICAL PIP\n- PMID 7840903: EP-GP/SABP/GCDFP-15 binds actin and fibrinogen, binds bacteria - CANONICAL PIP\n- PMID 10504398: gp17/GCDFP-15 biosynthesis, binds CD4, inhibits T cell apoptosis - CANONICAL PIP\n- PMID 10402478: AR-mediated regulation of GCDFP-15 - CANONICAL PIP\n- PMID 6205595: ultrastructural localization in Golgi, secreted by exocytosis - CANONICAL PIP\n- PMID 34440877: PIP interacts with AQP5, regulates AQP5 localization - CANONICAL PIP\n- PMID 24416635: GCDFP-15/PIP correlates with AQP5 in salivary glands - lower confidence\n- PMID 19262752: PIP functional network in breast cancer - mostly expression\n- PMID 31468711: Slug/PIP axis in PF-PH, PIP induces PASMC proliferation - CANONICAL PIP\n- PMID 15182429: PIP expression in prostate - mostly expression\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1983,\n      \"finding\": \"GCDFP-15 (PIP) protein was localized by immunoperoxidase technique to apocrine glandular epithelium (breast cysts, axillary/vulval/eyelid/ear canal apocrine glands) and to serous cells of submandibular salivary gland and bronchial submucosal glands, establishing it as a tissue marker of apocrine differentiation.\",\n      \"method\": \"Immunoperoxidase immunohistochemistry on normal and tumor tissues\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by IHC across multiple tissue types, single lab, single method but broad survey with consistent results\",\n      \"pmids\": [\"6130702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"Ultrastructural localization of GCDFP-15 (PIP) in metaplastic apocrine epithelium of the breast showed the protein is stored in Golgi vesicles and cytoplasmic granules, packaged into apical vacuoles, and secreted by exocytosis into cyst fluid lumens.\",\n      \"method\": \"Low-temperature embedding colloidal gold immunoelectron microscopy\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct ultrastructural localization with colloidal gold EM, single lab but rigorous method definitively establishing secretory pathway\",\n      \"pmids\": [\"6205595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The human PIP gene (7 kb, 4 exons) is transcriptionally upregulated by both androgen and prolactin; neither hormone affected stability of PIP precursor RNA or mature mRNA, establishing that hormonal regulation occurs at the level of transcription.\",\n      \"method\": \"Gene cloning, nuclear run-on transcription assays with PIP genomic fragments\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — nuclear run-on assay directly measuring nascent transcription, distinguishing transcriptional from post-transcriptional regulation; single lab with two orthogonal hormone conditions\",\n      \"pmids\": [\"1955075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Estradiol (E2) inhibits GCDFP-15 mRNA accumulation and secretion in ZR-75-1 breast cancer cells, an effect reversed by the antiestrogen LY156758; dihydrotestosterone (DHT) and dexamethasone (DEX) stimulate GCDFP-15 expression, and E2 antagonizes DHT- and DEX-induced stimulation.\",\n      \"method\": \"Northern blot for mRNA levels; ELISA/RIA for secreted protein; competition with antiestrogen\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (mRNA measurement, secretion assay, competitive antagonism with antiestrogen), single lab\",\n      \"pmids\": [\"2725533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"EP-GP (extra-parotid glycoprotein), shown to be identical to SABP/GCDFP-15/PIP by immunochemical and biochemical analysis, binds actin and fibrinogen in vitro; additionally, PIP/SABP binds to the cell wall of Streptococcus salivarius, suggesting a role in innate mucosal immunity.\",\n      \"method\": \"Immunochemical identity assays; biochemical binding assays (actin, fibrinogen); electron microscopy for bacterial cell-wall localization\",\n      \"journal\": \"Biological chemistry Hoppe-Seyler\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding assays demonstrated actin/fibrinogen and bacterial interactions, electron microscopy for ultrastructural localization; authors note physiological relevance of actin/fibrinogen binding is unclear\",\n      \"pmids\": [\"7840903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IL-4 and IL-13 stimulate GCDFP-15 mRNA expression (5.5- to 6-fold) and protein secretion in ZR-75-1 and T-47D breast cancer cells; this stimulation is additive to that of DHT and dexamethasone but IL-13 is not additive to IL-4, suggesting shared signaling pathway between IL-4 and IL-13 for PIP regulation.\",\n      \"method\": \"Northern blot for mRNA; RIA/ELISA for secreted protein; dose-response analysis\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cytokine conditions, mRNA and protein secretion measured, additivity experiments; single lab\",\n      \"pmids\": [\"8865161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Recombinant gp17/GCDFP-15 (PIP) produced in Pichia pastoris retains the ability to bind CD4 and blocks CD4-mediated T lymphocyte programmed death; expression with incorrect signal peptide in HeLa cells resulted in misfolded insoluble protein, demonstrating the requirement for proper secretory processing.\",\n      \"method\": \"Recombinant expression in HeLa cells and P. pastoris; CD4 binding assay; functional apoptosis inhibition assay\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein with functional validation (CD4 binding and T cell apoptosis inhibition), single lab, two systems tested\",\n      \"pmids\": [\"10504398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Androgen receptor (AR)-mediated regulation of GCDFP-15 was confirmed in AR-positive breast cancer cell lines: DHT stimulated GCDFP-15 mRNA and secretion, and this was blocked by pure antiandrogens (hydroxyflutamide, casodex), which also suppressed basal expression, establishing AR as a direct transcriptional regulator of PIP.\",\n      \"method\": \"RT-PCR/Northern blot for mRNA; secretion measurement; antiandrogen competition assays in MFM-223 and ZR-75-1 cells\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive pharmacological antagonism confirming AR involvement, two cell lines tested, mRNA and secretion measured; single lab\",\n      \"pmids\": [\"10402478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP directly interacts with the aquaporin AQP5, with the interaction involving the AQP5 C-terminus and the N-terminal region of PIP (one PIP molecule per AQP5 tetramer); PIP misexpression or knockout in mice and in Sjögren's syndrome patient salivary glands correlates with altered AQP5 apical membrane localization, indicating PIP controls AQP5 trafficking to the apical membrane.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays in vitro and in mouse tissues; immunohistochemistry in PIP knockout mice and human minor salivary gland biopsies; domain mapping\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction shown in vitro and in vivo, domain mapping, functional consequence (AQP5 mislocalization) demonstrated in KO mice and patient tissue; single lab\",\n      \"pmids\": [\"34440877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The transcription factor Slug drives PIP (prolactin-induced protein) expression in macrophages in pulmonary fibrosis-associated pulmonary hypertension (PF-PH); PIP in turn acts as an extracellular matrix protein that induces pulmonary arterial smooth muscle cell (PASMC) proliferation, and Slug inhibition decreased PH severity in a rat model.\",\n      \"method\": \"Immunohistochemistry in human PF-PH tissue and rat model; Slug inhibition in vivo; PASMC proliferation assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/pharmacological epistasis (Slug inhibition reduces PIP and PH severity), functional assay (PASMC proliferation), validated in both human tissue and animal model; single lab\",\n      \"pmids\": [\"31468711\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIP (GCDFP-15/prolactin-inducible protein) is a small secreted glycoprotein whose transcription is upregulated by androgen receptor (via DHT), prolactin, glucocorticoids, IL-4, and IL-13, and repressed by estrogens; it is synthesized in the Golgi, packaged into cytoplasmic granules, and secreted by exocytosis from apocrine-type epithelial cells; extracellularly, PIP binds CD4 on lymphocytes and spermatozoa (inhibiting CD4-mediated T cell apoptosis), binds actin and fibrinogen, and interacts with bacterial cell walls; PIP also directly binds the water channel AQP5 (one PIP per tetramer, via AQP5 C-terminus) to promote AQP5 apical membrane localization in salivary glands, and in a pathological context acts downstream of the transcription factor Slug to stimulate pulmonary arterial smooth muscle cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIP (GCDFP-15/prolactin-inducible protein) is a small secreted glycoprotein that serves as a marker of apocrine epithelial differentiation and functions extracellularly as a multivalent binding protein with roles in secretion, immune modulation, and aquaporin trafficking [#0, #4, #8]. It is synthesized through the secretory pathway, stored in Golgi vesicles and cytoplasmic granules, packaged into apical vacuoles, and released by exocytosis from apocrine-type epithelial cells; correct secretory processing via its signal peptide is required for proper folding and solubility [#1, #6]. Its expression is controlled at the level of transcription: androgen receptor signaling (DHT), prolactin, glucocorticoids, and the cytokines IL-4 and IL-13 each upregulate PIP, whereas estradiol represses it and antagonizes androgen- and glucocorticoid-driven induction [#2, #3, #5, #7]. Extracellularly PIP binds actin, fibrinogen, and bacterial cell walls, and binds CD4 on lymphocytes where it blocks CD4-mediated T-cell programmed death [#4, #6]. PIP also directly binds the water channel AQP5 through the AQP5 C-terminus and its own N-terminal region (one PIP per AQP5 tetramer), controlling AQP5 trafficking to the apical membrane in salivary glands [#8]. In a pathological context, PIP acts downstream of the transcription factor Slug as an extracellular matrix protein that drives pulmonary arterial smooth muscle cell proliferation in pulmonary hypertension [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1983,\n      \"claim\": \"Established where PIP/GCDFP-15 is expressed, defining it as a marker of apocrine differentiation across diverse epithelia.\",\n      \"evidence\": \"Immunoperoxidase IHC across normal and tumor tissues\",\n      \"pmids\": [\"6130702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization alone did not define molecular function\", \"No mechanism for tissue-restricted expression\"]\n    },\n    {\n      \"year\": 1984,\n      \"claim\": \"Resolved the subcellular route of PIP, showing it traverses the regulated secretory pathway rather than acting intracellularly.\",\n      \"evidence\": \"Colloidal gold immunoelectron microscopy in metaplastic apocrine breast epithelium\",\n      \"pmids\": [\"6205595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify extracellular binding partners or function of secreted protein\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Defined the hormonal logic of PIP regulation, showing androgens and glucocorticoids induce while estrogens repress and antagonize that induction.\",\n      \"evidence\": \"Northern blot, ELISA/RIA, and antiestrogen competition in ZR-75-1 breast cancer cells\",\n      \"pmids\": [\"2725533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map cis-regulatory elements or confirm direct receptor binding to the promoter\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Determined that hormonal control of PIP operates at transcription rather than RNA stability, localizing regulation to the gene level.\",\n      \"evidence\": \"Gene cloning and nuclear run-on transcription assays with PIP genomic fragments\",\n      \"pmids\": [\"1955075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific promoter elements and bound factors not identified\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identified PIP as a multivalent extracellular binding protein, linking it to cytoskeletal/coagulation ligands and mucosal bacteria.\",\n      \"evidence\": \"Immunochemical identity assays and in vitro binding to actin, fibrinogen, and Streptococcus salivarius cell walls\",\n      \"pmids\": [\"7840903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of actin/fibrinogen binding noted as unclear by authors\", \"No structural basis for the interactions\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Extended PIP regulation to cytokine signaling, showing IL-4 and IL-13 induce PIP via an apparently shared pathway additive to steroid hormone induction.\",\n      \"evidence\": \"Northern blot, RIA/ELISA, and additivity/dose-response in ZR-75-1 and T-47D cells\",\n      \"pmids\": [\"8865161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared IL-4/IL-13 signaling pathway inferred from additivity, not directly mapped\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Provided functional evidence that secreted PIP binds CD4 and inhibits CD4-mediated T-cell apoptosis, and that secretory processing is required for proper folding.\",\n      \"evidence\": \"Recombinant expression in HeLa and P. pastoris; CD4 binding and apoptosis inhibition assays\",\n      \"pmids\": [\"10504398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CD4-binding interface not mapped\", \"In vivo relevance of T-cell apoptosis inhibition not established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Confirmed the androgen receptor as a regulator of PIP using antiandrogen antagonism in AR-positive cells.\",\n      \"evidence\": \"RT-PCR/Northern blot, secretion measurement, and antiandrogen competition in MFM-223 and ZR-75-1 cells\",\n      \"pmids\": [\"10402478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR binding to PIP regulatory DNA not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PIP in a pathological signaling axis, acting downstream of Slug as an extracellular matrix protein driving smooth muscle proliferation in pulmonary hypertension.\",\n      \"evidence\": \"IHC in human PF-PH tissue and rat model, Slug inhibition in vivo, PASMC proliferation assays\",\n      \"pmids\": [\"31468711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signaling mechanism for PASMC proliferation not identified\", \"Single lab, one disease context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a direct molecular function for PIP as an AQP5 trafficking regulator, mapping the interaction and showing functional consequences for apical membrane localization.\",\n      \"evidence\": \"Co-IP/pulldown in vitro and in mouse tissue, domain mapping, IHC in PIP-knockout mice and Sjögren's patient salivary glands\",\n      \"pmids\": [\"34440877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PIP promotes AQP5 trafficking unresolved\", \"Stoichiometry-to-function relationship not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIP's diverse extracellular binding activities (CD4, actin, fibrinogen, AQP5, ECM) integrate into a unified physiological role, and the structural basis for its multivalent binding, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking distinct binding partners\", \"No single in vivo phenotype unifying its secretory, immune, and trafficking roles\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD4\", \"AQP5\", \"ACTB\", \"FGB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}