{"gene":"PSTPIP1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"PSTPIP1 was identified as a substrate and binding partner of PEST-type protein tyrosine phosphatase PTP-HSCF; the interaction is mediated by the coiled-coil region of PSTPIP1 and the proline-rich C-terminus of the phosphatase. PSTPIP1 is tyrosine-phosphorylated endogenously and by v-Src, and dominant-negative PTP-HSCF causes PSTPIP1 hyperphosphorylation. PSTPIP1 colocalizes with cortical actin, lamellipodia, and the cytokinetic cleavage furrow; overexpression induces filopodia and inhibits cytokinesis in S. pombe.","method":"Yeast two-hybrid, co-transfection, dominant-negative overexpression, confocal microscopy, phosphorylation assays in COS cells and S. pombe","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, in vivo phosphorylation, dominant-negative genetics, confocal localization) in founding paper; replicated by subsequent studies","pmids":["9265651"],"is_preprint":false},{"year":1998,"finding":"PSTPIP1 SH3 domain directly binds two polyproline-rich regions of WASP; co-expression abolishes WASP-induced actin bundling. Tyrosine phosphorylation of PSTPIP1 (at a site within the SH3 domain poly-proline recognition site) disrupts WASP binding in vitro and co-localization in vivo, establishing phosphorylation as a regulatory switch for this interaction.","method":"In vitro binding assays, co-transfection co-localization, site-directed mutagenesis (Y→D/E phosphomimetics), pervanadate treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding with mutagenesis plus in vivo co-localization; independently confirmed by subsequent studies","pmids":["9488710"],"is_preprint":false},{"year":1998,"finding":"CD2BP1/PSTPIP1 SH3 domain binds directly to the CD2 cytoplasmic sequence KGPPLPRPRV (aa 300-309); the N-terminal segment augments this interaction. Upon CD2 clustering, CD2BP1 redistributes from cytosol to the surface membrane co-localizing with CD2. CD2-stimulated adhesion is downregulated by CD2BP1, apparently through coupling of PTP-PEST to CD2.","method":"Interaction trap cloning, in vitro binding, immunofluorescence co-localization, adhesion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding mapped to specific sequence, redistribution shown by imaging, functional adhesion readout; replicated in subsequent studies","pmids":["9857189"],"is_preprint":false},{"year":2000,"finding":"PSTPIP1 acts as a scaffold bridging c-Abl kinase to PEST-type PTPs: c-Abl phosphorylates PSTPIP1, and PSTPIP1 brings PTP-PEST to dephosphorylate and negatively regulate c-Abl. c-Abl is hyperphosphorylated in PTP-PEST-deficient cells and PDGF-induced c-Abl activation is prolonged without PTP-PEST, confirming the ternary complex function.","method":"Co-immunoprecipitation, overexpression of PSTPIP1 mutants, phosphorylation assays in Abl-null fibroblasts and PTP-PEST-deficient cells, PDGF stimulation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical approaches, multiple cell systems, confirmed by gain- and loss-of-function","pmids":["11163214"],"is_preprint":false},{"year":2001,"finding":"PTP-PEST and PSTPIP1 form a complex in vivo via the CTH domain of PTP-PEST and the coiled-coil domain of PSTPIP1; PTP-PEST dephosphorylates PSTPIP1 at tyrosine 344 (the main phosphorylation site mapped by tryptic phosphopeptide mapping). PSTPIP1 serves as a scaffold between PTP-PEST and WASP, enabling PTP-PEST to dephosphorylate WASP and thereby modulate actin remodeling.","method":"Co-immunoprecipitation, tryptic phosphopeptide mapping, in vitro dephosphorylation assays, co-expression studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphorylation site mapped biochemically, scaffolding function demonstrated with multiple orthogonal methods, builds on replicated prior findings","pmids":["11711533"],"is_preprint":false},{"year":2002,"finding":"PAPA syndrome-causing mutations E250Q and A230T in PSTPIP1/CD2BP1 severely reduce binding to PTP-PEST in yeast two-hybrid assays, establishing that disrupted PSTPIP1-PTP-PEST interaction is the molecular basis of PAPA syndrome.","method":"Yeast two-hybrid, gene sequencing in PAPA families","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid binding assay plus genetic linkage; functional mechanism supported by single lab","pmids":["11971877"],"is_preprint":false},{"year":2003,"finding":"PSTPIP1 interacts with pyrin (the FMF protein) in myeloid cells; the B-box of pyrin and both the SH3 and coiled-coil domains of PSTPIP1 are required for the interaction. PAPA-associated PSTPIP1 mutants (A230T and E250Q) are hyperphosphorylated when co-expressed with c-Abl and show markedly increased pyrin binding, linking PSTPIP1 phosphorylation state to pyrin interaction and IL-1β overproduction.","method":"Yeast two-hybrid, co-immunoprecipitation from THP-1 cells, domain-deletion mutants, c-Abl co-expression phosphorylation assays, IL-1β measurement in patient PBLs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous co-IP, domain mapping, phosphorylation assays, patient cells; multiple orthogonal methods in one study replicated by subsequent work","pmids":["14595024"],"is_preprint":false},{"year":2003,"finding":"PSTPIP1 acts downstream of CD2/CD2AP to link CD2 engagement to WASp-evoked actin polymerization required for immunological synapse formation; the PSTPIP1 SH3 domain interacts with WASp's proline-rich region, and the PSTPIP1 coiled-coil domain interacts with CD2 and CD2AP. Deletion of the coiled-coil domain disrupts induced co-localization of these proteins at the synapse.","method":"Co-IP, dominant-negative coiled-coil deletion, confocal co-localization, T cell:APC conjugate and synapse formation assays in WASp-deficient T cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (WASp-KO) and biochemical (co-IP, domain deletion) approaches with functional synapse readout","pmids":["12530983"],"is_preprint":false},{"year":2005,"finding":"PSTPIP1 SH3 domain binds the proline-rich domain of FasL cytoplasmic tail; co-expression of PSTPIP1 increases intracellular localization of FasL, reducing its extracellular availability and cytotoxic activity, and recruits PTP-PEST into a FasL-PSTPIP1-PTP-PEST ternary complex.","method":"Co-immunoprecipitation, co-localization by fluorescence microscopy, cytotoxicity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional localization and cytotoxicity readout, single lab","pmids":["16204241"],"is_preprint":false},{"year":2006,"finding":"CD2BP1/PSTPIP1 negatively regulates T cell activation downstream of CD2 by scaffolding PTP-PEST to the CD2 signalsome; overexpression selectively attenuates PLCγ1, ERK1/2, and p38 phosphorylation. Disruption of PTP-PEST or CD2BP1 association with the CD2 complex rescues T cells from inhibition.","method":"Primary T cell transduction, cytokine expression assays (CD69, IL-2, IFN-γ), phosphorylation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary T cell functional assays with specific pathway readouts; single lab","pmids":["16670297"],"is_preprint":false},{"year":2007,"finding":"PSTPIP1 acts as a cytosolic receptor for pyrin; pyrin exists as an autoinhibited homotrimer with intramolecular PYD-B-box interactions. Ligation by PSTPIP1 (also a homotrimer) unmasks pyrin's PYD, enabling ASC recruitment and oligomerization into an active ASC pyroptosome that recruits and activates caspase-1. PAPA-associated PSTPIP1 mutants bind pyrin with higher affinity, causing constitutive pyrin activation and heightened caspase-1/IL-1β processing.","method":"In vitro binding assays, co-immunoprecipitation, pyroptosome assembly assays, caspase-1 activation assays, gel filtration for oligomeric state","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic reconstitution of pyroptosome assembly, structural oligomeric characterization, multiple biochemical methods in one study","pmids":["17964261"],"is_preprint":false},{"year":2009,"finding":"PSTPIP1 forms homodimers and generates membrane-associated filaments in cells; the extended FCH (Fes-Cip4 homology / F-BAR) domain is necessary and sufficient for self-aggregation. The filament network depends on an intact tubulin cytoskeleton. Pyrin modulates PSTPIP1 filament distribution and can recruit PSTPIP1 into ASC specks (inflammasome aggregates); PAPA-associated PSTPIP1 mutants are recruited to ASC specks with particularly high efficiency.","method":"Transfection with deletion constructs, immunofluorescence microscopy, co-localization with ASC specks, tubulin disruption experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping in cells with functional readout (ASC speck recruitment); single lab, multiple constructs","pmids":["19584923"],"is_preprint":false},{"year":2014,"finding":"Endogenous PSTPIP1 negatively regulates macrophage podosome organization and extracellular matrix degradation. A disease-associated PSTPIP1-R405C mutation (in the SH3 domain) impairs WASP binding but not PTP-PEST binding, causing elevated F-actin, excessive filopodia formation, and increased matrix degradation. WASP inhibition reverses these phenotypes, placing PSTPIP1 upstream of WASP in podosome/filopodia balance.","method":"Endogenous knockdown, overexpression of R405C mutant, WASP inhibition, F-actin quantification, matrix degradation assays in macrophages","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function, gain-of-function with disease mutant, epistasis via WASP inhibition, multiple orthogonal readouts","pmids":["24421327"],"is_preprint":false},{"year":2015,"finding":"PSTPIP1 E250K and E257K mutations (associated with PAMI/Hz-Hc syndrome) substantially increase PSTPIP1 interaction with pyrin through enhanced PSTPIP1 phosphorylation, as demonstrated by immunoprecipitation and Western blotting, and are predicted by structural modeling to alter the electrostatic potential of the PSTPIP1 dimer at a protein-protein interaction surface.","method":"Immunoprecipitation, Western blotting, structural modeling of PSTPIP1 dimer","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with disease mutants supported by structural model; single lab","pmids":["26025129"],"is_preprint":false},{"year":2015,"finding":"Pyrin co-localizes with PSTPIP1 and polymerized actin at the leading edge of migrating HL-60 cells, demonstrating that PSTPIP1 interacts with dynamic actin and pyrin at the site of cell polarization during migration.","method":"Immunofluorescence co-localization in differentiated HL-60 cells during scratch-wound migration assay","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-localization method, no direct interaction or functional perturbation shown in this study","pmids":["26179737"],"is_preprint":false},{"year":2016,"finding":"In osteoclasts, PSTPIP1 F-BAR domain recruits the phosphatase PTPN6 (SHP-1), which dephosphorylates the phosphoinositide 5-phosphatases SHIP1/2 that are bound to PSTPIP1's SH3 domain. This PSTPIP1/PTPN6/SHIP1-SHIP2 complex negatively regulates podosome disassembly and sealing zone dynamics; depletion of any component prevents disassembly and increases osteoclast bone resorption activity.","method":"Co-immunoprecipitation, siRNA knockdown, confocal microscopy, bone resorption assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain attribution, functional rescue assays; single lab","pmids":["27760174"],"is_preprint":false},{"year":2018,"finding":"PSTPIP1 controls immunological synapse (IS) formation and F-actin polymerization in human T cells; loss-of-function mutations R228C and T274M impair F-actin accumulation at the IS, disrupt CD2 membrane microdomain capping, and alter T cell migration and calcium flux. The T274M mutation causes a preactivated F-actin state particularly damaging to T cell differentiation. CD2-PSTPIP1 association was confirmed by immunoprecipitation.","method":"Flow cytometry (F-actin), immunoprecipitation, IS formation assay in Jurkat transfectants, 3D collagen migration assay, calcium flux measurement in primary patient T cells","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary patient cells plus Jurkat transfectants, multiple orthogonal methods; single lab","pmids":["29432774"],"is_preprint":false},{"year":2022,"finding":"The crystal structure of the PSTPIP1 F-BAR domain alone and bound to the C-terminal homology segment of LYP (PTPN22) was solved, revealing that a single LYP molecule binds to the PSTPIP1 F-BAR dimer via a novel recognition mechanism for proline-rich motifs. Disease-associated residues R228, D246, E250, and E257 of PSTPIP1 directly contact LYP, linking disruption of PSTPIP1-LYP interaction to autoinflammatory pathogenesis.","method":"X-ray crystallography, structural analysis, binding assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with direct residue-contact mapping; single lab but Tier 1 method","pmids":["35152348"],"is_preprint":false},{"year":2023,"finding":"PSTPIP1 (F-BAR domain protein) is required for clathrin-independent endocytosis of L1CAM; it acts together with the N-BAR protein endophilin-A3, and galectins serve as endocytic partners that negatively regulate this process.","method":"siRNA knockdown, fluorescence microscopy, endocytosis assays","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with specific endocytosis readout; single lab","pmids":["36843549"],"is_preprint":false},{"year":2025,"finding":"A CRISPR/Cas9 knockout screen identified PSTPIP1 as a regulatory factor of macrophage differentiation; deletion of PSTPIP1 results in hampered differentiation, decreased inflammatory response, altered morphology, and impaired cell adhesion and migration. Deletion of pyrin similarly disrupts cellular dynamics, placing both proteins as crucial factors in the same macrophage differentiation pathway.","method":"Genome-wide CRISPR/Cas9 knockout screen (GeCKO), independent KO/KI validation, FACS immunophenotyping, fluorescence microscopy, ELISA, RNA-seq","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen with independent validation, multiple orthogonal readouts; single lab, recent publication","pmids":["40997504"],"is_preprint":false},{"year":2026,"finding":"PTPN22 modulates actin cytoskeletal dynamics at the T cell immunological synapse through a direct interaction with PSTPIP1; PTPN22 deficiency or inhibition causes aberrant Arp2/3-dependent actin remodeling, excessive central F-actin foci, PSTPIP1 mislocalization, and aberrant PSTPIP1-TCR nanoscale co-localization, leading to enhanced calcium signaling especially under low-affinity TCR stimulation.","method":"Super-resolution DNA-PAINT, live/fixed multi-color fluorescence imaging, PTPN22 knockdown/inhibition in Jurkat cells, calcium flux assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — super-resolution imaging plus functional signaling readout; single lab, genetic and pharmacological perturbation","pmids":["42263152"],"is_preprint":false},{"year":2026,"finding":"A novel gain-of-function PSTPIP1 mutation (p.N236K) shows increased binding to pyrin and leads to heightened inflammasome formation relative to WT PSTPIP1, causing PAMI syndrome with severe neutropenia.","method":"Co-immunoprecipitation (PSTPIP1-pyrin binding), inflammasome formation assay, patient genetic characterization","journal":"Journal of human immunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP/inflammasome assay, single case report context, limited detail in abstract","pmids":["42007463"],"is_preprint":false}],"current_model":"PSTPIP1 is a cytoskeletal F-BAR adaptor protein that functions as a molecular scaffold linking PEST-type protein tyrosine phosphatases (PTP-PEST/PTP-HSCF) to substrates including WASP, c-Abl, and SHIP1/2, while simultaneously coupling upstream receptors (CD2, CD2AP) to downstream actin-regulatory effectors (WASp/Arp2/3) for immunological synapse formation and podosome/filopodia balance; its phosphorylation at Y344 by c-Abl regulates WASP and pyrin binding, and disease-associated PSTPIP1 mutants (A230T, E250Q, E250K, E257K, N236K) exhibit hyperphosphorylation and markedly increased binding to pyrin, which constitutively unmasks pyrin's pyrin domain (PYD) to drive ASC pyroptosome assembly and caspase-1/IL-1β/IL-18 activation, explaining the autoinflammatory phenotypes of PAPA and PAMI syndromes."},"narrative":{"mechanistic_narrative":"PSTPIP1 is an F-BAR/coiled-coil cytoskeletal adaptor that organizes actin dynamics and inflammatory signaling by scaffolding PEST-type protein tyrosine phosphatases to specific substrates and receptors in hematopoietic cells [PMID:9265651, PMID:11711533]. Its coiled-coil region binds PTP-PEST/PTP-HSCF, while its SH3 domain engages proline-rich partners including WASP, CD2, and FasL, and its phosphorylation state acts as a regulatory switch: c-Abl phosphorylates PSTPIP1 (principally at Y344), and PTP-PEST reverses this modification, with phosphorylation disrupting WASP binding [PMID:9488710, PMID:11163214, PMID:11711533]. Through these interactions PSTPIP1 couples CD2/CD2AP engagement to WASp/Arp2/3-driven actin polymerization at the immunological synapse and balances podosome versus filopodia formation, acting upstream of WASP to restrain macrophage matrix degradation and, with PTPN6 and SHIP1/2, to control osteoclast podosome disassembly [PMID:12530983, PMID:24421327, PMID:27760174]. PSTPIP1 self-assembles via its F-BAR domain into membrane-associated filaments and serves as a cytosolic ligand for pyrin: homotrimeric PSTPIP1 binds the pyrin B-box and unmasks the pyrin PYD, enabling ASC pyroptosome assembly and caspase-1/IL-1β activation [PMID:17964261, PMID:19584923]. PSTPIP1 also functions in clathrin-independent endocytosis of L1CAM with endophilin-A3 and is required for macrophage differentiation [PMID:36843549, PMID:40997504]. Gain-of-function mutations (A230T, E250Q, E250K, E257K) are hyperphosphorylated and bind pyrin with markedly increased affinity to drive constitutive inflammasome activation, the molecular basis of PAPA and PAMI syndromes, whereas these and other disease residues also disrupt PSTPIP1 binding to PTP-PEST and to LYP/PTPN22 [PMID:11971877, PMID:14595024, PMID:26025129, PMID:35152348].","teleology":[{"year":1997,"claim":"Establishing that PSTPIP1 is a phosphatase-associated cytoskeletal protein defined its founding biochemical identity and linked it to actin and cell division.","evidence":"Yeast two-hybrid, dominant-negative overexpression and confocal localization identifying PTP-HSCF binding and actin/cleavage-furrow colocalization in COS and S. pombe","pmids":["9265651"],"confidence":"High","gaps":["Y344 phosphorylation site not yet mapped","Physiological consequences of cytokinesis effect in mammalian cells unaddressed"]},{"year":1998,"claim":"Identifying SH3-mediated binding to WASP and CD2 established PSTPIP1 as an adaptor coupling actin effectors and surface receptors, with phosphorylation as a binding switch.","evidence":"In vitro binding, site-directed phosphomimetic mutagenesis and co-localization for WASP; interaction trap and adhesion assays for CD2","pmids":["9488710","9857189"],"confidence":"High","gaps":["Kinase responsible for the regulatory phosphorylation not identified here","In vivo physiological readouts limited"]},{"year":2000,"claim":"Demonstrating that PSTPIP1 bridges c-Abl to PTP-PEST defined a ternary phosphoregulatory module and identified the kinase acting on PSTPIP1.","evidence":"Co-IP, PSTPIP1 mutants and phosphorylation assays in Abl-null and PTP-PEST-deficient cells with PDGF stimulation","pmids":["11163214"],"confidence":"High","gaps":["Direct structural basis of the ternary complex not resolved","Quantitative kinetics of dephosphorylation not measured"]},{"year":2001,"claim":"Mapping Y344 as the PTP-PEST dephosphorylation site and showing PSTPIP1 scaffolds PTP-PEST onto WASP clarified how phosphatase activity is targeted to actin regulators.","evidence":"Tryptic phosphopeptide mapping, in vitro dephosphorylation and co-expression studies","pmids":["11711533"],"confidence":"High","gaps":["Stoichiometry of scaffold assembly in vivo unclear"]},{"year":2002,"claim":"Linking PAPA-causing mutations to loss of PTP-PEST binding gave the first disease-mechanism connection for PSTPIP1.","evidence":"Yeast two-hybrid binding of A230T and E250Q mutants plus genetic sequencing in PAPA families","pmids":["11971877"],"confidence":"Medium","gaps":["Mechanism connecting reduced phosphatase binding to inflammation not yet established","Single-method binding assay"]},{"year":2003,"claim":"Discovering the PSTPIP1-pyrin interaction and showing disease mutants are hyperphosphorylated with increased pyrin binding reframed PSTPIP1 as an inflammatory regulator, and defining the CD2/CD2AP-WASp synapse axis tied it to T cell actin dynamics.","evidence":"Co-IP from THP-1 cells, domain-deletion mapping, c-Abl phosphorylation assays and patient IL-1β measurement; co-IP and synapse assays in WASp-deficient T cells","pmids":["14595024","12530983"],"confidence":"High","gaps":["Structural basis of mutant-enhanced pyrin binding unresolved at this stage","Direct link from pyrin binding to IL-1β processing mechanism not yet reconstituted"]},{"year":2005,"claim":"Showing PSTPIP1 sequesters FasL and recruits PTP-PEST extended its adaptor function to death-ligand availability.","evidence":"Co-IP, fluorescence co-localization and cytotoxicity assays","pmids":["16204241"],"confidence":"Medium","gaps":["Single-lab finding without genetic loss-of-function","Physiological context of FasL regulation unconfirmed"]},{"year":2006,"claim":"Demonstrating that PSTPIP1 scaffolds PTP-PEST to the CD2 signalsome to dampen TCR-proximal signaling defined its negative-regulatory role in T cell activation.","evidence":"Primary T cell transduction with PLCγ1/ERK/p38 phosphorylation and cytokine readouts","pmids":["16670297"],"confidence":"Medium","gaps":["Direct phosphatase substrates in CD2 signalsome not enumerated","Single lab"]},{"year":2007,"claim":"Reconstituting pyrin autoinhibition relief by PSTPIP1 ligation provided the mechanistic basis for inflammasome activation and for mutant gain-of-function.","evidence":"In vitro binding, pyroptosome assembly, caspase-1 activation assays and gel filtration for oligomeric state","pmids":["17964261"],"confidence":"High","gaps":["Trigger controlling PSTPIP1-pyrin engagement in normal cells not defined","Atomic-resolution structure of the complex absent"]},{"year":2009,"claim":"Showing F-BAR-driven PSTPIP1 self-assembly into tubulin-dependent filaments and recruitment to ASC specks connected its membrane/cytoskeletal scaffolding to inflammasome aggregation.","evidence":"Deletion-construct transfection, immunofluorescence and ASC-speck co-localization with tubulin disruption","pmids":["19584923"],"confidence":"Medium","gaps":["Functional role of filaments distinct from speck recruitment unclear","Single lab"]},{"year":2014,"claim":"Placing PSTPIP1 upstream of WASP in podosome/filopodia balance and showing the R405C SH3 mutant selectively loses WASP binding clarified genotype-to-cytoskeleton mechanism.","evidence":"Endogenous knockdown, R405C overexpression, WASP-inhibition epistasis, F-actin and matrix-degradation assays in macrophages","pmids":["24421327"],"confidence":"High","gaps":["Relationship of cytoskeletal defect to inflammatory phenotype not bridged"]},{"year":2015,"claim":"Defining the PSTPIP1/PTPN6/SHIP1-2 complex in osteoclasts and PAMI-associated E250K/E257K enhanced pyrin binding broadened the substrate repertoire and the disease-mutation spectrum.","evidence":"Reciprocal co-IP, siRNA depletion and bone-resorption assays; immunoprecipitation and structural modeling of disease mutants; HL-60 leading-edge co-localization","pmids":["27760174","26025129","26179737"],"confidence":"Medium","gaps":["Mechanism of dimer electrostatic change on binding modeled but not crystallographically resolved","HL-60 co-localization lacks direct interaction or perturbation evidence"]},{"year":2018,"claim":"Linking loss-of-function PSTPIP1 mutations to defective immunological synapse F-actin and altered T cell behavior established its requirement for synapse architecture in human T cells.","evidence":"Flow cytometry F-actin, IP, IS-formation and migration assays in Jurkat and primary patient T cells","pmids":["29432774"],"confidence":"Medium","gaps":["Mechanistic link between F-actin preactivation and differentiation defect incomplete","Single lab"]},{"year":2022,"claim":"Solving the F-BAR/LYP co-structure revealed a novel proline-recognition mechanism and showed disease residues directly contact LYP, adding a structural basis for pathogenesis.","evidence":"X-ray crystallography of PSTPIP1 F-BAR alone and with LYP/PTPN22 C-terminal segment plus binding assays","pmids":["35152348"],"confidence":"High","gaps":["Cellular consequence of disrupted PSTPIP1-LYP binding not directly tested in this study"]},{"year":2023,"claim":"Identifying PSTPIP1 as required for clathrin-independent L1CAM endocytosis with endophilin-A3 extended its F-BAR membrane-remodeling function to receptor trafficking.","evidence":"siRNA knockdown, fluorescence microscopy and endocytosis assays","pmids":["36843549"],"confidence":"Medium","gaps":["Generality across cargoes beyond L1CAM unknown","Direct membrane-curvature contribution not isolated"]},{"year":2025,"claim":"A genome-wide screen placing PSTPIP1 and pyrin in the same macrophage differentiation pathway connected the adaptor's cytoskeletal and inflammatory roles to a developmental program.","evidence":"GeCKO CRISPR knockout screen with KO/KI validation, immunophenotyping, RNA-seq and functional adhesion/migration assays","pmids":["40997504"],"confidence":"Medium","gaps":["Molecular steps linking PSTPIP1 loss to differentiation block undefined","Single lab"]},{"year":2026,"claim":"Defining a direct PTPN22-PSTPIP1 interaction controlling synapse actin nanoscale organization, and identifying a new pyrin-binding gain-of-function mutation (N236K), refined both the cytoskeletal-regulatory and autoinflammatory arms.","evidence":"Super-resolution DNA-PAINT with PTPN22 perturbation and calcium assays in Jurkat cells; co-IP and inflammasome assay with N236K patient characterization","pmids":["42263152","42007463"],"confidence":"Medium","gaps":["N236K finding rests on single co-IP/inflammasome assay in case-report context","How PTPN22-PSTPIP1 binding integrates with phosphatase scaffolding not fully resolved"]},{"year":null,"claim":"How the phosphorylation switch, F-BAR membrane filaments, and pyrin ligation are coordinated under physiological triggers to toggle PSTPIP1 between actin-regulatory and inflammasome-activating states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic-resolution structure of the PSTPIP1-pyrin complex","Endogenous signals controlling PSTPIP1 phosphorylation in vivo undefined","Integration of endocytic and scaffolding functions unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,7,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,7,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9,10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,18]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,12,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,11,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7,10,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19]}],"complexes":["PSTPIP1/PTP-PEST/WASP scaffold complex","PSTPIP1/PTPN6/SHIP1-SHIP2 complex","ASC pyroptosome (via pyrin)"],"partners":["PTPN12","WAS","CD2","CD2AP","MEFV","ABL1","PTPN6","PTPN22"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43586","full_name":"Proline-serine-threonine phosphatase-interacting protein 1","aliases":["CD2-binding protein 1","H-PIP"],"length_aa":416,"mass_kda":47.6,"function":"Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation (By similarity). Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils","subcellular_location":"Cytoplasm; Cell membrane; Cell projection, uropodium; Cytoplasm, cytoskeleton; Cytoplasm, perinuclear region; Cell projection, lamellipodium; Cleavage furrow","url":"https://www.uniprot.org/uniprotkb/O43586/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSTPIP1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PSTPIP1","total_profiled":1310},"omim":[{"mim_id":"616046","title":"PROLINE/SERINE/THREONINE PHOSPHATASE-INTERACTING PROTEIN 2; PSTPIP2","url":"https://www.omim.org/entry/616046"},{"mim_id":"608107","title":"MEFV INNATE IMMUNITY REGULATOR, PYRIN; MEFV","url":"https://www.omim.org/entry/608107"},{"mim_id":"606347","title":"PROLINE/SERINE/THREONINE PHOSPHATASE-INTERACTING PROTEIN 1; PSTPIP1","url":"https://www.omim.org/entry/606347"},{"mim_id":"605254","title":"NICASTRIN; NCSTN","url":"https://www.omim.org/entry/605254"},{"mim_id":"604416","title":"PYOGENIC STERILE ARTHRITIS, PYODERMA GANGRENOSUM, AND ACNE; PAPA","url":"https://www.omim.org/entry/604416"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":55.1},{"tissue":"lymphoid tissue","ntpm":30.4}],"url":"https://www.proteinatlas.org/search/PSTPIP1"},"hgnc":{"alias_symbol":["PSTPIP","CD2BP1L","CD2BP1","CD2BP1S","H-PIP","PAPAS"],"prev_symbol":[]},"alphafold":{"accession":"O43586","domains":[{"cath_id":"1.20.1270.60","chopping":"8-259","consensus_level":"high","plddt":96.7667,"start":8,"end":259},{"cath_id":"2.30.30.40","chopping":"363-416","consensus_level":"high","plddt":90.9352,"start":363,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43586","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43586-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43586-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSTPIP1","jax_strain_url":"https://www.jax.org/strain/search?query=PSTPIP1"},"sequence":{"accession":"O43586","fasta_url":"https://rest.uniprot.org/uniprotkb/O43586.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43586/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43586"}},"corpus_meta":[{"pmid":"14595024","id":"PMC_14595024","title":"Pyrin 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\"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"PSTPIP1 was identified as a substrate and binding partner of PEST-type protein tyrosine phosphatase PTP-HSCF; the interaction is mediated by the coiled-coil region of PSTPIP1 and the proline-rich C-terminus of the phosphatase. PSTPIP1 is tyrosine-phosphorylated endogenously and by v-Src, and dominant-negative PTP-HSCF causes PSTPIP1 hyperphosphorylation. PSTPIP1 colocalizes with cortical actin, lamellipodia, and the cytokinetic cleavage furrow; overexpression induces filopodia and inhibits cytokinesis in S. pombe.\",\n      \"method\": \"Yeast two-hybrid, co-transfection, dominant-negative overexpression, confocal microscopy, phosphorylation assays in COS cells and S. pombe\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, in vivo phosphorylation, dominant-negative genetics, confocal localization) in founding paper; replicated by subsequent studies\",\n      \"pmids\": [\"9265651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PSTPIP1 SH3 domain directly binds two polyproline-rich regions of WASP; co-expression abolishes WASP-induced actin bundling. Tyrosine phosphorylation of PSTPIP1 (at a site within the SH3 domain poly-proline recognition site) disrupts WASP binding in vitro and co-localization in vivo, establishing phosphorylation as a regulatory switch for this interaction.\",\n      \"method\": \"In vitro binding assays, co-transfection co-localization, site-directed mutagenesis (Y→D/E phosphomimetics), pervanadate treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding with mutagenesis plus in vivo co-localization; independently confirmed by subsequent studies\",\n      \"pmids\": [\"9488710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD2BP1/PSTPIP1 SH3 domain binds directly to the CD2 cytoplasmic sequence KGPPLPRPRV (aa 300-309); the N-terminal segment augments this interaction. Upon CD2 clustering, CD2BP1 redistributes from cytosol to the surface membrane co-localizing with CD2. CD2-stimulated adhesion is downregulated by CD2BP1, apparently through coupling of PTP-PEST to CD2.\",\n      \"method\": \"Interaction trap cloning, in vitro binding, immunofluorescence co-localization, adhesion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding mapped to specific sequence, redistribution shown by imaging, functional adhesion readout; replicated in subsequent studies\",\n      \"pmids\": [\"9857189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PSTPIP1 acts as a scaffold bridging c-Abl kinase to PEST-type PTPs: c-Abl phosphorylates PSTPIP1, and PSTPIP1 brings PTP-PEST to dephosphorylate and negatively regulate c-Abl. c-Abl is hyperphosphorylated in PTP-PEST-deficient cells and PDGF-induced c-Abl activation is prolonged without PTP-PEST, confirming the ternary complex function.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of PSTPIP1 mutants, phosphorylation assays in Abl-null fibroblasts and PTP-PEST-deficient cells, PDGF stimulation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical approaches, multiple cell systems, confirmed by gain- and loss-of-function\",\n      \"pmids\": [\"11163214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PTP-PEST and PSTPIP1 form a complex in vivo via the CTH domain of PTP-PEST and the coiled-coil domain of PSTPIP1; PTP-PEST dephosphorylates PSTPIP1 at tyrosine 344 (the main phosphorylation site mapped by tryptic phosphopeptide mapping). PSTPIP1 serves as a scaffold between PTP-PEST and WASP, enabling PTP-PEST to dephosphorylate WASP and thereby modulate actin remodeling.\",\n      \"method\": \"Co-immunoprecipitation, tryptic phosphopeptide mapping, in vitro dephosphorylation assays, co-expression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphorylation site mapped biochemically, scaffolding function demonstrated with multiple orthogonal methods, builds on replicated prior findings\",\n      \"pmids\": [\"11711533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PAPA syndrome-causing mutations E250Q and A230T in PSTPIP1/CD2BP1 severely reduce binding to PTP-PEST in yeast two-hybrid assays, establishing that disrupted PSTPIP1-PTP-PEST interaction is the molecular basis of PAPA syndrome.\",\n      \"method\": \"Yeast two-hybrid, gene sequencing in PAPA families\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid binding assay plus genetic linkage; functional mechanism supported by single lab\",\n      \"pmids\": [\"11971877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PSTPIP1 interacts with pyrin (the FMF protein) in myeloid cells; the B-box of pyrin and both the SH3 and coiled-coil domains of PSTPIP1 are required for the interaction. PAPA-associated PSTPIP1 mutants (A230T and E250Q) are hyperphosphorylated when co-expressed with c-Abl and show markedly increased pyrin binding, linking PSTPIP1 phosphorylation state to pyrin interaction and IL-1β overproduction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from THP-1 cells, domain-deletion mutants, c-Abl co-expression phosphorylation assays, IL-1β measurement in patient PBLs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous co-IP, domain mapping, phosphorylation assays, patient cells; multiple orthogonal methods in one study replicated by subsequent work\",\n      \"pmids\": [\"14595024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PSTPIP1 acts downstream of CD2/CD2AP to link CD2 engagement to WASp-evoked actin polymerization required for immunological synapse formation; the PSTPIP1 SH3 domain interacts with WASp's proline-rich region, and the PSTPIP1 coiled-coil domain interacts with CD2 and CD2AP. Deletion of the coiled-coil domain disrupts induced co-localization of these proteins at the synapse.\",\n      \"method\": \"Co-IP, dominant-negative coiled-coil deletion, confocal co-localization, T cell:APC conjugate and synapse formation assays in WASp-deficient T cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (WASp-KO) and biochemical (co-IP, domain deletion) approaches with functional synapse readout\",\n      \"pmids\": [\"12530983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PSTPIP1 SH3 domain binds the proline-rich domain of FasL cytoplasmic tail; co-expression of PSTPIP1 increases intracellular localization of FasL, reducing its extracellular availability and cytotoxic activity, and recruits PTP-PEST into a FasL-PSTPIP1-PTP-PEST ternary complex.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by fluorescence microscopy, cytotoxicity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional localization and cytotoxicity readout, single lab\",\n      \"pmids\": [\"16204241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD2BP1/PSTPIP1 negatively regulates T cell activation downstream of CD2 by scaffolding PTP-PEST to the CD2 signalsome; overexpression selectively attenuates PLCγ1, ERK1/2, and p38 phosphorylation. Disruption of PTP-PEST or CD2BP1 association with the CD2 complex rescues T cells from inhibition.\",\n      \"method\": \"Primary T cell transduction, cytokine expression assays (CD69, IL-2, IFN-γ), phosphorylation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary T cell functional assays with specific pathway readouts; single lab\",\n      \"pmids\": [\"16670297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PSTPIP1 acts as a cytosolic receptor for pyrin; pyrin exists as an autoinhibited homotrimer with intramolecular PYD-B-box interactions. Ligation by PSTPIP1 (also a homotrimer) unmasks pyrin's PYD, enabling ASC recruitment and oligomerization into an active ASC pyroptosome that recruits and activates caspase-1. PAPA-associated PSTPIP1 mutants bind pyrin with higher affinity, causing constitutive pyrin activation and heightened caspase-1/IL-1β processing.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, pyroptosome assembly assays, caspase-1 activation assays, gel filtration for oligomeric state\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic reconstitution of pyroptosome assembly, structural oligomeric characterization, multiple biochemical methods in one study\",\n      \"pmids\": [\"17964261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSTPIP1 forms homodimers and generates membrane-associated filaments in cells; the extended FCH (Fes-Cip4 homology / F-BAR) domain is necessary and sufficient for self-aggregation. The filament network depends on an intact tubulin cytoskeleton. Pyrin modulates PSTPIP1 filament distribution and can recruit PSTPIP1 into ASC specks (inflammasome aggregates); PAPA-associated PSTPIP1 mutants are recruited to ASC specks with particularly high efficiency.\",\n      \"method\": \"Transfection with deletion constructs, immunofluorescence microscopy, co-localization with ASC specks, tubulin disruption experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping in cells with functional readout (ASC speck recruitment); single lab, multiple constructs\",\n      \"pmids\": [\"19584923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Endogenous PSTPIP1 negatively regulates macrophage podosome organization and extracellular matrix degradation. A disease-associated PSTPIP1-R405C mutation (in the SH3 domain) impairs WASP binding but not PTP-PEST binding, causing elevated F-actin, excessive filopodia formation, and increased matrix degradation. WASP inhibition reverses these phenotypes, placing PSTPIP1 upstream of WASP in podosome/filopodia balance.\",\n      \"method\": \"Endogenous knockdown, overexpression of R405C mutant, WASP inhibition, F-actin quantification, matrix degradation assays in macrophages\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function, gain-of-function with disease mutant, epistasis via WASP inhibition, multiple orthogonal readouts\",\n      \"pmids\": [\"24421327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSTPIP1 E250K and E257K mutations (associated with PAMI/Hz-Hc syndrome) substantially increase PSTPIP1 interaction with pyrin through enhanced PSTPIP1 phosphorylation, as demonstrated by immunoprecipitation and Western blotting, and are predicted by structural modeling to alter the electrostatic potential of the PSTPIP1 dimer at a protein-protein interaction surface.\",\n      \"method\": \"Immunoprecipitation, Western blotting, structural modeling of PSTPIP1 dimer\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with disease mutants supported by structural model; single lab\",\n      \"pmids\": [\"26025129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pyrin co-localizes with PSTPIP1 and polymerized actin at the leading edge of migrating HL-60 cells, demonstrating that PSTPIP1 interacts with dynamic actin and pyrin at the site of cell polarization during migration.\",\n      \"method\": \"Immunofluorescence co-localization in differentiated HL-60 cells during scratch-wound migration assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-localization method, no direct interaction or functional perturbation shown in this study\",\n      \"pmids\": [\"26179737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In osteoclasts, PSTPIP1 F-BAR domain recruits the phosphatase PTPN6 (SHP-1), which dephosphorylates the phosphoinositide 5-phosphatases SHIP1/2 that are bound to PSTPIP1's SH3 domain. This PSTPIP1/PTPN6/SHIP1-SHIP2 complex negatively regulates podosome disassembly and sealing zone dynamics; depletion of any component prevents disassembly and increases osteoclast bone resorption activity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, confocal microscopy, bone resorption assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain attribution, functional rescue assays; single lab\",\n      \"pmids\": [\"27760174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSTPIP1 controls immunological synapse (IS) formation and F-actin polymerization in human T cells; loss-of-function mutations R228C and T274M impair F-actin accumulation at the IS, disrupt CD2 membrane microdomain capping, and alter T cell migration and calcium flux. The T274M mutation causes a preactivated F-actin state particularly damaging to T cell differentiation. CD2-PSTPIP1 association was confirmed by immunoprecipitation.\",\n      \"method\": \"Flow cytometry (F-actin), immunoprecipitation, IS formation assay in Jurkat transfectants, 3D collagen migration assay, calcium flux measurement in primary patient T cells\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary patient cells plus Jurkat transfectants, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"29432774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The crystal structure of the PSTPIP1 F-BAR domain alone and bound to the C-terminal homology segment of LYP (PTPN22) was solved, revealing that a single LYP molecule binds to the PSTPIP1 F-BAR dimer via a novel recognition mechanism for proline-rich motifs. Disease-associated residues R228, D246, E250, and E257 of PSTPIP1 directly contact LYP, linking disruption of PSTPIP1-LYP interaction to autoinflammatory pathogenesis.\",\n      \"method\": \"X-ray crystallography, structural analysis, binding assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with direct residue-contact mapping; single lab but Tier 1 method\",\n      \"pmids\": [\"35152348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSTPIP1 (F-BAR domain protein) is required for clathrin-independent endocytosis of L1CAM; it acts together with the N-BAR protein endophilin-A3, and galectins serve as endocytic partners that negatively regulate this process.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, endocytosis assays\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with specific endocytosis readout; single lab\",\n      \"pmids\": [\"36843549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A CRISPR/Cas9 knockout screen identified PSTPIP1 as a regulatory factor of macrophage differentiation; deletion of PSTPIP1 results in hampered differentiation, decreased inflammatory response, altered morphology, and impaired cell adhesion and migration. Deletion of pyrin similarly disrupts cellular dynamics, placing both proteins as crucial factors in the same macrophage differentiation pathway.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout screen (GeCKO), independent KO/KI validation, FACS immunophenotyping, fluorescence microscopy, ELISA, RNA-seq\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen with independent validation, multiple orthogonal readouts; single lab, recent publication\",\n      \"pmids\": [\"40997504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTPN22 modulates actin cytoskeletal dynamics at the T cell immunological synapse through a direct interaction with PSTPIP1; PTPN22 deficiency or inhibition causes aberrant Arp2/3-dependent actin remodeling, excessive central F-actin foci, PSTPIP1 mislocalization, and aberrant PSTPIP1-TCR nanoscale co-localization, leading to enhanced calcium signaling especially under low-affinity TCR stimulation.\",\n      \"method\": \"Super-resolution DNA-PAINT, live/fixed multi-color fluorescence imaging, PTPN22 knockdown/inhibition in Jurkat cells, calcium flux assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution imaging plus functional signaling readout; single lab, genetic and pharmacological perturbation\",\n      \"pmids\": [\"42263152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A novel gain-of-function PSTPIP1 mutation (p.N236K) shows increased binding to pyrin and leads to heightened inflammasome formation relative to WT PSTPIP1, causing PAMI syndrome with severe neutropenia.\",\n      \"method\": \"Co-immunoprecipitation (PSTPIP1-pyrin binding), inflammasome formation assay, patient genetic characterization\",\n      \"journal\": \"Journal of human immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP/inflammasome assay, single case report context, limited detail in abstract\",\n      \"pmids\": [\"42007463\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSTPIP1 is a cytoskeletal F-BAR adaptor protein that functions as a molecular scaffold linking PEST-type protein tyrosine phosphatases (PTP-PEST/PTP-HSCF) to substrates including WASP, c-Abl, and SHIP1/2, while simultaneously coupling upstream receptors (CD2, CD2AP) to downstream actin-regulatory effectors (WASp/Arp2/3) for immunological synapse formation and podosome/filopodia balance; its phosphorylation at Y344 by c-Abl regulates WASP and pyrin binding, and disease-associated PSTPIP1 mutants (A230T, E250Q, E250K, E257K, N236K) exhibit hyperphosphorylation and markedly increased binding to pyrin, which constitutively unmasks pyrin's pyrin domain (PYD) to drive ASC pyroptosome assembly and caspase-1/IL-1β/IL-18 activation, explaining the autoinflammatory phenotypes of PAPA and PAMI syndromes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSTPIP1 is an F-BAR/coiled-coil cytoskeletal adaptor that organizes actin dynamics and inflammatory signaling by scaffolding PEST-type protein tyrosine phosphatases to specific substrates and receptors in hematopoietic cells [#0, #4]. Its coiled-coil region binds PTP-PEST/PTP-HSCF, while its SH3 domain engages proline-rich partners including WASP, CD2, and FasL, and its phosphorylation state acts as a regulatory switch: c-Abl phosphorylates PSTPIP1 (principally at Y344), and PTP-PEST reverses this modification, with phosphorylation disrupting WASP binding [#1, #3, #4]. Through these interactions PSTPIP1 couples CD2/CD2AP engagement to WASp/Arp2/3-driven actin polymerization at the immunological synapse and balances podosome versus filopodia formation, acting upstream of WASP to restrain macrophage matrix degradation and, with PTPN6 and SHIP1/2, to control osteoclast podosome disassembly [#7, #12, #15]. PSTPIP1 self-assembles via its F-BAR domain into membrane-associated filaments and serves as a cytosolic ligand for pyrin: homotrimeric PSTPIP1 binds the pyrin B-box and unmasks the pyrin PYD, enabling ASC pyroptosome assembly and caspase-1/IL-1\\u03b2 activation [#10, #11]. PSTPIP1 also functions in clathrin-independent endocytosis of L1CAM with endophilin-A3 and is required for macrophage differentiation [#18, #19]. Gain-of-function mutations (A230T, E250Q, E250K, E257K) are hyperphosphorylated and bind pyrin with markedly increased affinity to drive constitutive inflammasome activation, the molecular basis of PAPA and PAMI syndromes, whereas these and other disease residues also disrupt PSTPIP1 binding to PTP-PEST and to LYP/PTPN22 [#5, #6, #13, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that PSTPIP1 is a phosphatase-associated cytoskeletal protein defined its founding biochemical identity and linked it to actin and cell division.\",\n      \"evidence\": \"Yeast two-hybrid, dominant-negative overexpression and confocal localization identifying PTP-HSCF binding and actin/cleavage-furrow colocalization in COS and S. pombe\",\n      \"pmids\": [\"9265651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Y344 phosphorylation site not yet mapped\", \"Physiological consequences of cytokinesis effect in mammalian cells unaddressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying SH3-mediated binding to WASP and CD2 established PSTPIP1 as an adaptor coupling actin effectors and surface receptors, with phosphorylation as a binding switch.\",\n      \"evidence\": \"In vitro binding, site-directed phosphomimetic mutagenesis and co-localization for WASP; interaction trap and adhesion assays for CD2\",\n      \"pmids\": [\"9488710\", \"9857189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for the regulatory phosphorylation not identified here\", \"In vivo physiological readouts limited\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that PSTPIP1 bridges c-Abl to PTP-PEST defined a ternary phosphoregulatory module and identified the kinase acting on PSTPIP1.\",\n      \"evidence\": \"Co-IP, PSTPIP1 mutants and phosphorylation assays in Abl-null and PTP-PEST-deficient cells with PDGF stimulation\",\n      \"pmids\": [\"11163214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of the ternary complex not resolved\", \"Quantitative kinetics of dephosphorylation not measured\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapping Y344 as the PTP-PEST dephosphorylation site and showing PSTPIP1 scaffolds PTP-PEST onto WASP clarified how phosphatase activity is targeted to actin regulators.\",\n      \"evidence\": \"Tryptic phosphopeptide mapping, in vitro dephosphorylation and co-expression studies\",\n      \"pmids\": [\"11711533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of scaffold assembly in vivo unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linking PAPA-causing mutations to loss of PTP-PEST binding gave the first disease-mechanism connection for PSTPIP1.\",\n      \"evidence\": \"Yeast two-hybrid binding of A230T and E250Q mutants plus genetic sequencing in PAPA families\",\n      \"pmids\": [\"11971877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting reduced phosphatase binding to inflammation not yet established\", \"Single-method binding assay\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovering the PSTPIP1-pyrin interaction and showing disease mutants are hyperphosphorylated with increased pyrin binding reframed PSTPIP1 as an inflammatory regulator, and defining the CD2/CD2AP-WASp synapse axis tied it to T cell actin dynamics.\",\n      \"evidence\": \"Co-IP from THP-1 cells, domain-deletion mapping, c-Abl phosphorylation assays and patient IL-1\\u03b2 measurement; co-IP and synapse assays in WASp-deficient T cells\",\n      \"pmids\": [\"14595024\", \"12530983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mutant-enhanced pyrin binding unresolved at this stage\", \"Direct link from pyrin binding to IL-1\\u03b2 processing mechanism not yet reconstituted\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing PSTPIP1 sequesters FasL and recruits PTP-PEST extended its adaptor function to death-ligand availability.\",\n      \"evidence\": \"Co-IP, fluorescence co-localization and cytotoxicity assays\",\n      \"pmids\": [\"16204241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without genetic loss-of-function\", \"Physiological context of FasL regulation unconfirmed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that PSTPIP1 scaffolds PTP-PEST to the CD2 signalsome to dampen TCR-proximal signaling defined its negative-regulatory role in T cell activation.\",\n      \"evidence\": \"Primary T cell transduction with PLC\\u03b31/ERK/p38 phosphorylation and cytokine readouts\",\n      \"pmids\": [\"16670297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase substrates in CD2 signalsome not enumerated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reconstituting pyrin autoinhibition relief by PSTPIP1 ligation provided the mechanistic basis for inflammasome activation and for mutant gain-of-function.\",\n      \"evidence\": \"In vitro binding, pyroptosome assembly, caspase-1 activation assays and gel filtration for oligomeric state\",\n      \"pmids\": [\"17964261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger controlling PSTPIP1-pyrin engagement in normal cells not defined\", \"Atomic-resolution structure of the complex absent\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing F-BAR-driven PSTPIP1 self-assembly into tubulin-dependent filaments and recruitment to ASC specks connected its membrane/cytoskeletal scaffolding to inflammasome aggregation.\",\n      \"evidence\": \"Deletion-construct transfection, immunofluorescence and ASC-speck co-localization with tubulin disruption\",\n      \"pmids\": [\"19584923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of filaments distinct from speck recruitment unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placing PSTPIP1 upstream of WASP in podosome/filopodia balance and showing the R405C SH3 mutant selectively loses WASP binding clarified genotype-to-cytoskeleton mechanism.\",\n      \"evidence\": \"Endogenous knockdown, R405C overexpression, WASP-inhibition epistasis, F-actin and matrix-degradation assays in macrophages\",\n      \"pmids\": [\"24421327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of cytoskeletal defect to inflammatory phenotype not bridged\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the PSTPIP1/PTPN6/SHIP1-2 complex in osteoclasts and PAMI-associated E250K/E257K enhanced pyrin binding broadened the substrate repertoire and the disease-mutation spectrum.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA depletion and bone-resorption assays; immunoprecipitation and structural modeling of disease mutants; HL-60 leading-edge co-localization\",\n      \"pmids\": [\"27760174\", \"26025129\", \"26179737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of dimer electrostatic change on binding modeled but not crystallographically resolved\", \"HL-60 co-localization lacks direct interaction or perturbation evidence\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking loss-of-function PSTPIP1 mutations to defective immunological synapse F-actin and altered T cell behavior established its requirement for synapse architecture in human T cells.\",\n      \"evidence\": \"Flow cytometry F-actin, IP, IS-formation and migration assays in Jurkat and primary patient T cells\",\n      \"pmids\": [\"29432774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between F-actin preactivation and differentiation defect incomplete\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Solving the F-BAR/LYP co-structure revealed a novel proline-recognition mechanism and showed disease residues directly contact LYP, adding a structural basis for pathogenesis.\",\n      \"evidence\": \"X-ray crystallography of PSTPIP1 F-BAR alone and with LYP/PTPN22 C-terminal segment plus binding assays\",\n      \"pmids\": [\"35152348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of disrupted PSTPIP1-LYP binding not directly tested in this study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying PSTPIP1 as required for clathrin-independent L1CAM endocytosis with endophilin-A3 extended its F-BAR membrane-remodeling function to receptor trafficking.\",\n      \"evidence\": \"siRNA knockdown, fluorescence microscopy and endocytosis assays\",\n      \"pmids\": [\"36843549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across cargoes beyond L1CAM unknown\", \"Direct membrane-curvature contribution not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A genome-wide screen placing PSTPIP1 and pyrin in the same macrophage differentiation pathway connected the adaptor's cytoskeletal and inflammatory roles to a developmental program.\",\n      \"evidence\": \"GeCKO CRISPR knockout screen with KO/KI validation, immunophenotyping, RNA-seq and functional adhesion/migration assays\",\n      \"pmids\": [\"40997504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular steps linking PSTPIP1 loss to differentiation block undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defining a direct PTPN22-PSTPIP1 interaction controlling synapse actin nanoscale organization, and identifying a new pyrin-binding gain-of-function mutation (N236K), refined both the cytoskeletal-regulatory and autoinflammatory arms.\",\n      \"evidence\": \"Super-resolution DNA-PAINT with PTPN22 perturbation and calcium assays in Jurkat cells; co-IP and inflammasome assay with N236K patient characterization\",\n      \"pmids\": [\"42263152\", \"42007463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"N236K finding rests on single co-IP/inflammasome assay in case-report context\", \"How PTPN22-PSTPIP1 binding integrates with phosphatase scaffolding not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the phosphorylation switch, F-BAR membrane filaments, and pyrin ligation are coordinated under physiological triggers to toggle PSTPIP1 between actin-regulatory and inflammasome-activating states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic-resolution structure of the PSTPIP1-pyrin complex\", \"Endogenous signals controlling PSTPIP1 phosphorylation in vivo undefined\", \"Integration of endocytic and scaffolding functions unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 7, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 7, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9, 10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 12, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 11, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7, 10, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"PSTPIP1/PTP-PEST/WASP scaffold complex\",\n      \"PSTPIP1/PTPN6/SHIP1-SHIP2 complex\",\n      \"ASC pyroptosome (via pyrin)\"\n    ],\n    \"partners\": [\n      \"PTPN12\",\n      \"WAS\",\n      \"CD2\",\n      \"CD2AP\",\n      \"MEFV\",\n      \"ABL1\",\n      \"PTPN6\",\n      \"PTPN22\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}