{"gene":"PPFIBP1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2001,"finding":"S100A4 (Mts1) directly interacts with liprin-β1 (PPFIBP1) in vivo, as demonstrated by immunoprecipitation. Co-localization was observed in the cytoplasm and at plasma membrane protrusion sites. The S100A4 binding site was mapped to the C-terminus of liprin-β1 between amino acid residues 938 and 1005. S100A4-liprin-β1 interaction resulted in inhibition of liprin-β1 phosphorylation by protein kinase C and protein kinase CK2 in vitro.","method":"Co-immunoprecipitation, immunofluorescence co-localization, deletion mapping, in vitro kinase phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, binding site mapped by deletion analysis, and functional consequence (inhibition of phosphorylation) confirmed by in vitro kinase assay; multiple orthogonal methods in single study","pmids":["11836260"],"is_preprint":false},{"year":2011,"finding":"PPFIBP1-ALK fusion protein (generated by chromosomal rearrangement) has oncogenic/transforming activity, as demonstrated by focus formation assay and in vivo tumorigenicity assay using 3T3 fibroblasts infected with a retrovirus encoding PPFIBP1-ALK.","method":"Focus formation assay, in vivo tumorigenicity assay (xenograft), RT-PCR, genomic PCR, FISH","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution (focus formation + in vivo tumorigenicity) with multiple confirmatory methods for fusion identification; single lab but two orthogonal functional assays","pmids":["21430068"],"is_preprint":false},{"year":2009,"finding":"Liprin-β1 (PPFIBP1) is highly expressed in lymphatic endothelial cells and plays an important role in the maintenance of lymphatic vessel integrity, as demonstrated by loss-of-function experiments in Xenopus tadpoles showing disrupted lymphatic vessel integrity upon liprin-β1 knockdown.","method":"Gene expression profiling, in vivo loss-of-function (Xenopus tadpole model), immunostaining","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined phenotypic readout (vessel integrity) in Xenopus model; single lab, limited mechanistic detail beyond localization and integrity","pmids":["19965622"],"is_preprint":false},{"year":2016,"finding":"Liprin-β1 (PPFIBP1) was identified as a proximal component of focal adhesions (within 15–25 nm of kindlin-2/β-integrin) by proximity-dependent biotinylation (BioID), establishing its localization at the adhesome near the plasma membrane. Liprin-β1 was identified as a novel binding partner for kindlin-2 (an endocytosis-promoting protein context).","method":"Proximity-dependent biotinylation (BioID), stable isotope-labeled mass spectrometry","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID proximity labeling with quantitative MS; single lab, proximity-based rather than direct binding confirmation","pmids":["27303058"],"is_preprint":false},{"year":2016,"finding":"SIRT2 interacts with liprin-β1 (PPFIBP1) and they co-regulate each other; SIRT2 localizes to the ER-Golgi intermediate compartment (ERGIC) and this interaction was established by microscopy and interaction assays in primary human fibroblasts. SIRT2 levels affect the cellular proteome including proteins functioning in membrane trafficking.","method":"Immunoaffinity purification, quantitative mass spectrometry, microscopy, interaction assays","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays with microscopy colocalization; single lab, limited mechanistic depth on the PPFIBP1 side specifically","pmids":["27503897"],"is_preprint":false},{"year":2016,"finding":"Liprin-β1 (PPFIBP1) contributes positively to tumor cell motility in vitro in MDA-MB-231 breast cancer cells, whereas liprin-β2 has a negative effect. Liprin-β1 also differentially affects extracellular matrix degradation by invadopodia. These roles were established by siRNA knockdown and overexpression experiments with defined motility and invasion phenotypic readouts.","method":"siRNA knockdown, overexpression, cell motility assays (migration, invasion), extracellular matrix degradation assay, in vivo lung metastasis assay","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes (motility, invasion, ECM degradation); single lab, multiple orthogonal assays","pmids":["26663347"],"is_preprint":false},{"year":2021,"finding":"PPFIBP1 promotes glioma cell invasion and migration through the FAK/Src/JNK signaling pathway. Overexpression of PPFIBP1 activates FAK, Src, c-Jun N-terminal kinase (JNK), and c-Jun, enhancing MMP-2 expression, potentially through interaction with SRCIN1 (p140Cap). Inhibition of Src and FAK phosphorylation reversed PPFIBP1-overexpression-induced invasion. PPFIBP1 promotes tumor infiltration and reduces survival in xenograft models.","method":"Scratch assay, transwell assay, overexpression/knockdown, RNA-Seq, GO enrichment, western blotting for pathway activation, xenograft model, pharmacological inhibition of FAK/Src","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain-of-function with defined phenotype, pathway activation measured, pharmacological rescue; single lab with multiple orthogonal methods","pmids":["34480020"],"is_preprint":false},{"year":2022,"finding":"Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder. In C. elegans, PPFIBP1/hlb-1 knockout revealed defects in spontaneous and light-induced behavior and resistance to the acetylcholinesterase inhibitor aldicarb, indicating a defect in the neuronal presynaptic zone. A missense variant in the SAM domain (predicted to disturb SAM domain topology essential for protein-protein interaction) was also identified.","method":"Exome/genome sequencing in human patients, C. elegans knockout behavioral phenotyping (automated), aldicarb resistance assay, structural modeling of SAM domain","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function in C. elegans with behavioral and pharmacological readouts establishing presynaptic role; structural prediction supporting SAM domain function; corroborated by human genetics","pmids":["35830857"],"is_preprint":false},{"year":2023,"finding":"PPFIBP1 directly binds and stabilizes RelA (NF-κB subunit), promotes cytoplasm-to-nucleus translocation of RelA, and activates NF-κB signaling in multiple myeloma cells, thereby enhancing chemoresistance to bortezomib. This was demonstrated by co-immunoprecipitation and functional rescue experiments.","method":"Co-immunoprecipitation, overexpression/knockdown, western blotting for NF-κB pathway activation, nuclear/cytoplasmic fractionation, xenograft mouse model","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding (Co-IP) plus nuclear translocation assay and functional consequence (chemoresistance); single lab with multiple orthogonal methods","pmids":["37619524"],"is_preprint":false},{"year":2025,"finding":"Liprin-β1 (PPFIBP1) is a potent inhibitor of liprin-α1 liquid-liquid phase separation (LLPS). Liprin-α1/β1 heterodimerization is regulated by PP2A-PPP2R5D-mediated dephosphorylation of liprin-α1. A liprin-α1 E942A mutant unable to bind liprin-β1 underwent increased LLPS. Under conditions promoting liprin-α1 LLPS (SLiM4 or S763E mutation, or PPP2R5D KO/E420K cells), liprin-α1/β1 heterodimerization was significantly decreased, indicating that β1 binding suppresses α1 LLPS.","method":"Mass spectrometry-based interactomics, mutagenesis (E942A liprin-α1), GFP-liprin-α1 LLPS imaging in HEK293 cells, PPP2R5D KO cells, phospho-specific antibody, phospho-mimetic mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, KO cells, phospho-mimetic and phospho-dead mutants, quantitative imaging of LLPS, and phospho-specific antibody validation in a single rigorous study","pmids":["40484382"],"is_preprint":false},{"year":2025,"finding":"KANK1 is a component of a complex that links the focal adhesion protein talin to liprin-β1 (PPFIBP1), which in turn anchors liprin-α1 through binding at its C-terminus. KANK1 knockdown disrupts the subcellular localization of liprin-α1 in pancreatic β cells, and this complex positions insulin granule fusion at the capillary interface.","method":"Co-immunoprecipitation (complex components), KANK1 knockdown, live imaging of subcellular localization, insulin secretion assay, insulin granule fusion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex identified by Co-IP, knockdown with defined localization and secretion phenotype; single lab with multiple functional readouts","pmids":["41380968"],"is_preprint":false},{"year":2020,"finding":"A nuclear intronic mitochondrial-derived tRNA (nimtRNALys) within intron 28 of the PPFIBP1 gene regulates splicing of exon 29. CRISPR/Cas9-mediated partial deletion of this endogenous nimtRNALys decreased inclusion of the downstream exon 29 of PPFIBP1 mRNA, demonstrating that the intronic element regulates alternative splicing of PPFIBP1.","method":"CRISPR/Cas9 deletion of intronic nimtRNA, RT-PCR splicing analysis, pull-down mass spectrometry, EMSA","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct CRISPR loss-of-function with defined splicing phenotype; single lab, single method for PPFIBP1 specifically","pmids":["33292386"],"is_preprint":false}],"current_model":"PPFIBP1/liprin-β1 is a cytoplasmic scaffold protein that (1) interacts with liprin-α1 to heterodimerize and suppress liprin-α1 liquid-liquid phase separation, a process regulated by PP2A-mediated dephosphorylation; (2) links focal adhesion components (talin via KANK1) to liprin-α1 to position insulin granule fusion and regulate focal adhesion dynamics; (3) binds S100A4, which inhibits liprin-β1 phosphorylation by PKC and CK2; (4) interacts with SIRT2 at the ER-Golgi compartment; (5) activates FAK/Src/JNK signaling to promote glioma cell invasion via interaction with SRCIN1; (6) stabilizes RelA and promotes NF-κB nuclear translocation to drive chemoresistance; (7) is essential for neuronal presynaptic zone function (established by C. elegans knockout); (8) maintains lymphatic vessel integrity; and (9) acts as a fusion partner for ALK and other kinases (generating oncogenic fusion proteins with transforming activity) in various tumor types."},"narrative":{"mechanistic_narrative":"PPFIBP1 (liprin-β1) is a cytoplasmic scaffold protein that organizes liprin-α complexes at adhesion and presynaptic sites, coordinating cell adhesion, motility, and secretory function [PMID:40484382, PMID:41380968, PMID:35830857]. It heterodimerizes with liprin-α1 and acts as a potent suppressor of liprin-α1 liquid-liquid phase separation, a binding event gated by PP2A-PPP2R5D-mediated dephosphorylation of liprin-α1; a liprin-α1 E942A mutant unable to bind liprin-β1 undergoes increased phase separation [PMID:40484382]. Through KANK1, liprin-β1 links the focal-adhesion protein talin to liprin-α1, anchoring liprin-α1 at its C-terminus and positioning insulin granule fusion at the capillary interface [PMID:41380968], and it sits proximal to the kindlin-2/β-integrin adhesome near the plasma membrane [PMID:27303058]. Its scaffolding output is modulated by S100A4, which binds the liprin-β1 C-terminus and inhibits its phosphorylation by PKC and CK2 [PMID:11836260]. In cancer contexts PPFIBP1 promotes invasion through FAK/Src/JNK signaling via SRCIN1 [PMID:34480020] and stabilizes RelA to drive NF-κB nuclear translocation and chemoresistance [PMID:37619524]. Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder, with C. elegans knockout revealing a presynaptic zone defect [PMID:35830857]. PPFIBP1 also serves as a 5' fusion partner that confers transforming activity on ALK in rearranged tumors [PMID:21430068].","teleology":[{"year":2001,"claim":"Established the first regulatory input on liprin-β1, showing its phosphorylation state is controlled by a direct protein partner.","evidence":"Reciprocal co-IP, deletion mapping, and in vitro kinase assays in cells","pmids":["11836260"],"confidence":"High","gaps":["Functional consequence of S100A4-regulated phosphorylation on scaffolding not defined","Phospho-sites on liprin-β1 not mapped"]},{"year":2009,"claim":"Assigned an in vivo physiological role by showing liprin-β1 is required for lymphatic vessel integrity.","evidence":"Expression profiling and loss-of-function knockdown in Xenopus tadpoles","pmids":["19965622"],"confidence":"Medium","gaps":["Molecular mechanism linking liprin-β1 to vessel integrity unknown","Endothelial partners not identified"]},{"year":2011,"claim":"Demonstrated that genomic rearrangement converts PPFIBP1 into an oncogenic driver by fusing it to ALK.","evidence":"Focus formation and in vivo tumorigenicity assays in 3T3 fibroblasts with fusion confirmation","pmids":["21430068"],"confidence":"High","gaps":["Contribution of PPFIBP1 portion (e.g. dimerization) to ALK activation not dissected","Tumor spectrum not fully defined"]},{"year":2016,"claim":"Placed liprin-β1 within the focal-adhesion machinery and identified new interactors, linking it to adhesion and motility.","evidence":"BioID proximity labeling/MS at the adhesome, SIRT2 interaction assays, and knockdown/overexpression motility/invasion assays across studies","pmids":["27303058","27503897","26663347"],"confidence":"Medium","gaps":["BioID is proximity-based, not direct binding for kindlin-2","Mechanism of differential liprin-β1 vs β2 effect on motility unresolved","Functional consequence of SIRT2 interaction on PPFIBP1 unclear"]},{"year":2020,"claim":"Revealed that an intronic element embedded in the PPFIBP1 gene controls its own alternative splicing.","evidence":"CRISPR/Cas9 deletion of intronic nimtRNALys with RT-PCR splicing readout","pmids":["33292386"],"confidence":"Medium","gaps":["Functional difference between exon 29 isoforms not characterized","Single deletion approach for PPFIBP1 specifically"]},{"year":2021,"claim":"Mechanistically connected PPFIBP1 to invasive signaling through FAK/Src/JNK activation in glioma.","evidence":"Gain/loss-of-function, RNA-Seq, pathway western blots, pharmacological FAK/Src inhibition, and xenografts","pmids":["34480020"],"confidence":"Medium","gaps":["Directness of SRCIN1 interaction not fully validated","Single tumor-type context"]},{"year":2022,"claim":"Defined PPFIBP1 as essential for presynaptic zone function and causally linked it to human neurodevelopmental disease.","evidence":"Human exome/genome sequencing plus C. elegans hlb-1 knockout behavioral and aldicarb assays with SAM-domain structural modeling","pmids":["35830857"],"confidence":"Medium","gaps":["Mammalian neuronal mechanism not directly tested","SAM-domain partner interactions disrupted by missense variant not enumerated"]},{"year":2023,"claim":"Identified a nuclear/transcriptional output by which PPFIBP1 stabilizes RelA to activate NF-κB and drive chemoresistance.","evidence":"Co-IP, nuclear/cytoplasmic fractionation, NF-κB pathway westerns, and xenografts in multiple myeloma","pmids":["37619524"],"confidence":"Medium","gaps":["Mechanism of RelA stabilization (e.g. degradation block) not defined","Reciprocal validation of binding limited"]},{"year":2025,"claim":"Defined the core biochemical function: liprin-β1 suppresses liprin-α1 phase separation and bridges talin to liprin-α1 to spatially organize secretion.","evidence":"Interactomics, E942A and phospho-mimetic mutagenesis, PPP2R5D KO cells, LLPS imaging, and KANK1-knockdown insulin granule fusion assays","pmids":["40484382","41380968"],"confidence":"High","gaps":["Structural basis of β1-mediated LLPS suppression not resolved","Whether adhesion-anchoring and LLPS suppression are coupled functions unclear"]},{"year":null,"claim":"How the distinct activities of PPFIBP1 — LLPS suppression, adhesome scaffolding, presynaptic function, and pro-oncogenic signaling — are integrated or differentially deployed across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of PPFIBP1 domain architecture coordinating its partners","Tissue-specific regulation of which interactions dominate is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8]}],"complexes":["talin-KANK1-liprin-β1-liprin-α1 adhesion complex"],"partners":["PPFIA1","KANK1","S100A4","SIRT2","RELA","SRCIN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86W92","full_name":"Liprin-beta-1","aliases":["Protein tyrosine phosphatase receptor type f polypeptide-interacting protein-binding protein 1","PTPRF-interacting protein-binding protein 1","hSGT2"],"length_aa":1011,"mass_kda":114.0,"function":"May regulate the disassembly of focal adhesions. Did not bind receptor-like tyrosine phosphatases type 2A","subcellular_location":"Cytoplasm, cell cortex","url":"https://www.uniprot.org/uniprotkb/Q86W92/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPFIBP1","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":"CAPZB","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPFIBP1","total_profiled":1310},"omim":[{"mim_id":"620024","title":"NEURODEVELOPMENTAL DISORDER WITH SEIZURES, MICROCEPHALY, AND BRAIN ABNORMALITIES; NEDSMBA","url":"https://www.omim.org/entry/620024"},{"mim_id":"611054","title":"PTPRF-INTERACTING PROTEIN ALPHA-1; PPFIA1","url":"https://www.omim.org/entry/611054"},{"mim_id":"603141","title":"PPFIA-BINDING PROTEIN 1; PPFIBP1","url":"https://www.omim.org/entry/603141"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPFIBP1"},"hgnc":{"alias_symbol":["L2","hSGT2","hSgt2p","SGT2","liprin-beta1"],"prev_symbol":[]},"alphafold":{"accession":"Q86W92","domains":[{"cath_id":"1.10.150.50","chopping":"765-903","consensus_level":"medium","plddt":92.2983,"start":765,"end":903}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86W92","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86W92-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86W92-F1-predicted_aligned_error_v6.png","plddt_mean":67.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPFIBP1","jax_strain_url":"https://www.jax.org/strain/search?query=PPFIBP1"},"sequence":{"accession":"Q86W92","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86W92.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86W92/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86W92"}},"corpus_meta":[{"pmid":"25737553","id":"PMC_25737553","title":"Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25737553","citation_count":121,"is_preprint":false},{"pmid":"11836260","id":"PMC_11836260","title":"Liprin beta 1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, is a new target for the metastasis-associated protein S100A4 (Mts1).","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11836260","citation_count":114,"is_preprint":false},{"pmid":"17504119","id":"PMC_17504119","title":"Metastasis-associated protein S100A4: spotlight on its role in cell migration.","date":"2007","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/17504119","citation_count":89,"is_preprint":false},{"pmid":"29327718","id":"PMC_29327718","title":"Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases.","date":"2018","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/29327718","citation_count":81,"is_preprint":false},{"pmid":"21430068","id":"PMC_21430068","title":"Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/21430068","citation_count":78,"is_preprint":false},{"pmid":"27303058","id":"PMC_27303058","title":"Proximity biotinylation provides insight into the molecular composition of focal adhesions at the nanometer scale.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/27303058","citation_count":78,"is_preprint":false},{"pmid":"28118661","id":"PMC_28118661","title":"Trinucleotide Repeat Expansion in the Transcription Factor 4 (TCF4) Gene Leads to Widespread mRNA Splicing Changes in Fuchs' Endothelial Corneal Dystrophy.","date":"2017","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/28118661","citation_count":72,"is_preprint":false},{"pmid":"15750623","id":"PMC_15750623","title":"Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15750623","citation_count":59,"is_preprint":false},{"pmid":"19965622","id":"PMC_19965622","title":"Liprin (beta)1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19965622","citation_count":40,"is_preprint":false},{"pmid":"34480020","id":"PMC_34480020","title":"PPFIBP1 induces glioma cell migration and invasion through FAK/Src/JNK signaling pathway.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34480020","citation_count":39,"is_preprint":false},{"pmid":"11979555","id":"PMC_11979555","title":"Detailed genomic mapping and expression analyses of 12p amplifications in pancreatic carcinomas reveal a 3.5-Mb target region for amplification.","date":"2002","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11979555","citation_count":36,"is_preprint":false},{"pmid":"16779802","id":"PMC_16779802","title":"Array-comparative genomic hybridization of central chondrosarcoma: identification of ribosomal protein S6 and cyclin-dependent kinase 4 as candidate target genes for genomic aberrations.","date":"2006","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16779802","citation_count":35,"is_preprint":false},{"pmid":"26663347","id":"PMC_26663347","title":"Effects of the scaffold proteins liprin-α1, β1 and β2 on invasion by breast cancer cells.","date":"2016","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26663347","citation_count":30,"is_preprint":false},{"pmid":"27503897","id":"PMC_27503897","title":"Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking.","date":"2016","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/27503897","citation_count":30,"is_preprint":false},{"pmid":"31889940","id":"PMC_31889940","title":"The plasma peptides of breast versus ovarian cancer.","date":"2019","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/31889940","citation_count":27,"is_preprint":false},{"pmid":"14550394","id":"PMC_14550394","title":"Differences between retinal and choroidal microvascular endothelial cells (MVECs) under normal and hypoxic conditions.","date":"2003","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/14550394","citation_count":25,"is_preprint":false},{"pmid":"35289445","id":"PMC_35289445","title":"Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation.","date":"2022","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35289445","citation_count":19,"is_preprint":false},{"pmid":"29635259","id":"PMC_29635259","title":"Melanocytic Myxoid Spindle Cell Tumor With ALK Rearrangement (MMySTAR): Report of 4 Cases of a Nevus Variant With Potential Diagnostic Challenge.","date":"2018","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29635259","citation_count":17,"is_preprint":false},{"pmid":"35830857","id":"PMC_35830857","title":"Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35830857","citation_count":13,"is_preprint":false},{"pmid":"26882029","id":"PMC_26882029","title":"Role of Liprins in the Regulation of Tumor Cell Motility and Invasion.","date":"2016","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/26882029","citation_count":13,"is_preprint":false},{"pmid":"35615029","id":"PMC_35615029","title":"Whole exome sequencing reveals the genetic heterogeneity and evolutionary history of primary gliomas and matched recurrences.","date":"2022","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/35615029","citation_count":12,"is_preprint":false},{"pmid":"37229200","id":"PMC_37229200","title":"Genetic diagnosis of fetal microcephaly at a single tertiary center in China.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37229200","citation_count":11,"is_preprint":false},{"pmid":"33292386","id":"PMC_33292386","title":"Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing.","date":"2020","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/33292386","citation_count":9,"is_preprint":false},{"pmid":"34231248","id":"PMC_34231248","title":"ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis.","date":"2021","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/34231248","citation_count":6,"is_preprint":false},{"pmid":"35738865","id":"PMC_35738865","title":"Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas.","date":"2023","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35738865","citation_count":5,"is_preprint":false},{"pmid":"36527195","id":"PMC_36527195","title":"A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1-associated neurodevelopmental disorder.","date":"2022","source":"International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36527195","citation_count":3,"is_preprint":false},{"pmid":"37619524","id":"PMC_37619524","title":"PPFIBP1 activates NF-κB signaling to enhance chemoresistance of multiple myeloma.","date":"2023","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37619524","citation_count":3,"is_preprint":false},{"pmid":"41097820","id":"PMC_41097820","title":"Molecular Heterogeneity and Clinicopathologic Correlations in Inflammatory Myofibroblastic Tumors of the Urinary Bladder: A Study of 20 Cases With Predominant FN1::ALK Fusions and Novel Kinase Rearrangements.","date":"2025","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41097820","citation_count":3,"is_preprint":false},{"pmid":"37563198","id":"PMC_37563198","title":"A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37563198","citation_count":3,"is_preprint":false},{"pmid":"25926793","id":"PMC_25926793","title":"Identifying genes that mediate anthracyline toxicity in immune cells.","date":"2015","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25926793","citation_count":2,"is_preprint":false},{"pmid":"40484382","id":"PMC_40484382","title":"The phosphatase activity of the PPP2R5D-PP2A holoenzyme modulates liprin-α1 liquid-liquid phase separation.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40484382","citation_count":1,"is_preprint":false},{"pmid":"39099665","id":"PMC_39099665","title":"Development and Validation of Diagnostic Models for Transcriptomic Signature Genes for Multiple Tissues in Osteoarthritis.","date":"2024","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/39099665","citation_count":1,"is_preprint":false},{"pmid":"40011971","id":"PMC_40011971","title":"Exploring the hepatic-ophthalmic axis through immune modulation and cellular dynamics in diabetic retinopathy and non-alcoholic fatty liver disease.","date":"2025","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40011971","citation_count":1,"is_preprint":false},{"pmid":"39955644","id":"PMC_39955644","title":"NTRK3-rearranged spindle cell neoplasm of the skin: diagnostic pitfalls of an emerging entity, a case report.","date":"2025","source":"Acta dermatovenerologica Alpina, Pannonica, et Adriatica","url":"https://pubmed.ncbi.nlm.nih.gov/39955644","citation_count":1,"is_preprint":false},{"pmid":"40884866","id":"PMC_40884866","title":"Genome-wide association study reveals candidate genes associated with egg-laying performance in Wuhua yellow chicken.","date":"2025","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/40884866","citation_count":1,"is_preprint":false},{"pmid":"40688914","id":"PMC_40688914","title":"Epithelioid Fibrous Histiocytoma (EFH) With Rare PPFIBP1-ALK Fusion: A Predominantly Spindle Cell Variant Within the Emerging Spectrum of Myxoid Spindle Cell EFH.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/40688914","citation_count":0,"is_preprint":false},{"pmid":"41755369","id":"PMC_41755369","title":"Identification of NTRK3 fusions in plaque-like CD34-positive dermal fibroma.","date":"2026","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/41755369","citation_count":0,"is_preprint":false},{"pmid":"37034680","id":"PMC_37034680","title":"A microdeletion del(12)(p11.21p11.23) with a cryptic unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37034680","citation_count":0,"is_preprint":false},{"pmid":"41380968","id":"PMC_41380968","title":"KANK1 regulates the positioning of liprin-α1 and the spatial organization of insulin granule fusion in pancreatic β cells.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41380968","citation_count":0,"is_preprint":false},{"pmid":"42222974","id":"PMC_42222974","title":"Detecting Rare ALK Gene Fusions in Unclassified Spindle Cell Lung Tumors Using Anchored Multiplex PCR/Targeted RNA Next-Generation Sequencing.","date":"2026","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/42222974","citation_count":0,"is_preprint":false},{"pmid":"41595523","id":"PMC_41595523","title":"Interstitial 12p Deletion Syndrome: Revised Minimal Critical Region and Review of the Literature.","date":"2026","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41595523","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24558,"output_tokens":3518,"usd":0.063222,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11238,"output_tokens":3111,"usd":0.066983,"stage2_stop_reason":"end_turn"},"total_usd":0.130205,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"S100A4 (Mts1) directly interacts with liprin-β1 (PPFIBP1) in vivo, as demonstrated by immunoprecipitation. Co-localization was observed in the cytoplasm and at plasma membrane protrusion sites. The S100A4 binding site was mapped to the C-terminus of liprin-β1 between amino acid residues 938 and 1005. S100A4-liprin-β1 interaction resulted in inhibition of liprin-β1 phosphorylation by protein kinase C and protein kinase CK2 in vitro.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, deletion mapping, in vitro kinase phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, binding site mapped by deletion analysis, and functional consequence (inhibition of phosphorylation) confirmed by in vitro kinase assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"11836260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PPFIBP1-ALK fusion protein (generated by chromosomal rearrangement) has oncogenic/transforming activity, as demonstrated by focus formation assay and in vivo tumorigenicity assay using 3T3 fibroblasts infected with a retrovirus encoding PPFIBP1-ALK.\",\n      \"method\": \"Focus formation assay, in vivo tumorigenicity assay (xenograft), RT-PCR, genomic PCR, FISH\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution (focus formation + in vivo tumorigenicity) with multiple confirmatory methods for fusion identification; single lab but two orthogonal functional assays\",\n      \"pmids\": [\"21430068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Liprin-β1 (PPFIBP1) is highly expressed in lymphatic endothelial cells and plays an important role in the maintenance of lymphatic vessel integrity, as demonstrated by loss-of-function experiments in Xenopus tadpoles showing disrupted lymphatic vessel integrity upon liprin-β1 knockdown.\",\n      \"method\": \"Gene expression profiling, in vivo loss-of-function (Xenopus tadpole model), immunostaining\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined phenotypic readout (vessel integrity) in Xenopus model; single lab, limited mechanistic detail beyond localization and integrity\",\n      \"pmids\": [\"19965622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Liprin-β1 (PPFIBP1) was identified as a proximal component of focal adhesions (within 15–25 nm of kindlin-2/β-integrin) by proximity-dependent biotinylation (BioID), establishing its localization at the adhesome near the plasma membrane. Liprin-β1 was identified as a novel binding partner for kindlin-2 (an endocytosis-promoting protein context).\",\n      \"method\": \"Proximity-dependent biotinylation (BioID), stable isotope-labeled mass spectrometry\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID proximity labeling with quantitative MS; single lab, proximity-based rather than direct binding confirmation\",\n      \"pmids\": [\"27303058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT2 interacts with liprin-β1 (PPFIBP1) and they co-regulate each other; SIRT2 localizes to the ER-Golgi intermediate compartment (ERGIC) and this interaction was established by microscopy and interaction assays in primary human fibroblasts. SIRT2 levels affect the cellular proteome including proteins functioning in membrane trafficking.\",\n      \"method\": \"Immunoaffinity purification, quantitative mass spectrometry, microscopy, interaction assays\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays with microscopy colocalization; single lab, limited mechanistic depth on the PPFIBP1 side specifically\",\n      \"pmids\": [\"27503897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Liprin-β1 (PPFIBP1) contributes positively to tumor cell motility in vitro in MDA-MB-231 breast cancer cells, whereas liprin-β2 has a negative effect. Liprin-β1 also differentially affects extracellular matrix degradation by invadopodia. These roles were established by siRNA knockdown and overexpression experiments with defined motility and invasion phenotypic readouts.\",\n      \"method\": \"siRNA knockdown, overexpression, cell motility assays (migration, invasion), extracellular matrix degradation assay, in vivo lung metastasis assay\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes (motility, invasion, ECM degradation); single lab, multiple orthogonal assays\",\n      \"pmids\": [\"26663347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPFIBP1 promotes glioma cell invasion and migration through the FAK/Src/JNK signaling pathway. Overexpression of PPFIBP1 activates FAK, Src, c-Jun N-terminal kinase (JNK), and c-Jun, enhancing MMP-2 expression, potentially through interaction with SRCIN1 (p140Cap). Inhibition of Src and FAK phosphorylation reversed PPFIBP1-overexpression-induced invasion. PPFIBP1 promotes tumor infiltration and reduces survival in xenograft models.\",\n      \"method\": \"Scratch assay, transwell assay, overexpression/knockdown, RNA-Seq, GO enrichment, western blotting for pathway activation, xenograft model, pharmacological inhibition of FAK/Src\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain-of-function with defined phenotype, pathway activation measured, pharmacological rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34480020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder. In C. elegans, PPFIBP1/hlb-1 knockout revealed defects in spontaneous and light-induced behavior and resistance to the acetylcholinesterase inhibitor aldicarb, indicating a defect in the neuronal presynaptic zone. A missense variant in the SAM domain (predicted to disturb SAM domain topology essential for protein-protein interaction) was also identified.\",\n      \"method\": \"Exome/genome sequencing in human patients, C. elegans knockout behavioral phenotyping (automated), aldicarb resistance assay, structural modeling of SAM domain\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function in C. elegans with behavioral and pharmacological readouts establishing presynaptic role; structural prediction supporting SAM domain function; corroborated by human genetics\",\n      \"pmids\": [\"35830857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PPFIBP1 directly binds and stabilizes RelA (NF-κB subunit), promotes cytoplasm-to-nucleus translocation of RelA, and activates NF-κB signaling in multiple myeloma cells, thereby enhancing chemoresistance to bortezomib. This was demonstrated by co-immunoprecipitation and functional rescue experiments.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, western blotting for NF-κB pathway activation, nuclear/cytoplasmic fractionation, xenograft mouse model\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding (Co-IP) plus nuclear translocation assay and functional consequence (chemoresistance); single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37619524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Liprin-β1 (PPFIBP1) is a potent inhibitor of liprin-α1 liquid-liquid phase separation (LLPS). Liprin-α1/β1 heterodimerization is regulated by PP2A-PPP2R5D-mediated dephosphorylation of liprin-α1. A liprin-α1 E942A mutant unable to bind liprin-β1 underwent increased LLPS. Under conditions promoting liprin-α1 LLPS (SLiM4 or S763E mutation, or PPP2R5D KO/E420K cells), liprin-α1/β1 heterodimerization was significantly decreased, indicating that β1 binding suppresses α1 LLPS.\",\n      \"method\": \"Mass spectrometry-based interactomics, mutagenesis (E942A liprin-α1), GFP-liprin-α1 LLPS imaging in HEK293 cells, PPP2R5D KO cells, phospho-specific antibody, phospho-mimetic mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, KO cells, phospho-mimetic and phospho-dead mutants, quantitative imaging of LLPS, and phospho-specific antibody validation in a single rigorous study\",\n      \"pmids\": [\"40484382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KANK1 is a component of a complex that links the focal adhesion protein talin to liprin-β1 (PPFIBP1), which in turn anchors liprin-α1 through binding at its C-terminus. KANK1 knockdown disrupts the subcellular localization of liprin-α1 in pancreatic β cells, and this complex positions insulin granule fusion at the capillary interface.\",\n      \"method\": \"Co-immunoprecipitation (complex components), KANK1 knockdown, live imaging of subcellular localization, insulin secretion assay, insulin granule fusion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex identified by Co-IP, knockdown with defined localization and secretion phenotype; single lab with multiple functional readouts\",\n      \"pmids\": [\"41380968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A nuclear intronic mitochondrial-derived tRNA (nimtRNALys) within intron 28 of the PPFIBP1 gene regulates splicing of exon 29. CRISPR/Cas9-mediated partial deletion of this endogenous nimtRNALys decreased inclusion of the downstream exon 29 of PPFIBP1 mRNA, demonstrating that the intronic element regulates alternative splicing of PPFIBP1.\",\n      \"method\": \"CRISPR/Cas9 deletion of intronic nimtRNA, RT-PCR splicing analysis, pull-down mass spectrometry, EMSA\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct CRISPR loss-of-function with defined splicing phenotype; single lab, single method for PPFIBP1 specifically\",\n      \"pmids\": [\"33292386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPFIBP1/liprin-β1 is a cytoplasmic scaffold protein that (1) interacts with liprin-α1 to heterodimerize and suppress liprin-α1 liquid-liquid phase separation, a process regulated by PP2A-mediated dephosphorylation; (2) links focal adhesion components (talin via KANK1) to liprin-α1 to position insulin granule fusion and regulate focal adhesion dynamics; (3) binds S100A4, which inhibits liprin-β1 phosphorylation by PKC and CK2; (4) interacts with SIRT2 at the ER-Golgi compartment; (5) activates FAK/Src/JNK signaling to promote glioma cell invasion via interaction with SRCIN1; (6) stabilizes RelA and promotes NF-κB nuclear translocation to drive chemoresistance; (7) is essential for neuronal presynaptic zone function (established by C. elegans knockout); (8) maintains lymphatic vessel integrity; and (9) acts as a fusion partner for ALK and other kinases (generating oncogenic fusion proteins with transforming activity) in various tumor types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPFIBP1 (liprin-\\u03b21) is a cytoplasmic scaffold protein that organizes liprin-\\u03b1 complexes at adhesion and presynaptic sites, coordinating cell adhesion, motility, and secretory function [#9, #10, #7]. It heterodimerizes with liprin-\\u03b11 and acts as a potent suppressor of liprin-\\u03b11 liquid-liquid phase separation, a binding event gated by PP2A-PPP2R5D-mediated dephosphorylation of liprin-\\u03b11; a liprin-\\u03b11 E942A mutant unable to bind liprin-\\u03b21 undergoes increased phase separation [#9]. Through KANK1, liprin-\\u03b21 links the focal-adhesion protein talin to liprin-\\u03b11, anchoring liprin-\\u03b11 at its C-terminus and positioning insulin granule fusion at the capillary interface [#10], and it sits proximal to the kindlin-2/\\u03b2-integrin adhesome near the plasma membrane [#3]. Its scaffolding output is modulated by S100A4, which binds the liprin-\\u03b21 C-terminus and inhibits its phosphorylation by PKC and CK2 [#0]. In cancer contexts PPFIBP1 promotes invasion through FAK/Src/JNK signaling via SRCIN1 [#6] and stabilizes RelA to drive NF-\\u03baB nuclear translocation and chemoresistance [#8]. Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder, with C. elegans knockout revealing a presynaptic zone defect [#7]. PPFIBP1 also serves as a 5' fusion partner that confers transforming activity on ALK in rearranged tumors [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the first regulatory input on liprin-\\u03b21, showing its phosphorylation state is controlled by a direct protein partner.\",\n      \"evidence\": \"Reciprocal co-IP, deletion mapping, and in vitro kinase assays in cells\",\n      \"pmids\": [\"11836260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of S100A4-regulated phosphorylation on scaffolding not defined\", \"Phospho-sites on liprin-\\u03b21 not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Assigned an in vivo physiological role by showing liprin-\\u03b21 is required for lymphatic vessel integrity.\",\n      \"evidence\": \"Expression profiling and loss-of-function knockdown in Xenopus tadpoles\",\n      \"pmids\": [\"19965622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking liprin-\\u03b21 to vessel integrity unknown\", \"Endothelial partners not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that genomic rearrangement converts PPFIBP1 into an oncogenic driver by fusing it to ALK.\",\n      \"evidence\": \"Focus formation and in vivo tumorigenicity assays in 3T3 fibroblasts with fusion confirmation\",\n      \"pmids\": [\"21430068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of PPFIBP1 portion (e.g. dimerization) to ALK activation not dissected\", \"Tumor spectrum not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed liprin-\\u03b21 within the focal-adhesion machinery and identified new interactors, linking it to adhesion and motility.\",\n      \"evidence\": \"BioID proximity labeling/MS at the adhesome, SIRT2 interaction assays, and knockdown/overexpression motility/invasion assays across studies\",\n      \"pmids\": [\"27303058\", \"27503897\", \"26663347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BioID is proximity-based, not direct binding for kindlin-2\", \"Mechanism of differential liprin-\\u03b21 vs \\u03b22 effect on motility unresolved\", \"Functional consequence of SIRT2 interaction on PPFIBP1 unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that an intronic element embedded in the PPFIBP1 gene controls its own alternative splicing.\",\n      \"evidence\": \"CRISPR/Cas9 deletion of intronic nimtRNALys with RT-PCR splicing readout\",\n      \"pmids\": [\"33292386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional difference between exon 29 isoforms not characterized\", \"Single deletion approach for PPFIBP1 specifically\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistically connected PPFIBP1 to invasive signaling through FAK/Src/JNK activation in glioma.\",\n      \"evidence\": \"Gain/loss-of-function, RNA-Seq, pathway western blots, pharmacological FAK/Src inhibition, and xenografts\",\n      \"pmids\": [\"34480020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of SRCIN1 interaction not fully validated\", \"Single tumor-type context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined PPFIBP1 as essential for presynaptic zone function and causally linked it to human neurodevelopmental disease.\",\n      \"evidence\": \"Human exome/genome sequencing plus C. elegans hlb-1 knockout behavioral and aldicarb assays with SAM-domain structural modeling\",\n      \"pmids\": [\"35830857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian neuronal mechanism not directly tested\", \"SAM-domain partner interactions disrupted by missense variant not enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a nuclear/transcriptional output by which PPFIBP1 stabilizes RelA to activate NF-\\u03baB and drive chemoresistance.\",\n      \"evidence\": \"Co-IP, nuclear/cytoplasmic fractionation, NF-\\u03baB pathway westerns, and xenografts in multiple myeloma\",\n      \"pmids\": [\"37619524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RelA stabilization (e.g. degradation block) not defined\", \"Reciprocal validation of binding limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the core biochemical function: liprin-\\u03b21 suppresses liprin-\\u03b11 phase separation and bridges talin to liprin-\\u03b11 to spatially organize secretion.\",\n      \"evidence\": \"Interactomics, E942A and phospho-mimetic mutagenesis, PPP2R5D KO cells, LLPS imaging, and KANK1-knockdown insulin granule fusion assays\",\n      \"pmids\": [\"40484382\", \"41380968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of \\u03b21-mediated LLPS suppression not resolved\", \"Whether adhesion-anchoring and LLPS suppression are coupled functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct activities of PPFIBP1 \\u2014 LLPS suppression, adhesome scaffolding, presynaptic function, and pro-oncogenic signaling \\u2014 are integrated or differentially deployed across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of PPFIBP1 domain architecture coordinating its partners\", \"Tissue-specific regulation of which interactions dominate is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [\"talin-KANK1-liprin-\\u03b21-liprin-\\u03b11 adhesion complex\"],\n    \"partners\": [\"PPFIA1\", \"KANK1\", \"S100A4\", \"SIRT2\", \"RELA\", \"SRCIN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}