Affinage

Showing PPFIBP1 — SGT2 is a alias.

PPFIBP1

Liprin-beta-1 · UniProt Q86W92

Length
1011 aa
Mass
114.0 kDa
Annotated
2026-06-10
41 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 High

    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

    PMID:11836260

    Open questions at the time
    • Functional consequence of S100A4-regulated phosphorylation on scaffolding not defined
    • Phospho-sites on liprin-β1 not mapped
  2. 2009 Medium

    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

    PMID:19965622

    Open questions at the time
    • Molecular mechanism linking liprin-β1 to vessel integrity unknown
    • Endothelial partners not identified
  3. 2011 High

    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

    PMID:21430068

    Open questions at the time
    • Contribution of PPFIBP1 portion (e.g. dimerization) to ALK activation not dissected
    • Tumor spectrum not fully defined
  4. 2016 Medium

    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

    PMID:26663347 PMID:27303058 PMID:27503897

    Open questions at the time
    • 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
  5. 2020 Medium

    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

    PMID:33292386

    Open questions at the time
    • Functional difference between exon 29 isoforms not characterized
    • Single deletion approach for PPFIBP1 specifically
  6. 2021 Medium

    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

    PMID:34480020

    Open questions at the time
    • Directness of SRCIN1 interaction not fully validated
    • Single tumor-type context
  7. 2022 Medium

    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

    PMID:35830857

    Open questions at the time
    • Mammalian neuronal mechanism not directly tested
    • SAM-domain partner interactions disrupted by missense variant not enumerated
  8. 2023 Medium

    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

    PMID:37619524

    Open questions at the time
    • Mechanism of RelA stabilization (e.g. degradation block) not defined
    • Reciprocal validation of binding limited
  9. 2025 High

    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

    PMID:40484382 PMID:41380968

    Open questions at the time
    • Structural basis of β1-mediated LLPS suppression not resolved
    • Whether adhesion-anchoring and LLPS suppression are coupled functions unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified structural model of PPFIBP1 domain architecture coordinating its partners
  • Tissue-specific regulation of which interactions dominate is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-1474244 Extracellular matrix organization 2 R-HSA-162582 Signal Transduction 2
Partners
KANK1PPFIA1RELAS100A4SIRT2SRCIN1
Complex memberships
talin-KANK1-liprin-β1-liprin-α1 adhesion complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Co-immunoprecipitation, immunofluorescence co-localization, deletion mapping, in vitro kinase phosphorylation assay The Journal of biological chemistry High 11836260
2011 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. Focus formation assay, in vivo tumorigenicity assay (xenograft), RT-PCR, genomic PCR, FISH Clinical cancer research High 21430068
2009 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. Gene expression profiling, in vivo loss-of-function (Xenopus tadpole model), immunostaining Blood Medium 19965622
2016 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). Proximity-dependent biotinylation (BioID), stable isotope-labeled mass spectrometry Science signaling Medium 27303058
2016 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. Immunoaffinity purification, quantitative mass spectrometry, microscopy, interaction assays Molecular & cellular proteomics Medium 27503897
2016 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. siRNA knockdown, overexpression, cell motility assays (migration, invasion), extracellular matrix degradation assay, in vivo lung metastasis assay Biology of the cell Medium 26663347
2021 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. Scratch assay, transwell assay, overexpression/knockdown, RNA-Seq, GO enrichment, western blotting for pathway activation, xenograft model, pharmacological inhibition of FAK/Src Cell death & disease Medium 34480020
2022 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. Exome/genome sequencing in human patients, C. elegans knockout behavioral phenotyping (automated), aldicarb resistance assay, structural modeling of SAM domain American journal of human genetics Medium 35830857
2023 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. Co-immunoprecipitation, overexpression/knockdown, western blotting for NF-κB pathway activation, nuclear/cytoplasmic fractionation, xenograft mouse model Translational oncology Medium 37619524
2025 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. 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 The Journal of biological chemistry High 40484382
2025 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. Co-immunoprecipitation (complex components), KANK1 knockdown, live imaging of subcellular localization, insulin secretion assay, insulin granule fusion assay The Journal of biological chemistry Medium 41380968
2020 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. CRISPR/Cas9 deletion of intronic nimtRNA, RT-PCR splicing analysis, pull-down mass spectrometry, EMSA Genome biology Medium 33292386

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing. Proceedings of the National Academy of Sciences of the United States of America 121 25737553
2001 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). The Journal of biological chemistry 114 11836260
2007 Metastasis-associated protein S100A4: spotlight on its role in cell migration. Current cancer drug targets 89 17504119
2018 Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 81 29327718
2016 Proximity biotinylation provides insight into the molecular composition of focal adhesions at the nanometer scale. Science signaling 78 27303058
2011 Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification. Clinical cancer research : an official journal of the American Association for Cancer Research 78 21430068
2017 Trinucleotide Repeat Expansion in the Transcription Factor 4 (TCF4) Gene Leads to Widespread mRNA Splicing Changes in Fuchs' Endothelial Corneal Dystrophy. Investigative ophthalmology & visual science 72 28118661
2005 Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. Oncogene 59 15750623
2009 Liprin (beta)1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity. Blood 40 19965622
2021 PPFIBP1 induces glioma cell migration and invasion through FAK/Src/JNK signaling pathway. Cell death & disease 39 34480020
2002 Detailed genomic mapping and expression analyses of 12p amplifications in pancreatic carcinomas reveal a 3.5-Mb target region for amplification. Genes, chromosomes & cancer 36 11979555
2006 Array-comparative genomic hybridization of central chondrosarcoma: identification of ribosomal protein S6 and cyclin-dependent kinase 4 as candidate target genes for genomic aberrations. Cancer 35 16779802
2016 Effects of the scaffold proteins liprin-α1, β1 and β2 on invasion by breast cancer cells. Biology of the cell 30 26663347
2016 Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking. Molecular & cellular proteomics : MCP 30 27503897
2019 The plasma peptides of breast versus ovarian cancer. Clinical proteomics 27 31889940
2003 Differences between retinal and choroidal microvascular endothelial cells (MVECs) under normal and hypoxic conditions. Experimental eye research 25 14550394
2022 Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation. Genes, chromosomes & cancer 19 35289445
2018 Melanocytic Myxoid Spindle Cell Tumor With ALK Rearrangement (MMySTAR): Report of 4 Cases of a Nevus Variant With Potential Diagnostic Challenge. The American journal of surgical pathology 17 29635259
2022 Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications. American journal of human genetics 13 35830857
2016 Role of Liprins in the Regulation of Tumor Cell Motility and Invasion. Current cancer drug targets 13 26882029
2022 Whole exome sequencing reveals the genetic heterogeneity and evolutionary history of primary gliomas and matched recurrences. Computational and structural biotechnology journal 12 35615029
2023 Genetic diagnosis of fetal microcephaly at a single tertiary center in China. Frontiers in genetics 11 37229200
2020 Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing. Genome biology 9 33292386
2021 ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis. Histopathology 6 34231248
2023 Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas. Neuro-oncology 5 35738865
2025 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. The American journal of surgical pathology 3 41097820
2023 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. Scientific reports 3 37563198
2023 PPFIBP1 activates NF-κB signaling to enhance chemoresistance of multiple myeloma. Translational oncology 3 37619524
2022 A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1-associated neurodevelopmental disorder. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 3 36527195
2015 Identifying genes that mediate anthracyline toxicity in immune cells. Frontiers in pharmacology 2 25926793
2025 NTRK3-rearranged spindle cell neoplasm of the skin: diagnostic pitfalls of an emerging entity, a case report. Acta dermatovenerologica Alpina, Pannonica, et Adriatica 1 39955644
2025 Exploring the hepatic-ophthalmic axis through immune modulation and cellular dynamics in diabetic retinopathy and non-alcoholic fatty liver disease. Human genomics 1 40011971
2025 The phosphatase activity of the PPP2R5D-PP2A holoenzyme modulates liprin-α1 liquid-liquid phase separation. The Journal of biological chemistry 1 40484382
2025 Genome-wide association study reveals candidate genes associated with egg-laying performance in Wuhua yellow chicken. Poultry science 1 40884866
2024 Development and Validation of Diagnostic Models for Transcriptomic Signature Genes for Multiple Tissues in Osteoarthritis. Journal of inflammation research 1 39099665
2026 Interstitial 12p Deletion Syndrome: Revised Minimal Critical Region and Review of the Literature. Genes 0 41595523
2026 Identification of NTRK3 fusions in plaque-like CD34-positive dermal fibroma. Histopathology 0 41755369
2026 Detecting Rare ALK Gene Fusions in Unclassified Spindle Cell Lung Tumors Using Anchored Multiplex PCR/Targeted RNA Next-Generation Sequencing. Genes, chromosomes & cancer 0 42222974
2025 Epithelioid Fibrous Histiocytoma (EFH) With Rare PPFIBP1-ALK Fusion: A Predominantly Spindle Cell Variant Within the Emerging Spectrum of Myxoid Spindle Cell EFH. Cureus 0 40688914
2025 KANK1 regulates the positioning of liprin-α1 and the spatial organization of insulin granule fusion in pancreatic β cells. The Journal of biological chemistry 0 41380968
2023 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. Research square 0 37034680

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