Affinage

PPFIA1

Liprin-alpha-1 · UniProt Q13136

Length
1202 aa
Mass
135.8 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPFIA1 (liprin-α1) is a multidomain scaffolding protein that organizes membrane-associated signaling platforms in both neuronal and non-neuronal cells by bridging LAR-family receptor protein tyrosine phosphatases to a defined set of cytoplasmic effectors (PMID:8524829, PMID:31924785). It associates with LAR, PTPδ, and PTPσ through its intracellular region, an interaction that depends on liprin-α1 autophosphorylation and is weakened by dephosphorylation (PMID:8524829, PMID:16313174); structurally, the liprin-α tandem SAM domains engage the LAR D1D2 phosphatase region in a conserved two-site mode, and liprin-α–driven clustering of LAR disrupts homophilic D1/D1 contacts to increase phosphatase activity (PMID:31924785, PMID:32005855). The same SAM supramodule binds the CASK kinase-like domain and mediates liprin-α/liprin-β heterodimerization, enabling assembly of higher-order CASK–liprin complexes (PMID:21855798). At presynaptic terminals liprin-α acts as a hierarchical master organizer: recruited to nascent synaptic contacts by LAR-RPTP and neurexin–CASK interactions, it then recruits ELKS and other active-zone components to enable vesicle accumulation and release, and loss of all liprin-α isoforms produces structurally normal but functionally 'empty' boutons (PMID:38472649, PMID:16186258, PMID:27015872). In non-neuronal cells liprin-α1 builds plasma-membrane-associated platforms at the protruding cell edge together with ERC1 and LL5, driving cell spreading, lamellipodial persistence, focal adhesion turnover, and recycling of active α5β1 integrin from the TGN to the surface through a Rab11B–PTPRF–PPFIA1 axis (PMID:24982445, PMID:19690048, PMID:27659488, PMID:27876801). It links these platforms to actin regulation by negatively controlling the formin mDia—binding the mDia DID domain in competition with the DAD autoinhibitory segment to restrain RhoA-driven actin polymerization (PMID:22266902, PMID:25911102)—and to GIT1/ARF-GAP and PP2A-B56 activities (PMID:21695141, PMID:18235218, PMID:36171301). Liprin-α1 higher-order assembly is governed by phosphorylation-driven liquid–liquid phase separation: an LxxIxE SLiM recruits the B56δ/B56γ PP2A holoenzyme, and PP2A-mediated dephosphorylation (including at S763) dissolves condensates and favors liprin-α/liprin-β heterodimerization (PMID:40484382, PMID:38948786, PMID:36171301, PMID:33761347). Functionally, liprin-α1 promotes breast cancer cell migration and invasion and negatively regulates MAPK/ERK signaling, while CASK disease variants that weaken liprin binding implicate this axis in MICPCH and X-linked intellectual disability (PMID:21151172, PMID:38264964, PMID:36137748, PMID:21855798).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 Medium

    Established the founding molecular link of PPFIA1, showing it physically associates with LAR-family receptor tyrosine phosphatases and might recruit them to focal adhesions.

    Evidence Co-precipitation of LIP.1 with LAR, PTPδ, PTPσ via its coiled-coil domain

    PMID:8524829

    Open questions at the time
    • Did not resolve which liprin domain contacts the phosphatase at atomic level
    • Recruitment to focal adhesions postulated, not demonstrated functionally
    • No measure of effect on phosphatase activity
  2. 2002 High

    Connected liprin-α to postsynaptic receptor organization by showing the GRIP–liprin interaction controls AMPA receptor surface clustering.

    Evidence Co-IP from brain plus dominant-negative disruption in cultured neurons

    PMID:11931740

    Open questions at the time
    • Did not separate liprin-α1 from other liprin-α isoforms
    • Mechanism of clustering downstream of GRIP binding unresolved
  3. 2003 High

    Expanded the liprin effector network to GIT1, ERC/CAST, and the kinesin KIF1A, framing liprin-α as both a synaptic scaffold and a motor cargo adaptor.

    Evidence Co-IP from brain, dominant-negative neuronal expression, sciatic nerve ligation, in vitro binding and coexpression redistribution

    PMID:12522103 PMID:12629171 PMID:12923177

    Open questions at the time
    • Direct versus indirect nature of some interactions not uniformly established
    • Whether liprin is true KIF1A receptor or capture factor unresolved at this stage
  4. 2005 High

    Defined the biochemical requirement for liprin phosphorylation in LAR binding and placed liprin-α in a presynaptic MALS/Veli complex essential for vesicle cycling.

    Evidence In vitro autophosphorylation and ATP-agarose competition with purified protein; MALS triple-knockout mice with autaptic electrophysiology

    PMID:16186258 PMID:16313174

    Open questions at the time
    • Kinase responsible for liprin autophosphorylation in vivo not identified
    • MALS knockout phenotype not isoform-specific to PPFIA1
  5. 2007 Medium

    Implicated liprin-α1 in cell motility through ING4 and PP2A B56γ associations, linking the scaffold to migration control beyond neurons.

    Evidence Co-IP, RNAi epistasis, migration assays; TAP-MS identification of B56γ

    PMID:17363573 PMID:18235218

    Open questions at the time
    • Mechanism by which ING4 acts through liprin-α1 not resolved
    • Functional consequence of B56γ association limited to morphology
  6. 2009 Medium

    Demonstrated that membrane-associated liprin-α1 drives cell spreading and lamellipodia formation, partly through LAR-RPTP interaction and talin cooperation.

    Evidence RNAi and overexpression with fibronectin spreading assays, interaction mutants, membrane fractionation

    PMID:19690048

    Open questions at the time
    • LAR-independent cell-edge function mechanistically undefined
    • Nature of talin cooperation not molecularly mapped
  7. 2010 Medium

    Showed liprin-α1 stabilizes integrin at the surface and supports invadopodium-mediated ECM degradation, tying the scaffold to integrin trafficking and invasion.

    Evidence siRNA/overexpression integrin internalization assays; time-lapse invadopodia and ECM degradation tracking in MDA-MB-231 cells

    PMID:20096687 PMID:21151172

    Open questions at the time
    • Direct integrin binding not yet shown at this stage
    • Molecular link between liprin and the internalization machinery undefined
  8. 2011 High

    Provided structural and functional mechanism for liprin SAM-domain interactions with CASK and liprin-β, and tied them to X-linked intellectual disability CASK mutants.

    Evidence Crystal structures of liprin-α/CASK and liprin-α/liprin-β SAM complexes with disease-allele mutagenesis; GIT1 functional epistasis in spreading

    PMID:21695141 PMID:21855798

    Open questions at the time
    • In vivo consequence of disrupted ternary complex not tested
    • Regulation of SAM-domain availability not addressed
  9. 2012 High

    Identified liprin-α as a negative regulator of the formin mDia, connecting the scaffold to RhoA-driven actin dynamics.

    Evidence mDia pulldown, domain mapping, DAD-competition binding, bidirectional RNAi/overexpression of stress fibers

    PMID:22266902

    Open questions at the time
    • Spatial coordination of mDia inhibition at the cell edge not resolved
    • Whether inhibition is isoform-specific not addressed here
  10. 2014 Medium

    Defined a liprin-α1–ERC1–LL5 platform driving polarized migration and active-integrin internalization, and showed PPFIA1–PP2A dephosphorylates Kif7 to control ciliary Hedgehog signaling.

    Evidence Multi-component siRNA with live imaging and invasion assays; Kif7 interactome MS, Co-IP, knockdowns and Hedgehog reporters

    PMID:24982445 PMID:25492966

    Open questions at the time
    • Structural basis of the ERC1–LL5 platform unresolved
    • Direct versus PP2A-bridged action on Kif7 not separated
  11. 2015 High

    Resolved the biophysical mechanism of mDia inhibition, showing liprin allosterically blocks RhoA·GTP activation by competing for the DAD site.

    Evidence Reconstituted in vitro binding, ITC, mutagenesis, cellular actin content with liprin-α3

    PMID:25911102

    Open questions at the time
    • Demonstrated with liprin-α3; PPFIA1-specific affinity not directly measured
    • In vivo relevance at migrating cell edge not tested
  12. 2016 High

    Established PPFIA1 as a direct active-α5β1-integrin partner acting downstream of Rab11B/PTPRF to funnel integrin recycling and fibronectin secretion, with in vivo vascular relevance, and showed it drives focal adhesion turnover with ERC1.

    Evidence Co-IP, knockdowns, pathway ordering, zebrafish morpholino; dominant-negative liprin-N with FA turnover and Rab7 endosome readouts; CASK–neurexin1β presynaptic complex characterization

    PMID:27015872 PMID:27659488 PMID:27876801

    Open questions at the time
    • Stoichiometry of the TGN-to-surface trafficking complex unresolved
    • Coupling of FA turnover to integrin recycling not mechanistically unified
  13. 2018 Medium

    Refined liprin-α's role in transport, showing it acts as a capture/recruitment factor (not core cargo) for KIF1A-delivered dense core vesicles at dendritic spines.

    Evidence KIF1A interactome MS, Co-IP, live DCV imaging, neuronal knockdown

    PMID:30021165

    Open questions at the time
    • Molecular trigger linking liprin capture to vesicle release undefined
    • PPFIA1-specific contribution among isoforms not isolated
  14. 2020 High

    Provided atomic-resolution mechanism for liprin-α engagement of LAR and PTPδ phosphatase domains and showed liprin-driven LAR clustering activates phosphatase activity and allosterically tunes liprin heterodimerization.

    Evidence Crystal structures of LAR D1D2 and PTPδ D2 with liprin SAM repeats, structure-based mutagenesis, clustering, phosphatase and synaptogenic assays

    PMID:31924785 PMID:32005855

    Open questions at the time
    • Conformational coupling between LAR binding and effector recruitment not fully resolved
    • Cellular consequences of altered LAR phosphatase activity not mapped
  15. 2021 High

    Showed liprin-α oligomerizes via its coiled-coil to drive multivalent phase separation of active-zone proteins and partition components between ELKS and RIM/RIM-BP condensates.

    Evidence Coiled-coil oligomerization analysis, cellular phase-separation assays, gain-of-function mutation

    PMID:33761347

    Open questions at the time
    • Demonstrated with liprin-α2; PPFIA1-specific condensate behavior inferred
    • Physiological regulation of intramolecular inhibition not addressed here
  16. 2022 High

    Defined an LxxIxE SLiM in liprin-α1 that recruits the PP2A-B56γ holoenzyme to plasma-membrane platforms for migration, and linked CASK disease variants to defective suppression of liprin condensates.

    Evidence SLiM point mutagenesis, Co-IP, knockdown rescue with spreading/invasion assays; patient CASK variants with condensate and phosphorylation assays

    PMID:36137748 PMID:36171301

    Open questions at the time
    • Direct PP2A substrates at the migrating edge not identified
    • Mechanism of CASK suppression of condensates partially defined
  17. 2024 High

    Established liprin-α (including PPFIA1) as the hierarchical organizer of presynaptic active-zone assembly downstream of LAR-RPTP/neurexin–CASK adhesion, and identified it as a negative regulator of MAPK/ERK oncogenic signaling.

    Evidence CRISPR quadruple liprin-α knockout in human neurons with electrophysiology and EM; cancer cell siRNA with p-ERK and RAS localization analysis

    PMID:38264964 PMID:38472649

    Open questions at the time
    • Mechanism linking liprin-α1 to RAS/ERK suppression not resolved
    • Contribution of individual liprin-α isoforms to active-zone assembly not separated
  18. 2024 High

    Resolved the phosphorylation switch controlling liprin-α1 phase separation, showing B56δ-PP2A dephosphorylates S763 to dissolve condensates and promote liprin-α/β heterodimerization, with a disease variant compromising this control.

    Evidence MS interactomics, PPP2R5D knockout, phospho-mimetic and SLiM mutagenesis, phospho-specific antibody, live-cell LLPS assays

    PMID:38948786 PMID:40484382

    Open questions at the time
    • Upstream kinases setting the S763 phospho-state in vivo not defined
    • How condensate state controls specific downstream functions not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the phosphorylation/phase-separation state of liprin-α1 is dynamically integrated with its distinct neuronal active-zone and non-neuronal migration functions in vivo remains unresolved.
  • No in vivo demonstration linking condensate state to specific physiological output
  • Isoform-specific roles of PPFIA1 versus other liprin-α genes not delineated
  • Upstream kinases controlling the autophosphorylation/LLPS switch unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2
Partners
CASKDIAPH1ERC1GIT1GRIP1KIF1APPP2R5DPTPRF
Complex memberships
MALS/Veli presynaptic complexPP2A-B56 holoenzyme (liprin-recruited)liprin-α/CASK/neurexin1β presynaptic complexliprin-α1–ERC1–LL5 plasma-membrane-associated platform

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 PPFIA1 (LIP.1) physically associates with LAR, PTPδ, and PTPσ transmembrane receptor protein tyrosine phosphatases via its intracellular coiled-coil domain, and was postulated to recruit LAR to focal adhesions. Co-precipitation / biochemical association assay Proceedings of the National Academy of Sciences of the United States of America Medium 8524829
2005 Liprin-α1 (PPFIA1) autophosphorylates and phosphorylation of liprin-α1 is required for its binding to LAR; dephosphorylation by calf intestinal phosphatase weakens the liprin–LAR interaction, and liprin binds ATP-agarose in an ATP-competable manner. In vitro phosphorylation assay with purified protein from Sf-9 cells, co-precipitation with recombinant GST-LAR, ATP-agarose binding competition, [32P]-orthophosphate labeling in vivo Biochemistry Medium 16313174
2002 Liprin-α (PPFIA1 family) interacts with the multi-PDZ protein GRIP, and dominant-negative constructs that interfere with the GRIP–liprin interaction disrupt surface expression and dendritic clustering of AMPA receptors in cultured neurons. Liprin-α and LAR-RPTP coimmunoprecipitate with GRIP and AMPA receptors from neurons. Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, immunofluorescence Neuron High 11931740
2003 Liprin-α1 (PPFIA1) directly interacts with GIT1 (an ARF-GAP); dominant-negative constructs interfering with the GIT1–liprin-α1 interaction selectively reduce dendritic and surface clustering of AMPA receptors, and GIT1 forms a complex with liprin-α1, GRIP, and AMPA receptors in brain. Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, electron microscopy of GIT1 distribution The Journal of neuroscience High 12629171
2003 Liprin-α1 (PPFIA1) interacts with the kinesin motor KIF1A; KIF1A co-accumulates with liprin-α1 in ligated sciatic nerves and co-immunoprecipitates with liprin-α1 and associated proteins (AMPA receptors, GRIP/ABP, RIM, GIT1, βPIX), suggesting liprin-α functions as a KIF1A receptor for axonal transport. Co-immunoprecipitation, sciatic nerve ligation, co-fractionation The Journal of biological chemistry Medium 12522103
2003 Liprin-α1 (PPFIA1) directly interacts with ERC/CAST proteins (ERC2/CAST and ERC1b); coexpression of ERC2 with liprin-α1 in cultured neurons redistributes liprin-α1 to synaptic sites, and liprin-α1–ERC2 complex is detected in brain by co-immunoprecipitation. In vitro direct binding assay, co-immunoprecipitation from brain, coexpression in cultured neurons with immunofluorescence The Journal of biological chemistry Medium 12923177
2005 MALS/Veli proteins form a presynaptic complex with liprin-α (PPFIA1 family); mice lacking all three MALS isoforms die perinatally with reduced excitatory synaptic transmission due to a presynaptic vesicle cycling deficit. Liprin-α was identified as a major component of the MALS complex purified from brain. Affinity purification from brain, triple knockout mouse analysis, autaptic electrophysiology The Journal of cell biology High 16186258
2007 PPFIA1 (liprin-α1) interacts with ING4 (inhibitor of growth 4); the two proteins colocalize at lamellipodia near vinculin. Overexpressed liprin-α1 enhances cell spreading and migration, while knockdown suppresses cell motility. ING4-mediated suppression of cell motility requires liprin-α1, as ING4 does not further suppress motility when liprin-α1 is knocked down. Co-immunoprecipitation, RNAi knockdown, overexpression, wound healing / migration assay, immunofluorescence colocalization Cancer research Medium 17363573
2007 Liprin-α1 (PPFIA1) interacts with PP2A B56γ regulatory subunit; B56γ–liprin-α1 complexes are biochemically distinct from PP2A complexes. Suppression of liprin-α1 alters cell morphology. Tandem affinity purification / mass spectrometry, co-immunoprecipitation, RNAi knockdown Cell cycle Medium 18235218
2009 Liprin-α1 (PPFIA1) is stably associated with the cell membrane and is required for cell spreading on fibronectin; depletion inhibits lamellipodia formation, while overexpression enhances spreading and focal adhesion formation. The effects of liprin-α1 on spreading (but not cell-edge reorganization) require its interaction with LAR-type RPTPs. Cooperation between liprin-α1 and talin is required for spreading. RNAi knockdown, overexpression, cell spreading assay on fibronectin, immunofluorescence, membrane fractionation Journal of cell science Medium 19690048
2009 mAChR-LTD in hippocampus requires interactions among GluA2, GRIP, and liprin-α (PPFIA1 family); peptides that block GRIP–GluA2 or GRIP–liprin-α binding specifically block mAChR-LTD but not mGluR-LTD, linking these interactions to AMPA receptor endocytosis during LTD. Peptide inhibition of protein–protein interaction in hippocampal slice electrophysiology, LTD induction Molecular brain Medium 19534762
2010 Liprin-α1 (PPFIA1) overexpression inhibits antibody-induced β1 integrin internalization and stabilizes integrin receptors at the cell surface; depletion of liprin-α1 by siRNA increases the rate of integrin internalization, affecting focal adhesion size and distribution of inactive β1 integrins. siRNA knockdown, overexpression, antibody-induced internalization assay, immunofluorescence, focal adhesion measurement Experimental cell research Medium 20096687
2010 Liprin-α1 (PPFIA1) is required for migration and invasion of highly invasive MDA-MB-231 breast cancer cells; its depletion causes lamellipodia instability, reduces invadopodium lifetime and ECM degradation per invadopodium, while overexpression enhances these processes. siRNA knockdown, overexpression, time-lapse microscopy, invasion assay, ECM degradation assay, cortactin-GFP tracking of invadopodia Oncogene Medium 21151172
2011 Crystal structure of liprin-α2/CASK complex shows that the three SAM domains of liprin-α form an integrated supramodule binding the CASK kinase-like domain; this interaction is unique to vertebrates. Three X-linked mental retardation CASK mutants are defective in binding liprin-α. Crystal structure of the liprin-α/liprin-β SAM domain complex reveals the mechanism of liprin heterodimerization, and a CASK/liprin-α/liprin-β ternary complex can form. X-ray crystallography, biochemical binding assays, mutagenesis of CASK disease alleles, cellular studies Molecular cell High 21855798
2011 Liprin-α1 (PPFIA1) functionally interacts with GIT1 to regulate cell spreading and migration: GIT1 depletion phenocopies liprin-α1 depletion in lamellipodia formation, and liprin-α1 may compete with paxillin for GIT1 binding. GIT1 and liprin-α1 reciprocally regulate each other's subcellular localization at focal adhesions and cell edge. siRNA knockdown, dominant-negative (liprin-ΔCC3), co-immunoprecipitation, immunofluorescence, haptotactic migration assay PloS one Medium 21695141
2012 Liprin-α (PPFIA1 family) binds mDia (a Rho-effector actin nucleator) through the central region of liprin-α and the DID-DD domains of mDia, competing with the DAD autoregulatory domain. Liprin-α overexpression decreases mDia membrane localization and attenuates Rho-mDia-mediated stress fiber formation; liprin-α depletion by RNAi increases mDia in the membrane fraction and enhances stress fiber formation. Pulldown identifying liprin-α as mDia-binding protein, domain mapping, competition binding assay, RNAi knockdown, overexpression, membrane fractionation, immunofluorescence of stress fibers Journal of cell science High 22266902
2014 PPFIA1 (liprin-α1) forms a complex with ERC1a and LL5 proteins to drive cell migration; depletion of any component reduces migration, invasion, lamellipodial persistence, and internalization of active β1 integrin at the cell front. The complex defines polarized cytoplasmic structures at the protruding cell edge. siRNA knockdown, live-cell microscopy, invasion assay, integrin internalization assay, immunofluorescence Journal of cell science Medium 24982445
2014 PPFIA1 (liprin-α1) interacts with PP2A and Kif7, and the PPFIA1–PP2A complex promotes dephosphorylation of Kif7, triggering Kif7 trafficking to the tips of primary cilia and promoting Gli transcriptional activity downstream of Hedgehog signaling. Mass spectrometry identification of Kif7 interactors, Co-IP, siRNA knockdown of PPFIA1 and PP2A, immunofluorescence of cilia, Hedgehog reporter assays Science signaling Medium 25492966
2015 Liprin-α3 binds to the mDia1 N-terminal DID domain and allosterically inhibits mDia1 activation by RhoA·GTP; liprin-α3 competes with DAD for a highly overlapping binding site on mDiaN, lowers RhoA and DAD regulatory potency, and regulates actin polymerization. Reconstituted in vitro binding and competition assays, ITC thermodynamics, mutagenesis, cellular actin filament content measurement The Journal of biological chemistry High 25911102
2016 PPFIA1 interacts with active α5β1 integrin (via direct interaction shown by Co-IP) and localizes near endothelial cell adhesions where post-Golgi carriers are targeted. PPFIA1 is required for fibronectin polymerization-dependent vascular morphogenesis both in vitro and in developing zebrafish. PPFIA1 acts downstream of Rab11B and PTPRF in a pathway (PI4KB→AP-1A→Rab11B→PTPRF→PPFIA1) that funnels FN secretion and recycling of active α5β1 integrin from the TGN to the cell surface. Co-immunoprecipitation, siRNA knockdown, immunofluorescence, zebrafish morpholino knockdown, vesicle trafficking assays Nature communications High 27876801
2016 Liprin-α1 (PPFIA1) and ERC1 promote focal adhesion turnover at the cell edge; displacement of ERC1 from the cell edge (by dominant-negative liprin-N) inhibits disassembly of focal adhesions. Liprin-α1 and ERC1 colocalize with active integrin β1 clusters distinct from cytoplasmic FA proteins and influence localization of peripheral Rab7-positive endosomes. Dominant-negative expression (liprin-N fragment), siRNA knockdown, immunofluorescence, focal adhesion turnover assay, Rab7 endosome localization Scientific reports Medium 27659488
2016 CASK stabilizes neurexin1β and creates a structural link to liprin-α at the presynaptic active zone; liprin-α and Mint1 compete for CASK binding, but neurexin1β eliminates this competition, enabling a four-protein complex. CASK phosphorylation of neurexin1β modulates the interaction of liprin-α with the CASK–neurexin1β–Mint1 complex. Co-immunoprecipitation, in vitro binding/competition assays, neuronal culture, phosphorylation assay Cellular and molecular life sciences Medium 27015872
2018 Liprin-α/TANC2 capture KIF1A-transported dense core vesicles at dendritic spines; liprin-α is not part of the KIF1A-cargo complex itself but acts as a capture/recruitment factor at postsynaptic sites. Calcium acting via calmodulin enhances KIF1A binding to DCVs and increases vesicle motility. KIF1A interactome by mass spectrometry, co-immunoprecipitation, live imaging of DCV transport, neuronal knockdown Cell reports Medium 30021165
2020 Crystal structure of LAR D1D2 in complex with liprin-α3 SAM repeats at 1.91 Å reveals a conserved two-site binding mode involving the D2 phosphatase domain. Liprin-α promotes LAR clustering in cells via both the liprin-α/LAR interaction and liprin-α oligomerization; LAR forms homophilic D1/D1 interactions that are disrupted by liprin-α-promoted clustering, and this D1/D1 disruption increases LAR phosphatase activity. LAR binding to liprin-α allosterically regulates the liprin-α/liprin-β interaction. X-ray crystallography, structure-based mutagenesis, cellular clustering assays, phosphatase activity assay Nature communications High 31924785
2020 Crystal structure of mouse PTPδ D2 domain in complex with liprin-α3 tSAM at 1.91 Å shows PTPδ D2 interacts with the N-terminal helix and SAM1/SAM2 of liprin-α3; structure-based mutations of SAM1 and SAM2 contacts abolish binding and synaptogenic activity in cellulo. X-ray crystallography, structure-based mutagenesis, synaptogenic co-culture assay Nature communications High 32005855
2021 Liprin-α proteins oligomerize via the N-terminal coiled-coil region; oligomerized liprin-α2 drives phase separation of ELKS N-terminal segments through multivalent interactions, and liprin-α2 controls protein distribution between ELKS and RIM/RIM-BP condensates. A gain-of-function mutation in the coiled-coil disrupts intramolecular inhibition and promotes intermolecular interactions. Structural and biochemical characterization of coiled-coil oligomerization, phase separation assays in cells, gain-of-function mutation analysis Cell reports High 33761347
2022 Liprin-α1 (PPFIA1) contains an LxxIxE short linear motif in its N-terminal dimerization domain that mediates interaction with the B56γ regulatory subunit of PP2A. B56γ mediates recruitment of the PP2A holoenzyme to liprin-α1. Liprin-α1 recruits B56γ to plasma membrane-associated platforms (PMAPs) at the edge of migrating MDA-MB-231 cells; silencing of B56γ inhibits cell spreading, invasion and lamellipodia dynamics similarly to liprin-α1 silencing, and this requires an intact SLiM. Co-immunoprecipitation, point mutagenesis of SLiM, siRNA knockdown, cell spreading/invasion/lamellipodia assays, immunofluorescence Communications biology High 36171301
2022 CASK CaMK domain missense variants from MICPCH patients selectively weaken binding to liprin-α2; CASK suppresses liprin-α2 phase condensate formation in HEK293T cells and primary neurons, and this suppression is associated with altered liprin-α2 phosphorylation. The p.E115K variant fails to suppress condensate formation, correlating with the severe MICPCH phenotype. Co-immunoprecipitation with patient-derived CASK variants, condensate formation assay in HEK293T and neurons, phosphorylation analysis Life science alliance Medium 36137748
2024 In human neurons lacking all four liprin-α isoforms (including PPFIA1), nascent synaptic contacts form normally but recruitment of active zone components and accumulation of synaptic vesicles is fully blocked ('empty' boutons), abolishing synaptic transmission. LAR-RPTP family adhesion molecules and neurexin–CASK interactions are required to localize liprin-α to nascent synaptic sites; liprin-α then recruits presynaptic components via direct interaction with ELKS proteins, establishing a hierarchical assembly sequence. CRISPR/Cas9 quadruple knockout of all four liprin-α isoforms in human neurons, electrophysiology, electron microscopy, immunofluorescence, interaction studies Nature neuroscience High 38472649
2024 Depletion of liprin-α1 (PPFIA1) in cancer cells leads to increased phospho-ERK1/2 levels and more pronounced RAS protein redistribution to the cell membrane, regardless of KRAS mutational status, indicating liprin-α1 negatively regulates MAPK/ERK oncogenic signaling. siRNA knockdown, Western blot for p-ERK1/2, pharmacological ERK inhibitor screen (trametinib), immunofluorescence of RAS membrane localization Molecular oncology Medium 38264964
2024 PPP2R5D (B56δ) PP2A holoenzyme interacts with liprin-α1 via an LxxIxE SLiM in its N-terminal dimerization domain; mutation of SLiM or knockout of PPP2R5D increases liprin-α1 LLPS in HEK293 cells. Phospho-mimetic S763E mutation drives liprin-α1 LLPS, and B56δ-PP2A inhibits LLPS by dephosphorylation at S763 and other sites. Liprin-α1/β1 heterodimerization is decreased under conditions promoting LLPS, and liprin-β1 itself inhibits liprin-α1 LLPS. PPP2R5D E420K variant (Houge-Janssens Syndrome) compromises suppression of liprin-α1 LLPS. MS-based interactomics, co-immunoprecipitation, PPP2R5D knockout HEK293 cells, phospho-mimetic and SLiM mutagenesis, phospho-specific antibody, LLPS assay in live cells, domain-mapping The Journal of biological chemistry (and preprint bioRxiv) High 38948786 40484382

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 308 10517634
2002 Drosophila liprin-alpha and the receptor phosphatase Dlar control synapse morphogenesis. Neuron 244 11931739
2001 Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development. Science (New York, N.Y.) 216 11161219
2002 Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron 204 11931740
1995 The LAR/PTP delta/PTP sigma subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTP delta, and PTP sigma isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proceedings of the National Academy of Sciences of the United States of America 188 8524829
2006 SYD-2 Liprin-alpha organizes presynaptic active zone formation through ELKS. Nature neuroscience 179 17115037
2003 Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha. The Journal of biological chemistry 164 12522103
2003 Interaction of the ERC family of RIM-binding proteins with the liprin-alpha family of multidomain proteins. The Journal of biological chemistry 147 12923177
2003 Interaction between liprin-alpha and GIT1 is required for AMPA receptor targeting. The Journal of neuroscience : the official journal of the Society for Neuroscience 131 12629171
2005 Direct observation demonstrates that Liprin-alpha is required for trafficking of synaptic vesicles. Current biology : CB 119 15823543
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
2005 Neurotransmitter release regulated by a MALS-liprin-alpha presynaptic complex. The Journal of cell biology 109 16186258
2007 Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Cancer research 108 17363573
2013 Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. The Journal of cell biology 93 23751498
2021 PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure. Nature communications 84 34031393
2011 Liprin-mediated large signaling complex organization revealed by the liprin-α/CASK and liprin-α/liprin-β complex structures. Molecular cell 80 21855798
2007 LAR, liprin alpha and the regulation of active zone morphogenesis. Journal of cell science 72 17959628
2018 Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses. Proceedings of the National Academy of Sciences of the United States of America 69 29439199
2016 PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis. Nature communications 69 27876801
2014 Liprin-α1, ERC1 and LL5 define polarized and dynamic structures that are implicated in cell migration. Journal of cell science 66 24982445
2012 ERK2 drives tumour cell migration in three-dimensional microenvironments by suppressing expression of Rab17 and liprin-β2. Journal of cell science 66 22328529
2013 Liprin-α/SYD-2 determines the size of dense projections in presynaptic active zones in C. elegans. The Journal of cell biology 64 24322429
2012 Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PloS one 63 22295056
2009 A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-alpha. Molecular brain 62 19534762
2018 Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca2+/CaM Controls DCV Binding and Liprin-α/TANC2 Recruits DCVs to Postsynaptic Sites. Cell reports 61 30021165
2005 LIP-1 phosphatase controls the extent of germline proliferation in Caenorhabditis elegans. The EMBO journal 59 16319922
2009 Liprin-alpha1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins. Journal of cell science 58 19690048
2016 CASK stabilizes neurexin and links it to liprin-α in a neuronal activity-dependent manner. Cellular and molecular life sciences : CMLS 55 27015872
2003 Identification and characterization of mouse Ppfia1 gene in silico. International journal of molecular medicine 54 12851729
2006 Liprin-alpha is required for photoreceptor target selection in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 52 16864799
2014 The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling. Science signaling 48 25492966
2002 The C.elegans MAPK phosphatase LIP-1 is required for the G(2)/M meiotic arrest of developing oocytes. The EMBO journal 48 12169634
2010 Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation. Oncogene 47 21151172
2011 Analyses of the spatiotemporal expression and subcellular localization of liprin-α proteins. The Journal of comparative neurology 46 21618221
2008 The mouse and human Liprin-alpha family of scaffolding proteins: genomic organization, expression profiling and regulation by alternative splicing. Genomics 44 19013515
2006 Liprin-alpha has LAR-independent functions in R7 photoreceptor axon targeting. Proceedings of the National Academy of Sciences of the United States of America 43 16864797
2011 The Liprin homology domain is essential for the homomeric interaction of SYD-2/Liprin-α protein in presynaptic assembly. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 22072677
2016 Liprin-α1 and ERC1 control cell edge dynamics by promoting focal adhesion turnover. Scientific reports 41 27659488
2011 Differential expression of liprin-α family proteins in the brain suggests functional diversification. The Journal of comparative neurology 40 21618222
2009 Liprin (beta)1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity. Blood 40 19965622
2021 Oligomerized liprin-α promotes phase separation of ELKS for compartmentalization of presynaptic active zone proteins. Cell reports 39 33761347
2009 Complex interactions amongst N-cadherin, DLAR, and Liprin-alpha regulate Drosophila photoreceptor axon targeting. Developmental biology 37 19766621
2020 Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity. Nature communications 36 31924785
2008 Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma. Genes, chromosomes & cancer 35 18196592
2006 Synaptic transmission regulated by a presynaptic MALS/Liprin-alpha protein complex. Current opinion in cell biology 35 16504495
2012 Liprin-α controls stress fiber formation by binding to mDia and regulating its membrane localization. Journal of cell science 32 22266902
2020 Effects of buffer salts on the freeze-drying survival rate of Lactobacillus plantarum LIP-1 based on transcriptome and proteome analyses. Food chemistry 30 32447159
2016 Effects of the scaffold proteins liprin-α1, β1 and β2 on invasion by breast cancer cells. Biology of the cell 30 26663347
2009 KazrinE is a desmosome-associated liprin that colocalises with acetylated microtubules. Journal of cell science 29 19843585
2013 Intramolecular regulation of presynaptic scaffold protein SYD-2/liprin-α. Molecular and cellular neurosciences 28 23541703
2021 UNC-2 CaV2 Channel Localization at Presynaptic Active Zones Depends on UNC-10/RIM and SYD-2/Liprin-α in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 33975919
2010 Liprin-alpha1 affects the distribution of low-affinity beta1 integrins and stabilizes their permanence at the cell surface. Experimental cell research 27 20096687
2024 Liprin-α proteins are master regulators of human presynapse assembly. Nature neuroscience 25 38472649
2014 Drosophila Syd-1, liprin-α, and protein phosphatase 2A B' subunit Wrd function in a linear pathway to prevent ectopic accumulation of synaptic materials in distal axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 24948803
2020 Improving the freeze-drying survival rate of Lactobacillus plantarum LIP-1 by increasing biofilm formation based on adjusting the composition of buffer salts in medium. Food chemistry 22 33091996
2010 PPFIA1 and CCND1 are frequently coamplified in breast cancer. Genes, chromosomes & cancer 22 19787783
2021 Liprin-α-Mediated Assemblies and Their Roles in Synapse Formation. Frontiers in cell and developmental biology 21 33869211
2013 The scaffolding protein SYD-2/Liprin-α regulates the mobility and polarized distribution of dense-core vesicles in C. elegans motor neurons. PloS one 20 23358451
2020 circ_0080145 Enhances Imatinib Resistance of Chronic Myeloid Leukemia by Regulating miR-326/PPFIA1 Axis. Cancer biotherapy & radiopharmaceuticals 19 32598170
2018 Liprin-α1 modulates cancer cell signaling by transmembrane protein CD82 in adhesive membrane domains linked to cytoskeleton. Cell communication and signaling : CCS 19 30005669
2005 Liprin phosphorylation regulates binding to LAR: evidence for liprin autophosphorylation. Biochemistry 19 16313174
2025 Iron-Chelating and ROS-Scavenging Polymers with Thioketal and Thioether Bonds Delivering Ferroptosis Inhibitor Lip-1 Provide a Triple Therapeutic Strategy for Retina Ganglion Cells in Acute Glaucoma. Advanced materials (Deerfield Beach, Fla.) 18 40641252
2020 Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α. Nature communications 18 32005855
2010 Liprin-α4 is a new hypoxia-inducible target gene required for maintenance of cell-cell contacts. Experimental cell research 17 20599943
2021 Effects of different initial pH values on freeze-drying resistance of Lactiplantibacillus plantarum LIP-1 based on transcriptomics and proteomics. Food research international (Ottawa, Ont.) 16 34600689
2019 Discovery of the Oncogenic Parp1, a Target of bcr-abl and a Potential Therapeutic, in mir-181a/PPFIA1 Signaling Pathway. Molecular therapy. Nucleic acids 16 30825668
2016 Liprin-α1 is a regulator of vimentin intermediate filament network in the cancer cell adhesion machinery. Scientific reports 16 27075696
2010 Sub-cellular distribution of UNC-104(KIF1A) upon binding to adaptors as UNC-16(JIP3), DNC-1(DCTN1/Glued) and SYD-2(Liprin-α) in C. elegans neurons. Neuroscience 16 21195138
2013 Amplification of the PPFIA1 gene region on 11q13 in oral squamous cell carcinomas (OSCC). Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 15 23453270
2007 Liprin alpha1 interacts with PP2A B56gamma. Cell cycle (Georgetown, Tex.) 15 18235218
2005 APC/C regulation of axonal growth and synaptic functions in postmitotic neurons: the Liprin-alpha connection. Cellular and molecular life sciences : CMLS 14 15924262
2020 PPFIA1 expression associates with poor response to endocrine treatment in luminal breast cancer. BMC cancer 13 32410585
2023 SAD-1 kinase controls presynaptic phase separation by relieving SYD-2/Liprin-α autoinhibition. PLoS biology 12 38048304
2022 Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain. Life science alliance 12 36137748
2017 Liprin-α4 as a Possible New Therapeutic Target for Pancreatic Cancer. Anticancer research 12 29187440
2002 Liprin-alpha2 gene, protein tyrosine phosphatase LAR interacting protein related gene, is downregulated by androgens in the human prostate cancer cell line LNCaP. International journal of molecular medicine 12 12119554
2022 Effects of salt stress on the freeze-drying survival rate of Lactiplantibacillus plantarum LIP-1. Food microbiology 10 35473971
2015 Structural and Biochemical Basis for the Inhibitory Effect of Liprin-α3 on Mouse Diaphanous 1 (mDia1) Function. The Journal of biological chemistry 10 25911102
2011 Biochemical and functional characterization of the interaction between liprin-α1 and GIT1: implications for the regulation of cell motility. PloS one 10 21695141
2008 The candidate MAP kinase phosphorylation substrate DPL-1 (DP) promotes expression of the MAP kinase phosphatase LIP-1 in C. elegans germ cells. Developmental biology 10 18304523
2023 PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration. Molecular therapy. Nucleic acids 9 37234746
2013 Regulation of acrosome reaction by Liprin α3, LAR and its ligands in mouse spermatozoa. Andrology 9 24327330
2012 Liprin α3: a putative estrogen regulated acrosomal protein. Histochemistry and cell biology 9 23124857
2024 LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α. PLoS genetics 8 38722918
2019 Liprin-α4 as a New Therapeutic Target for SCLC as an Upstream Mediator of HIF1α. Anticancer research 8 30842147
2011 Upregulation of liprin-α1 protein in the temporal neocortex of intractable epileptic patients and experimental rats. Synapse (New York, N.Y.) 8 21157931
2018 Lamprey immune protein-1 (LIP-1) from Lampetra japonica induces cell cycle arrest and cell death in HeLa cells. Fish & shellfish immunology 7 29410138
2011 Liprin-α is involved in exocytosis and cell spreading in mast cells. Immunology letters 7 21683737
2023 Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome. Cells 6 37190086
2022 A functional interaction between liprin-α1 and B56γ regulatory subunit of protein phosphatase 2A supports tumor cell motility. Communications biology 6 36171301
2012 A new role of multi scaffold protein Liprin-α: Liprin-α suppresses Rho-mDia mediated stress fiber formation. Bioarchitecture 6 22754629
2022 Reevaluation of the role of LIP-1 as an ERK/MPK-1 dual specificity phosphatase in the C. elegans germline. Proceedings of the National Academy of Sciences of the United States of America 5 35022236
2011 Liprin-α4 is required for nickel induced receptor protein tyrosine phosphatase-leukocyte antigen related receptor F (RPTP-LAR) activity. PloS one 5 21829649
2009 Hook-up of GluA2, GRIP and liprin-alpha for cholinergic muscarinic receptor-dependent LTD in the hippocampus. Molecular brain 5 19534761
2025 Blocking YAP1-Liprin-β2 interaction impedes metastasis and promotes tumor suppression in head and neck squamous carcinoma. Scientific reports 4 40707583
2024 The role of liprin-α1 phosphorylation in its liquid-liquid phase separation: regulation by PPP2R5D/PP2A holoenzyme. bioRxiv : the preprint server for biology 4 38948786
2023 Novel PPFIA1-ALK, ALK-C2orf91(intergenic) double-fusion responded well to alectinib in an advanced lung adenocarcinoma patient: a case report. Frontiers in oncology 3 37706178
2022 High PPFIA1 expression promotes cancer survival by suppressing CD8+ T cells in breast cancer: drug discovery and machine learning approach. Breast cancer (Tokyo, Japan) 2 36478321
2025 The phosphatase activity of the PPP2R5D-PP2A holoenzyme modulates liprin-α1 liquid-liquid phase separation. The Journal of biological chemistry 1 40484382
2024 Liprin-α1 contributes to oncogenic MAPK signaling by counteracting ERK activity. Molecular oncology 0 38264964

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