Affinage

PPFIA1

Liprin-alpha-1 · UniProt Q13136

Length
1202 aa
Mass
135.8 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPFIA1/liprin-α1 is a multidomain scaffolding protein that organizes macromolecular assemblies at presynaptic active zones and at the leading edge of migrating cells. In neurons, liprin-α1 is recruited to nascent synaptic contacts through interactions with LAR-family receptor protein tyrosine phosphatases (via its C-terminal SAM domains) and neurexins (via CASK); it then recruits ELKS, RIM, CASK, GRIP, GIT1, and kinesin motors (KIF1A) to build the active zone scaffold and regulate synaptic vesicle transport and AMPA receptor trafficking (PMID:38472649, PMID:12522103, PMID:11931740). Liprin-α1 oligomerization through its N-terminal coiled-coil domain drives multivalent phase separation with ELKS and RIM, a process negatively regulated by PP2A/B56δ-mediated dephosphorylation at S763 and by liprin-β1 heterodimerization (PMID:33761347, PMID:40484382). In non-neuronal cells, liprin-α1 promotes cell migration and invasion by assembling a leading-edge platform with ERC1 and LL5 proteins that controls focal adhesion turnover, active β1 integrin recycling via PI4KB–Rab11B–PTPRF, actin dynamics through competitive displacement of mDia from the plasma membrane, and PP2A-B56γ recruitment via an LxxIxE short linear motif (PMID:24982445, PMID:27876801, PMID:22266902, PMID:36171301).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Identifying PPFIA1 as a LAR-RPTP interactor established the foundational molecular partnership that defined liprin-α biology, revealing that a cytoplasmic coiled-coil protein constitutively associates with a major family of transmembrane phosphatases.

    Evidence Co-precipitation of recombinant LIP.1 with LAR, PTPδ, and PTPσ

    PMID:8524829

    Open questions at the time
    • Functional consequence of LAR–liprin interaction unknown
    • No structural detail of the binding interface
    • In vivo relevance not tested
  2. 2002 High

    Discovery that liprin-α links GRIP to AMPA receptor surface trafficking established liprin-α as a scaffold coordinating postsynaptic receptor delivery, not merely a phosphatase-binding protein.

    Evidence Co-IP from brain and dominant-negative disruption of GRIP–liprin interaction in cultured neurons blocking AMPAR clustering

    PMID:11931740

    Open questions at the time
    • Whether liprin-α1 specifically or other isoforms contribute was unclear
    • Mechanism of AMPAR endocytic vs. exocytic regulation not resolved
  3. 2003 High

    Identification of KIF1A, ERC/CAST, and GIT1 as direct liprin-α partners expanded the scaffold model from a phosphatase-binding protein to a hub linking motor-driven transport, active zone assembly, and ARF-GAP signaling at synapses.

    Evidence Co-IP from brain, sciatic nerve ligation showing co-transport with KIF1A, in vitro binding and neuronal colocalization for ERC and GIT1

    PMID:12522103 PMID:12629171 PMID:12923177

    Open questions at the time
    • Whether all partners bind simultaneously or form mutually exclusive sub-complexes was unknown
    • Stoichiometry of assembled complexes unresolved
  4. 2005 High

    Drosophila mutant analysis and MALS complex purification demonstrated that liprin-α is essential in vivo for anterograde axonal transport of synaptic vesicle precursors and for linking the CASK/Mint-1 PDZ complex to presynaptic function.

    Evidence Live imaging in Drosophila liprin-α mutants showing transport defects; MALS triple KO mice with presynaptic vesicle cycling deficit; liprin-α identified as major MALS complex component

    PMID:15823543 PMID:16186258

    Open questions at the time
    • Mammalian liprin-α1-specific knockout not yet available
    • Whether transport and active zone assembly functions are separable was unclear
  5. 2009 High

    Extension of liprin-α1 function to non-neuronal cell spreading on fibronectin and to muscarinic receptor-dependent AMPAR endocytosis demonstrated that the scaffold operates in diverse cellular contexts through its LAR-RPTP and GRIP interactions.

    Evidence RNAi and overexpression in COS7 cells showing LAR-dependent spreading; peptide inhibition of GRIP–liprin interaction blocking mAChR-LTD in hippocampal slices

    PMID:19534762 PMID:19690048

    Open questions at the time
    • Downstream signaling from LAR that mediates spreading not identified
    • Whether liprin-α1 acts catalytically or purely as a scaffold in non-neuronal cells unknown
  6. 2010 High

    Demonstration that liprin-α1 stabilizes inactive β1 integrins at the cell surface and promotes cancer cell invasion through invadopodia established liprin-α1 as a regulator of integrin trafficking and tumor cell motility.

    Evidence siRNA and overexpression modulating β1 integrin internalization rates; bidirectional manipulation in MDA-MB-231 cells affecting ECM degradation and invadopodium lifetime

    PMID:20096687 PMID:21151172

    Open questions at the time
    • Molecular mechanism linking liprin-α1 to integrin endocytic machinery not resolved
    • In vivo tumor invasion data lacking
  7. 2011 High

    Crystal structures of liprin-α SAM domains in complex with CASK and liprin-β revealed the atomic basis for presynaptic scaffold assembly, showing that three SAM domains form an integrated supramodule and that X-linked mental retardation CASK mutations disrupt this interface.

    Evidence X-ray crystallography of liprin-α2/CASK and liprin-α/liprin-β SAM complexes with mutagenesis validation

    PMID:21855798

    Open questions at the time
    • Structure of full-length liprin-α not determined
    • Whether CASK and liprin-β binding to liprin-α is simultaneous or competitive in vivo unclear
  8. 2012 High

    Discovery that liprin-α binds mDia's DID domain competitively with DAD established a direct mechanism for liprin-α regulation of Rho-dependent actin dynamics, explaining how liprin-α modulates lamellipodia and stress fibers.

    Evidence Pulldown and Co-IP identifying mDia–liprin-α interaction; RNAi and overexpression showing bidirectional effects on membrane mDia levels and stress fibers

    PMID:22266902

    Open questions at the time
    • Whether liprin-α1 and liprin-α3 act redundantly or distinctly on mDia unclear
    • Spatiotemporal regulation of liprin–mDia interaction at the leading edge not resolved
  9. 2014 High

    Identification of the liprin-α1/ERC1/LL5 complex as a leading-edge platform controlling active integrin recycling, and of PPFIA1 as a Kif7 partner required for Hedgehog signaling at cilia, expanded the functional repertoire beyond adhesion to include morphogen signaling.

    Evidence Systematic RNAi of complex components with migration/invasion phenotypes; MS-based identification of PPFIA1–Kif7 interaction with PP2A-dependent ciliary trafficking readout and Hh reporter

    PMID:24982445 PMID:25492966

    Open questions at the time
    • How liprin-α1 coordinates Hh signaling and cell migration functions in the same cell unknown
    • Whether PP2A involvement is via B56γ or B56δ subunit in the ciliary context not defined
  10. 2016 High

    Delineation of the PPFIA1–PI4KB–Rab11B–PTPRF recycling pathway for active α5β1 integrin provided a complete molecular route from endosome to cell surface, validated in vivo in zebrafish vascular morphogenesis.

    Evidence Co-IP of PPFIA1 with active integrin, RNAi/TIRF microscopy in endothelial cells, zebrafish morpholino knockdown with vascular phenotype

    PMID:27876801

    Open questions at the time
    • Whether this pathway operates in non-endothelial cell types not tested
    • Direct vs. adaptor role of PPFIA1 in the recycling complex not structurally resolved
  11. 2020 High

    Crystal structures of LAR–liprin-α and PTPδ–liprin-α SAM complexes revealed a conserved two-site binding mode, showed that liprin-α-promoted LAR clustering negatively regulates phosphatase activity via D1 homophilic interaction, and demonstrated allosteric modulation of liprin-α/liprin-β binding by LAR.

    Evidence X-ray crystallography at up to 1.91 Å resolution, structure-guided mutagenesis, cellular clustering and phosphatase activity assays, synaptogenesis assay

    PMID:31924785 PMID:32005855

    Open questions at the time
    • Full-length liprin-α in complex with LAR not structurally resolved
    • In vivo confirmation that LAR clustering controls phosphatase output at synapses lacking
  12. 2021 High

    Reconstitution of liprin-α coiled-coil oligomerization driving ELKS phase separation, modulated by RIM/RIM-BP competition, established phase separation as the biophysical mechanism underlying active zone assembly.

    Evidence In vitro phase separation assays with recombinant proteins, gain-of-function oligomerization mutant, FRAP

    PMID:33761347

    Open questions at the time
    • Whether phase separation occurs at physiological concentrations in mammalian neurons unconfirmed
    • Role of liprin-α1 vs. liprin-α2 in phase separation not distinguished
  13. 2022 High

    Identification of a B56γ-binding LxxIxE SLiM in liprin-α1 and demonstration that PP2A-B56γ recruitment to membrane platforms is liprin-α1-dependent provided a molecular mechanism for phosphatase-dependent regulation of cell migration downstream of liprin-α1.

    Evidence SLiM mutagenesis blocking B56γ binding, rescue experiments showing SLiM-dependence of cell spreading, RNAi of B56γ phenocopying liprin-α1 depletion

    PMID:36171301

    Open questions at the time
    • Substrates dephosphorylated by the liprin-α1–PP2A-B56γ complex at the leading edge not identified
    • Whether B56γ and B56δ functions are redundant or distinct in liprin-α1 biology not resolved
  14. 2024 High

    Quadruple liprin-α knockout in human neurons established a definitive hierarchical model: liprin-α is recruited to nascent contacts via LAR-RPTPs/neurexin–CASK and then recruits ELKS to build the active zone, resolving decades of epistasis questions.

    Evidence iPSC-derived human neuron quadruple KO with isoform-specific and interaction-defective rescue, electrophysiology, EM

    PMID:38472649

    Open questions at the time
    • Whether liprin-α1 and liprin-α2 are functionally redundant or specialized at individual synapses not resolved
    • Mechanism by which liprin-α coordinates vesicle docking after scaffold assembly unclear
  15. 2024 High

    Identification of B56δ-PP2A as a negative regulator of liprin-α1 phase separation via S763 dephosphorylation, with disease-linked PPP2R5D variants compromising this control, connected liprin-α1 condensate biology to a human neurodevelopmental disease mechanism.

    Evidence PPP2R5D KO and SLiM4 mutagenesis in HEK293 cells, phospho-mimetic/null S763 mutants, phospho-specific antibody, GFP-liprin-α1 condensate assays, PPP2R5D E420K disease variant analysis

    PMID:40484382

    Open questions at the time
    • Whether S763 phosphorylation-driven LLPS occurs at neuronal active zones in vivo not shown
    • Kinase responsible for S763 phosphorylation not identified
    • Functional consequences of dysregulated liprin-α1 LLPS for synaptic transmission not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the identity of the kinase(s) controlling S763 phosphorylation, whether liprin-α1 phase separation occurs at physiological concentrations in mammalian neurons, the specific substrates of the liprin-α1-recruited PP2A complexes at the leading edge, and the structural basis for full-length liprin-α1 in its autoinhibited vs. oligomerized states.
  • No full-length liprin-α1 structure available
  • Kinase for S763 unknown
  • PP2A substrate specificity at the leading edge uncharacterized
  • Functional specialization among liprin-α isoforms at individual synapses not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 3 GO:0031410 cytoplasmic vesicle 2 GO:0005929 cilium 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-9609507 Protein localization 3 R-HSA-162582 Signal Transduction 2
Partners
CASKERC1GIT1GRIP1KIF1APPP2R5CPPP2R5DPTPRF
Complex memberships
CASK/Mint-1/MALS presynaptic complexLAR-RPTP/liprin-α/liprin-β complexLiprin-α1/ERC1/LL5 leading-edge complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 PPFIA1/liprin-α1 (LIP.1) was identified as a binding partner of the LAR family of transmembrane receptor protein tyrosine phosphatases (LAR, PTPδ, PTPσ), interacting via its coiled-coil domain; all three RPTPs associate with LIP.1 in co-precipitation assays. Co-precipitation / binding assays with recombinant proteins Proceedings of the National Academy of Sciences of the United States of America High 8524829
2002 Liprin-α/SYD2 interacts with the multi-PDZ protein GRIP, and this interaction is required for the surface expression and dendritic clustering of AMPA receptors in neurons; dominant-negative constructs disrupting the GRIP-liprin interaction disrupt AMPAR trafficking. Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, immunofluorescence Neuron High 11931740
2003 Liprin-α1 interacts with the kinesin motor KIF1A; liprin-α co-accumulates with KIF1A in ligated sciatic nerve and co-immunoprecipitates with KIF1A and associated cargo proteins (AMPA receptors, GRIP/ABP, RIM, GIT1, βPIX), suggesting liprin-α acts as a KIF1A receptor linking the motor to synaptic cargo. Co-immunoprecipitation, sciatic nerve ligation (axonal transport assay), co-fractionation The Journal of biological chemistry High 12522103
2003 Liprin-α directly interacts with ERC/CAST proteins (ERC2/CAST and ERC1b); co-expression with ERC2 redistributes liprin-α1 to synaptic sites in cultured neurons, identifying ERC-liprin-α interaction as a mechanism for presynaptic localization of liprin-α. In vitro binding assays, co-immunoprecipitation from brain, co-expression and immunofluorescence in cultured neurons The Journal of biological chemistry High 12923177
2003 Liprin-α1 directly interacts with GIT1 (a GTPase-activating protein for ARF family GTPases); dominant-negative constructs disrupting GIT1-liprin-α interaction cause a marked reduction in dendritic and surface clustering of AMPA receptors in cultured neurons, and GIT1 forms a complex with liprin-α, GRIP, and AMPA receptors in brain. Direct binding assay, co-immunoprecipitation from brain, electron microscopy, dominant-negative expression in neurons The Journal of neuroscience High 12629171
2005 Liprin-α is required for anterograde axonal transport of synaptic vesicle precursors; in Drosophila liprin-α mutants there is a decrease in anterograde processivity and an increase in retrograde transport initiation; pull-down shows liprin-α interacts with Kinesin-1 (Khc) but not dynein. Live imaging of GFP-tagged cargo in Drosophila mutants, pull-down assay, ultrastructural analysis Current biology High 15823543
2005 The MALS protein complex purified from brain contains liprin-α as a major component; liprin-α links the MALS/CASK/Mint-1 PDZ complex to presynaptic active zone organization; triple MALS knockout mice show reduced excitatory synaptic transmission due to a presynaptic vesicle cycling deficit. Protein purification from brain, co-immunoprecipitation, electrophysiology in MALS triple knockout mice The Journal of cell biology High 16186258
2005 Liprin-α1 phosphorylation regulates its binding to LAR; dephosphorylation by calf intestinal phosphatase weakens the liprin-LAR interaction; liprin-α1 autophosphorylates in vitro and binds ATP-agarose, suggesting it has intrinsic kinase-like activity mediating the phosphorylation that controls LAR association. In vitro phosphorylation assay, pulldown with GST-LAR, co-precipitation with ATP-agarose, phosphatase treatment Biochemistry Medium 16313174
2007 ING4 (inhibitor of growth 4) interacts with liprin-α1/PPFIA1; both proteins co-localize at lamellipodia near vinculin; overexpressed ING4 suppresses cell spreading and migration promoted by liprin-α1, and this suppression is lost when liprin-α1 is knocked down, indicating mechanistic interdependence. Co-immunoprecipitation, co-localization by immunofluorescence, RNAi knockdown, cell spreading/migration assays Cancer research Medium 17363573
2007 Liprin-α1 interacts with the B56γ regulatory subunit of PP2A; B56γ-liprin-α1 complexes are distinct from the PP2A holoenzyme; suppression of liprin-α1 by RNAi alters cell morphology. Tandem affinity purification and mass spectrometry, co-immunoprecipitation, RNAi knockdown Cell cycle Medium 18235218
2009 Liprin-α1 promotes cell spreading on fibronectin by affecting lamellipodia formation and focal adhesion dynamics; depletion of liprin-α1 inhibits spreading of COS7 cells on fibronectin; the effect of liprin on spreading (but not on cell edge reorganization) requires its interaction with LAR-type RPTPs. RNAi knockdown, overexpression, cell spreading assay on fibronectin, immunofluorescence Journal of cell science High 19690048
2009 mAChR-LTD in hippocampus requires interactions between GluA2, GRIP, and liprin-α; peptides that inhibit GRIP-GluA2 or GRIP-liprin-α binding block mAChR-LTD but not mGluR-LTD, indicating these interactions mediate AMPAR endocytosis selectively downstream of muscarinic receptor activation. Peptide inhibitor microinjection, electrophysiology (LTD recording) in hippocampal slices Molecular brain Medium 19534762
2010 Liprin-α1 stabilizes low-affinity (inactive) β1 integrins at the cell surface; overexpression inhibits antibody-induced β1 integrin internalization while depletion by siRNA increases the rate of integrin internalization, thereby regulating focal adhesion size. siRNA knockdown, overexpression, antibody-induced internalization assay, immunofluorescence Experimental cell research Medium 20096687
2010 Liprin-α1 is required for invasion of MDA-MB-231 breast cancer cells; depletion by RNAi destabilizes lamellipodia, reduces spreading, decreases invadopodium lifetime, and inhibits ECM degradation; overexpression has the opposite effects. RNAi knockdown, overexpression, time-lapse microscopy, ECM degradation assay, invadopodium analysis Oncogene High 21151172
2011 Crystal structures of the liprin-α2/CASK and liprin-α/liprin-β SAM domain complexes reveal: (1) the three SAM domains of liprin-α form an integrated supramodule binding the CASK kinase-like domain (a vertebrate-unique interaction); (2) the SAM domains mediate liprin-α/liprin-β heterodimerization; (3) three X-linked mental retardation CASK mutants are defective in liprin-α binding; (4) CASK/liprin-α/liprin-β can form a ternary complex. X-ray crystallography, biochemical binding assays, cellular studies Molecular cell High 21855798
2011 Liprin-α1 interacts with GIT1 and this functional interaction regulates integrin-dependent cell spreading and migration; 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 edges. Co-immunoprecipitation, RNAi knockdown, overexpression of truncation/deletion mutants, immunofluorescence, migration assays PloS one Medium 21695141
2012 Liprin-α binds mDia via the central region of liprin-α and the DID-DD region of mDia, competing with the DAD domain for DID binding; overexpression of the mDia-binding liprin-α fragment displaces mDia from the plasma membrane and attenuates Rho-mDia-mediated stress fiber formation; conversely, liprin-α depletion by RNAi increases membrane-associated mDia and enhances stress fiber formation. Pulldown assay, co-immunoprecipitation, RNAi knockdown, overexpression, cell fractionation, actin staining Journal of cell science High 22266902
2013 Liprin-α2 organizes presynaptic ultrastructure and controls synaptic vesicle pool size; liprin-α2 levels are regulated by synaptic activity and the ubiquitin-proteasome system; liprin-α2 is required for recruitment of RIM1 and CASK to presynaptic sites; FRAP shows liprin-α2 depletion reduces turnover of RIM1 and CASK at terminals. Knockdown/knockout in neurons, FRAP, electron microscopy of synaptic ultrastructure, electrophysiology The Journal of cell biology High 23751498
2014 PPFIA1/liprin-α1 forms a functional complex with ERC1a and LL5α/LL5β that drives cell motility and tumor invasion; depletion of any component negatively affects invasion, migration, lamellipodial persistence, and internalization of active β1 integrin at the cell front; the complex defines highly polarized dynamic cytoplasmic structures near the protruding cell edge. RNAi knockdown of individual components, invasion and migration assays, live imaging, integrin internalization assay, immunofluorescence Journal of cell science High 24982445
2014 PPFIA1 was identified by mass spectrometry as a Kif7-interacting protein; PPFIA1 and PP2A interact with Kif7 and are required for Kif7 and Gli protein trafficking to the tips of primary cilia and for transcriptional output of Hedgehog signaling; PPFIA1 appears to promote PP2A-mediated dephosphorylation of Kif7 to trigger its ciliary tip localization. Mass spectrometry-based interactomics, co-immunoprecipitation, RNAi knockdown, luciferase reporter assays for Hh output, immunofluorescence of cilia Science signaling High 25492966
2015 Liprin-α3 inhibits mDia1 by binding to the mDiaN (DID) region in a manner competitive with DAD and allosterically modulated by RhoA; RhoA displaces liprin-α3, while liprin-α3 lowers the regulatory potency of both RhoA and DAD on mDiaN; structural and biophysical characterization defines the minimal liprin-α3 core sufficient for these effects. In vitro binding assays (ITC, SPR), structural analysis, actin polymerization assays, competition assays The Journal of biological chemistry High 25911102
2016 PPFIA1 drives recycling of active α5β1 integrin back to the endothelial cell surface via a pathway involving PI4KB, AP-1A, Rab11B, and the phosphatase PTPRF; PPFIA1 interacts with active α5β1 integrin and localizes near adhesions where post-Golgi carriers are targeted; PPFIA1 is required for fibronectin fibrillogenesis and vascular morphogenesis in vitro and in zebrafish. Co-immunoprecipitation (PPFIA1 with active α5β1), RNAi knockdown, confocal/TIRF microscopy, zebrafish morpholino knockdown, fibronectin fibrillogenesis assay Nature communications High 27876801
2016 Liprin-α1 and ERC1 promote protrusion and focal adhesion disassembly at the cell front; they colocalize with active integrin β1 clusters distinct from cytoplasmic focal adhesion proteins and influence localization of peripheral Rab7-positive endosomes; ERC1 displacement from the cell edge (by a dominant-negative liprin-N fragment) inhibits focal adhesion disassembly. RNAi knockdown, dominant-negative expression (liprin-N fragment), immunofluorescence, live imaging, invasion assays Scientific reports Medium 27659488
2016 CASK stabilizes neurexin1β and links it to liprin-α in an activity-dependent manner; liprin-α and Mint1 compete for CASK binding, but neurexin1β eliminates this competition and allows all four proteins to form a complex; CASK phosphorylates neurexin, modulating the liprin-α/CASK-neurexin1β-Mint1 complex interaction. Co-immunoprecipitation, in vitro phosphorylation assay, neuronal culture, binding competition assays Cellular and molecular life sciences Medium 27015872
2018 PPFIA1/liprin-α1 localizes at invadosomes in cancer cells and regulates transmembrane protein CD82 (a metastasis suppressor); PPFIA1 knockdown upregulates CD82, linking PPFIA1 to cancer cell invasion pathways via membrane microdomain and protein trafficking regulation. RNAi knockdown, transcriptome profiling, immunofluorescence in 2D and 3D conditions Cell communication and signaling Low 30005669
2020 Crystal structure of LAR_D1D2 in complex with liprin-α3 SAM repeats reveals a conserved two-site binding mode; liprin-α proteins promote clustering of LAR in cells via both the liprin/LAR interaction and liprin-α oligomerization; the catalytically active D1 domain of LAR engages in homophilic interaction, and disruption of D1/D1 interaction diminishes liprin-α-promoted LAR clustering and increases LAR phosphatase activity, demonstrating that LAR clustering negatively regulates phosphatase activity; LAR binding to liprin-α allosterically modulates liprin-α/liprin-β interaction. X-ray crystallography, structure-based mutagenesis, cellular clustering assays, phosphatase activity assays Nature communications High 31924785
2020 Crystal structure of mouse PTPδ D2 in complex with liprin-α3 tSAM at 1.91 Å resolution shows PTPδ D2 contacts the N-terminal helix and SAM1/SAM2 of liprin-α3; structure-based mutagenesis confirms that SAM1 and SAM2 interactions are essential for binding and for synaptogenic activity. X-ray crystallography, structure-based mutagenesis, in vitro binding assays, cell-based synaptogenesis assay Nature communications High 32005855
2021 The N-terminal coiled-coil region of liprin-α oligomerizes; a gain-of-function mutation promotes self-assembly by disrupting intramolecular interactions and promoting intermolecular ones; oligomerized liprin-α2 enhances phase separation of the ELKS N-terminal segment through multivalent interactions; liprin-α2 controls protein distributions by regulating interplay between ELKS and RIM/RIM-BP phase separations. Structural and biochemical characterization of coiled-coil oligomerization, in vitro phase separation assays, FRAP Cell reports High 33761347
2022 Liprin-α1 contains an LxxIxE SLiM in its N-terminal dimerization domain that mediates interaction with B56γ regulatory subunit of PP2A; B56γ mediates liprin-α1 interaction with the PP2A holoenzyme; B56γ localization to plasma membrane-associated platforms requires liprin-α1; silencing B56γ or liprin-α1 similarly inhibits cell spreading, invasion, motility, and lamellipodia dynamics; mutation of the SLiM preventing B56γ binding blocks rescue of liprin-α1 knockdown spreading phenotype. Co-immunoprecipitation, point mutagenesis of SLiM, cell fractionation, RNAi knockdown, cell spreading/invasion assays, immunofluorescence Communications biology High 36171301
2024 In human neurons lacking all four liprin-α isoforms, nascent synaptic contacts form but active zone component recruitment and synaptic vesicle accumulation are blocked, producing empty boutons and loss of transmission; liprin-α localization to nascent synaptic sites requires interactions with LAR-RPTP family cell adhesion molecules or neurexins via CASK; liprin-α subsequently recruits presynaptic components via direct interaction with ELKS, establishing a hierarchical assembly sequence. Quadruple liprin-α knockout in human neurons (iPSC-derived), rescue with individual isoforms and interaction-defective mutants, electrophysiology, immunofluorescence, electron microscopy Nature neuroscience High 38472649
2024 PPP2R5D/B56δ-PP2A holoenzyme interacts with liprin-α1 via a canonical SLiM (SLiM4) in its N-terminal dimerization domain; mutation of SLiM4 or PPP2R5D knockout significantly increases liprin-α1 LLPS in HEK293 cells; phospho-mimetic mutation at S763 drives liprin-α1 LLPS; liprin-β1 heterodimerization inhibits liprin-α1 LLPS; the disease-associated PPP2R5D E420K variant compromises suppression of liprin-α1 LLPS with increased S763 phosphorylation. Mass spectrometry interactomics, SLiM mutagenesis, PPP2R5D knockout cells, phospho-mimetic and phospho-null mutants, phospho-specific antibody, GFP-liprin-α1 condensate assays in cells, co-immunoprecipitation The Journal of biological chemistry High 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 307 10517634
2002 Drosophila liprin-alpha and the receptor phosphatase Dlar control synapse morphogenesis. Neuron 243 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 202 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 177 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 146 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 113 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 92 23751498
2021 PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure. Nature communications 80 34031393
2011 Liprin-mediated large signaling complex organization revealed by the liprin-α/CASK and liprin-α/liprin-β complex structures. Molecular cell 79 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 68 29439199
2016 PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis. Nature communications 68 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
2012 Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PloS one 63 22295056
2013 Liprin-α/SYD-2 determines the size of dense projections in presynaptic active zones in C. elegans. The Journal of cell biology 62 24322429
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 60 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
2003 Identification and characterization of mouse Ppfia1 gene in silico. International journal of molecular medicine 54 12851729
2016 CASK stabilizes neurexin and links it to liprin-α in a neuronal activity-dependent manner. Cellular and molecular life sciences : CMLS 52 27015872
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 43 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
2016 Liprin-α1 and ERC1 control cell edge dynamics by promoting focal adhesion turnover. Scientific reports 41 27659488
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 41 22072677
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
2020 Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity. Nature communications 36 31924785
2009 Complex interactions amongst N-cadherin, DLAR, and Liprin-alpha regulate Drosophila photoreceptor axon targeting. Developmental biology 36 19766621
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 34 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 27 23541703
2010 Liprin-alpha1 affects the distribution of low-affinity beta1 integrins and stabilizes their permanence at the cell surface. Experimental cell research 27 20096687
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 25 33975919
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
2024 Liprin-α proteins are master regulators of human presynapse assembly. Nature neuroscience 22 38472649
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
2020 Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α. Nature communications 18 32005855
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
2016 Liprin-α1 is a regulator of vimentin intermediate filament network in the cancer cell adhesion machinery. Scientific reports 16 27075696
2010 Liprin-α4 is a new hypoxia-inducible target gene required for maintenance of cell-cell contacts. Experimental cell research 16 20599943
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
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 15 30825668
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
2023 SAD-1 kinase controls presynaptic phase separation by relieving SYD-2/Liprin-α autoinhibition. PLoS biology 12 38048304
2020 PPFIA1 expression associates with poor response to endocrine treatment in luminal breast cancer. BMC cancer 12 32410585
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 Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain. Life science alliance 11 36137748
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.) 10 40641252
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
2022 Effects of salt stress on the freeze-drying survival rate of Lactiplantibacillus plantarum LIP-1. Food microbiology 9 35473971
2015 Structural and Biochemical Basis for the Inhibitory Effect of Liprin-α3 on Mouse Diaphanous 1 (mDia1) Function. The Journal of biological chemistry 9 25911102
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
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 8 37234746
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
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
2023 Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome. Cells 5 37190086
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
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 4 35022236
2011 Liprin-α4 is required for nickel induced receptor protein tyrosine phosphatase-leukocyte antigen related receptor F (RPTP-LAR) activity. PloS one 4 21829649
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
2023 SAD-1 kinase controls presynaptic phase separation by relieving SYD-2/Liprin-α autoinhibition. bioRxiv : the preprint server for biology 0 37398223