{"gene":"PPFIA1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Co-precipitation / binding assays with recombinant proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — original discovery of interaction, replicated across multiple RPTP family members in the same study","pmids":["8524829"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, immunofluorescence","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP from brain plus dominant-negative functional rescue in neurons, replicated","pmids":["11931740"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Co-immunoprecipitation, sciatic nerve ligation (axonal transport assay), co-fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ligation, fractionation) in a single study","pmids":["12522103"],"is_preprint":false},{"year":2003,"finding":"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.","method":"In vitro binding assays, co-immunoprecipitation from brain, co-expression and immunofluorescence in cultured neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — direct binding confirmed in vitro plus Co-IP from brain and cellular localization rescue","pmids":["12923177"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Direct binding assay, co-immunoprecipitation from brain, electron microscopy, dominant-negative expression in neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1/2 — direct binding, Co-IP from brain, and functional dominant-negative rescue","pmids":["12629171"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Live imaging of GFP-tagged cargo in Drosophila mutants, pull-down assay, ultrastructural analysis","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1/2 — direct live observation in mutants plus biochemical pulldown, multiple orthogonal methods","pmids":["15823543"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Protein purification from brain, co-immunoprecipitation, electrophysiology in MALS triple knockout mice","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical purification from brain plus genetic knockout with defined physiological phenotype","pmids":["16186258"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro phosphorylation assay, pulldown with GST-LAR, co-precipitation with ATP-agarose, phosphatase treatment","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro biochemistry but single lab, mechanistic interpretation of autophosphorylation needs further validation","pmids":["16313174"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, RNAi knockdown, cell spreading/migration assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus functional epistasis via knockdown, single lab","pmids":["17363573"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Tandem affinity purification and mass spectrometry, co-immunoprecipitation, RNAi knockdown","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — TAP-MS discovery of interaction plus functional KD phenotype, single lab","pmids":["18235218"],"is_preprint":false},{"year":2009,"finding":"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.","method":"RNAi knockdown, overexpression, cell spreading assay on fibronectin, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — KD/OE with specific phenotypic readout plus domain-function dissection identifying LAR dependence","pmids":["19690048"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Peptide inhibitor microinjection, electrophysiology (LTD recording) in hippocampal slices","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 — peptide disruption of specific interactions with clean electrophysiological readout, single lab","pmids":["19534762"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown, overexpression, antibody-induced internalization assay, immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — KD and OE with specific integrin internalization readout, single lab","pmids":["20096687"],"is_preprint":false},{"year":2010,"finding":"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.","method":"RNAi knockdown, overexpression, time-lapse microscopy, ECM degradation assay, invadopodium analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — bidirectional manipulation (KD and OE) with multiple orthogonal functional readouts","pmids":["21151172"],"is_preprint":false},{"year":2011,"finding":"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.","method":"X-ray crystallography, biochemical binding assays, cellular studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional validation via mutagenesis and cell-based assays","pmids":["21855798"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, RNAi knockdown, overexpression of truncation/deletion mutants, immunofluorescence, migration assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple methods but single lab, complex epistasis","pmids":["21695141"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Pulldown assay, co-immunoprecipitation, RNAi knockdown, overexpression, cell fractionation, actin staining","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — direct binding identified biochemically plus bidirectional genetic manipulation with clear cytoskeletal phenotype","pmids":["22266902"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Knockdown/knockout in neurons, FRAP, electron microscopy of synaptic ultrastructure, electrophysiology","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including FRAP and ultrastructure in a single comprehensive study","pmids":["23751498"],"is_preprint":false},{"year":2014,"finding":"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.","method":"RNAi knockdown of individual components, invasion and migration assays, live imaging, integrin internalization assay, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — systematic depletion of multiple complex members with multiple functional readouts","pmids":["24982445"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Mass spectrometry-based interactomics, co-immunoprecipitation, RNAi knockdown, luciferase reporter assays for Hh output, immunofluorescence of cilia","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — MS identification plus functional KD with multiple orthogonal readouts (localization and transcriptional output)","pmids":["25492966"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vitro binding assays (ITC, SPR), structural analysis, actin polymerization assays, competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with thermodynamic and kinetic characterization","pmids":["25911102"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation (PPFIA1 with active α5β1), RNAi knockdown, confocal/TIRF microscopy, zebrafish morpholino knockdown, fibronectin fibrillogenesis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — biochemical interaction plus in vivo knockdown with multiple phenotypic readouts in two model systems","pmids":["27876801"],"is_preprint":false},{"year":2016,"finding":"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.","method":"RNAi knockdown, dominant-negative expression (liprin-N fragment), immunofluorescence, live imaging, invasion assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — dominant-negative and KD with mechanistic endpoint (FA disassembly, endosome localization), single lab","pmids":["27659488"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, in vitro phosphorylation assay, neuronal culture, binding competition assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical Co-IP and in vitro phosphorylation, single lab","pmids":["27015872"],"is_preprint":false},{"year":2018,"finding":"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.","method":"RNAi knockdown, transcriptome profiling, immunofluorescence in 2D and 3D conditions","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mostly transcriptomics; mechanism of CD82 regulation is indirect","pmids":["30005669"],"is_preprint":false},{"year":2020,"finding":"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.","method":"X-ray crystallography, structure-based mutagenesis, cellular clustering assays, phosphatase activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis-validated functional consequences, multiple orthogonal assays","pmids":["31924785"],"is_preprint":false},{"year":2020,"finding":"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.","method":"X-ray crystallography, structure-based mutagenesis, in vitro binding assays, cell-based synaptogenesis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structure plus mutagenesis with functional validation in cells","pmids":["32005855"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Structural and biochemical characterization of coiled-coil oligomerization, in vitro phase separation assays, FRAP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro phase separation plus structural characterization with gain-of-function mutation analysis","pmids":["33761347"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, point mutagenesis of SLiM, cell fractionation, RNAi knockdown, cell spreading/invasion assays, immunofluorescence","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with SLiM mutagenesis, bidirectional manipulation, and clear functional readout","pmids":["36171301"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Quadruple liprin-α knockout in human neurons (iPSC-derived), rescue with individual isoforms and interaction-defective mutants, electrophysiology, immunofluorescence, electron microscopy","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1/2 — complete genetic ablation in human neurons with domain-specific rescue experiments defining molecular hierarchy","pmids":["38472649"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — MS-identified interaction validated by mutagenesis, KO cells, phospho-specific antibody, and multiple condensate assays in a peer-reviewed study","pmids":["40484382"],"is_preprint":false}],"current_model":"PPFIA1/liprin-α1 is a multidomain scaffolding protein that constitutively associates with LAR-family receptor protein tyrosine phosphatases (via its SAM domains), promotes their clustering to negatively regulate phosphatase activity, and assembles large presynaptic active zone complexes (with ELKS, RIM, CASK, GRIP, GIT1, and KIF1A) through oligomerization and phase separation regulated by phosphorylation at S763 via PP2A/B56δ; in non-neuronal cells it drives cell migration and invasion by controlling focal adhesion turnover, active integrin β1 recycling (via a PI4KB–Rab11B–PTPRF pathway), actin dynamics (by displacing mDia from the plasma membrane), and by recruiting PP2A–B56γ to plasma membrane-associated platforms at the leading edge."},"narrative":{"teleology":[{"year":1995,"claim":"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","pmids":["8524829"],"confidence":"High","gaps":["Functional consequence of LAR–liprin interaction unknown","No structural detail of the binding interface","In vivo relevance not tested"]},{"year":2002,"claim":"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","pmids":["11931740"],"confidence":"High","gaps":["Whether liprin-α1 specifically or other isoforms contribute was unclear","Mechanism of AMPAR endocytic vs. exocytic regulation not resolved"]},{"year":2003,"claim":"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","pmids":["12522103","12923177","12629171"],"confidence":"High","gaps":["Whether all partners bind simultaneously or form mutually exclusive sub-complexes was unknown","Stoichiometry of assembled complexes unresolved"]},{"year":2005,"claim":"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","pmids":["15823543","16186258"],"confidence":"High","gaps":["Mammalian liprin-α1-specific knockout not yet available","Whether transport and active zone assembly functions are separable was unclear"]},{"year":2009,"claim":"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","pmids":["19690048","19534762"],"confidence":"High","gaps":["Downstream signaling from LAR that mediates spreading not identified","Whether liprin-α1 acts catalytically or purely as a scaffold in non-neuronal cells unknown"]},{"year":2010,"claim":"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","pmids":["20096687","21151172"],"confidence":"High","gaps":["Molecular mechanism linking liprin-α1 to integrin endocytic machinery not resolved","In vivo tumor invasion data lacking"]},{"year":2011,"claim":"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","pmids":["21855798"],"confidence":"High","gaps":["Structure of full-length liprin-α not determined","Whether CASK and liprin-β binding to liprin-α is simultaneous or competitive in vivo unclear"]},{"year":2012,"claim":"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","pmids":["22266902"],"confidence":"High","gaps":["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"]},{"year":2014,"claim":"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","pmids":["24982445","25492966"],"confidence":"High","gaps":["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"]},{"year":2016,"claim":"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","pmids":["27876801"],"confidence":"High","gaps":["Whether this pathway operates in non-endothelial cell types not tested","Direct vs. adaptor role of PPFIA1 in the recycling complex not structurally resolved"]},{"year":2020,"claim":"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","pmids":["31924785","32005855"],"confidence":"High","gaps":["Full-length liprin-α in complex with LAR not structurally resolved","In vivo confirmation that LAR clustering controls phosphatase output at synapses lacking"]},{"year":2021,"claim":"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","pmids":["33761347"],"confidence":"High","gaps":["Whether phase separation occurs at physiological concentrations in mammalian neurons unconfirmed","Role of liprin-α1 vs. liprin-α2 in phase separation not distinguished"]},{"year":2022,"claim":"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","pmids":["36171301"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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","pmids":["38472649"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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","pmids":["40484382"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,4,14,28,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,20,25]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[16,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,10,16,18,22,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,27,30]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[19]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[21,22]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,6,14,17,23,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,25]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,5,21]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12,18,21,22]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[10,13,18]}],"complexes":["Liprin-α1/ERC1/LL5 leading-edge complex","CASK/Mint-1/MALS presynaptic complex","LAR-RPTP/liprin-α/liprin-β complex"],"partners":["PTPRF","CASK","ERC1","GRIP1","GIT1","KIF1A","PPP2R5C","PPP2R5D"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q13136","full_name":"Liprin-alpha-1","aliases":["LAR-interacting protein 1","LIP-1","Protein tyrosine phosphatase receptor type f polypeptide-interacting protein alpha-1","PTPRF-interacting protein alpha-1"],"length_aa":1202,"mass_kda":135.8,"function":"May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates","subcellular_location":"Cytoplasm, cell cortex; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13136/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPFIA1","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPFIA1","total_profiled":1310},"omim":[{"mim_id":"621185","title":"HOUGE-JANSSENS SYNDROME 4; HJS4","url":"https://www.omim.org/entry/621185"},{"mim_id":"612597","title":"CYTOTOXIC AND REGULATORY T-CELL MOLECULE; CRTAM","url":"https://www.omim.org/entry/612597"},{"mim_id":"611054","title":"PTPRF-INTERACTING PROTEIN ALPHA-1; PPFIA1","url":"https://www.omim.org/entry/611054"},{"mim_id":"603145","title":"PTPRF-INTERACTING PROTEIN ALPHA-4; PPFIA4","url":"https://www.omim.org/entry/603145"},{"mim_id":"603144","title":"PTPRF-INTERACTING PROTEIN ALPHA-3; PPFIA3","url":"https://www.omim.org/entry/603144"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPFIA1"},"hgnc":{"alias_symbol":["LIP.1","LIPRIN"],"prev_symbol":[]},"alphafold":{"accession":"Q13136","domains":[{"cath_id":"1.10.150.50","chopping":"873-954","consensus_level":"medium","plddt":89.5784,"start":873,"end":954},{"cath_id":"1.10.150.50","chopping":"962-1126","consensus_level":"medium","plddt":94.8036,"start":962,"end":1126}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13136","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13136-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13136-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPFIA1","jax_strain_url":"https://www.jax.org/strain/search?query=PPFIA1"},"sequence":{"accession":"Q13136","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13136.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13136/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13136"}},"corpus_meta":[{"pmid":"10517634","id":"PMC_10517634","title":"The 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phosphatases (LAR, PTPδ, PTPσ), interacting via its coiled-coil domain; all three RPTPs associate with LIP.1 in co-precipitation assays.\",\n      \"method\": \"Co-precipitation / binding assays with recombinant proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery of interaction, replicated across multiple RPTP family members in the same study\",\n      \"pmids\": [\"8524829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, immunofluorescence\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from brain plus dominant-negative functional rescue in neurons, replicated\",\n      \"pmids\": [\"11931740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, sciatic nerve ligation (axonal transport assay), co-fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ligation, fractionation) in a single study\",\n      \"pmids\": [\"12522103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation from brain, co-expression and immunofluorescence in cultured neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct binding confirmed in vitro plus Co-IP from brain and cellular localization rescue\",\n      \"pmids\": [\"12923177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Direct binding assay, co-immunoprecipitation from brain, electron microscopy, dominant-negative expression in neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct binding, Co-IP from brain, and functional dominant-negative rescue\",\n      \"pmids\": [\"12629171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Live imaging of GFP-tagged cargo in Drosophila mutants, pull-down assay, ultrastructural analysis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct live observation in mutants plus biochemical pulldown, multiple orthogonal methods\",\n      \"pmids\": [\"15823543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Protein purification from brain, co-immunoprecipitation, electrophysiology in MALS triple knockout mice\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical purification from brain plus genetic knockout with defined physiological phenotype\",\n      \"pmids\": [\"16186258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro phosphorylation assay, pulldown with GST-LAR, co-precipitation with ATP-agarose, phosphatase treatment\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemistry but single lab, mechanistic interpretation of autophosphorylation needs further validation\",\n      \"pmids\": [\"16313174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, RNAi knockdown, cell spreading/migration assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus functional epistasis via knockdown, single lab\",\n      \"pmids\": [\"17363573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Tandem affinity purification and mass spectrometry, co-immunoprecipitation, RNAi knockdown\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — TAP-MS discovery of interaction plus functional KD phenotype, single lab\",\n      \"pmids\": [\"18235218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, overexpression, cell spreading assay on fibronectin, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with specific phenotypic readout plus domain-function dissection identifying LAR dependence\",\n      \"pmids\": [\"19690048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Peptide inhibitor microinjection, electrophysiology (LTD recording) in hippocampal slices\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — peptide disruption of specific interactions with clean electrophysiological readout, single lab\",\n      \"pmids\": [\"19534762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, overexpression, antibody-induced internalization assay, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD and OE with specific integrin internalization readout, single lab\",\n      \"pmids\": [\"20096687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, overexpression, time-lapse microscopy, ECM degradation assay, invadopodium analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (KD and OE) with multiple orthogonal functional readouts\",\n      \"pmids\": [\"21151172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, cellular studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation via mutagenesis and cell-based assays\",\n      \"pmids\": [\"21855798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, overexpression of truncation/deletion mutants, immunofluorescence, migration assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple methods but single lab, complex epistasis\",\n      \"pmids\": [\"21695141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Pulldown assay, co-immunoprecipitation, RNAi knockdown, overexpression, cell fractionation, actin staining\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding identified biochemically plus bidirectional genetic manipulation with clear cytoskeletal phenotype\",\n      \"pmids\": [\"22266902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Knockdown/knockout in neurons, FRAP, electron microscopy of synaptic ultrastructure, electrophysiology\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including FRAP and ultrastructure in a single comprehensive study\",\n      \"pmids\": [\"23751498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown of individual components, invasion and migration assays, live imaging, integrin internalization assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic depletion of multiple complex members with multiple functional readouts\",\n      \"pmids\": [\"24982445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based interactomics, co-immunoprecipitation, RNAi knockdown, luciferase reporter assays for Hh output, immunofluorescence of cilia\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS identification plus functional KD with multiple orthogonal readouts (localization and transcriptional output)\",\n      \"pmids\": [\"25492966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays (ITC, SPR), structural analysis, actin polymerization assays, competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with thermodynamic and kinetic characterization\",\n      \"pmids\": [\"25911102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (PPFIA1 with active α5β1), RNAi knockdown, confocal/TIRF microscopy, zebrafish morpholino knockdown, fibronectin fibrillogenesis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical interaction plus in vivo knockdown with multiple phenotypic readouts in two model systems\",\n      \"pmids\": [\"27876801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, dominant-negative expression (liprin-N fragment), immunofluorescence, live imaging, invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative and KD with mechanistic endpoint (FA disassembly, endosome localization), single lab\",\n      \"pmids\": [\"27659488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation assay, neuronal culture, binding competition assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical Co-IP and in vitro phosphorylation, single lab\",\n      \"pmids\": [\"27015872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, transcriptome profiling, immunofluorescence in 2D and 3D conditions\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mostly transcriptomics; mechanism of CD82 regulation is indirect\",\n      \"pmids\": [\"30005669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, cellular clustering assays, phosphatase activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis-validated functional consequences, multiple orthogonal assays\",\n      \"pmids\": [\"31924785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, in vitro binding assays, cell-based synaptogenesis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structure plus mutagenesis with functional validation in cells\",\n      \"pmids\": [\"32005855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Structural and biochemical characterization of coiled-coil oligomerization, in vitro phase separation assays, FRAP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro phase separation plus structural characterization with gain-of-function mutation analysis\",\n      \"pmids\": [\"33761347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis of SLiM, cell fractionation, RNAi knockdown, cell spreading/invasion assays, immunofluorescence\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with SLiM mutagenesis, bidirectional manipulation, and clear functional readout\",\n      \"pmids\": [\"36171301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Quadruple liprin-α knockout in human neurons (iPSC-derived), rescue with individual isoforms and interaction-defective mutants, electrophysiology, immunofluorescence, electron microscopy\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — complete genetic ablation in human neurons with domain-specific rescue experiments defining molecular hierarchy\",\n      \"pmids\": [\"38472649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — MS-identified interaction validated by mutagenesis, KO cells, phospho-specific antibody, and multiple condensate assays in a peer-reviewed study\",\n      \"pmids\": [\"40484382\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPFIA1/liprin-α1 is a multidomain scaffolding protein that constitutively associates with LAR-family receptor protein tyrosine phosphatases (via its SAM domains), promotes their clustering to negatively regulate phosphatase activity, and assembles large presynaptic active zone complexes (with ELKS, RIM, CASK, GRIP, GIT1, and KIF1A) through oligomerization and phase separation regulated by phosphorylation at S763 via PP2A/B56δ; in non-neuronal cells it drives cell migration and invasion by controlling focal adhesion turnover, active integrin β1 recycling (via a PI4KB–Rab11B–PTPRF pathway), actin dynamics (by displacing mDia from the plasma membrane), and by recruiting PP2A–B56γ to plasma membrane-associated platforms at the leading edge.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-precipitation of recombinant LIP.1 with LAR, PTPδ, and PTPσ\",\n      \"pmids\": [\"8524829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of LAR–liprin interaction unknown\", \"No structural detail of the binding interface\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP from brain and dominant-negative disruption of GRIP–liprin interaction in cultured neurons blocking AMPAR clustering\",\n      \"pmids\": [\"11931740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether liprin-α1 specifically or other isoforms contribute was unclear\", \"Mechanism of AMPAR endocytic vs. exocytic regulation not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP from brain, sciatic nerve ligation showing co-transport with KIF1A, in vitro binding and neuronal colocalization for ERC and GIT1\",\n      \"pmids\": [\"12522103\", \"12923177\", \"12629171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all partners bind simultaneously or form mutually exclusive sub-complexes was unknown\", \"Stoichiometry of assembled complexes unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"15823543\", \"16186258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian liprin-α1-specific knockout not yet available\", \"Whether transport and active zone assembly functions are separable was unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi and overexpression in COS7 cells showing LAR-dependent spreading; peptide inhibition of GRIP–liprin interaction blocking mAChR-LTD in hippocampal slices\",\n      \"pmids\": [\"19690048\", \"19534762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from LAR that mediates spreading not identified\", \"Whether liprin-α1 acts catalytically or purely as a scaffold in non-neuronal cells unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA and overexpression modulating β1 integrin internalization rates; bidirectional manipulation in MDA-MB-231 cells affecting ECM degradation and invadopodium lifetime\",\n      \"pmids\": [\"20096687\", \"21151172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking liprin-α1 to integrin endocytic machinery not resolved\", \"In vivo tumor invasion data lacking\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography of liprin-α2/CASK and liprin-α/liprin-β SAM complexes with mutagenesis validation\",\n      \"pmids\": [\"21855798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length liprin-α not determined\", \"Whether CASK and liprin-β binding to liprin-α is simultaneous or competitive in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pulldown and Co-IP identifying mDia–liprin-α interaction; RNAi and overexpression showing bidirectional effects on membrane mDia levels and stress fibers\",\n      \"pmids\": [\"22266902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"24982445\", \"25492966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of PPFIA1 with active integrin, RNAi/TIRF microscopy in endothelial cells, zebrafish morpholino knockdown with vascular phenotype\",\n      \"pmids\": [\"27876801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway operates in non-endothelial cell types not tested\", \"Direct vs. adaptor role of PPFIA1 in the recycling complex not structurally resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography at up to 1.91 Å resolution, structure-guided mutagenesis, cellular clustering and phosphatase activity assays, synaptogenesis assay\",\n      \"pmids\": [\"31924785\", \"32005855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length liprin-α in complex with LAR not structurally resolved\", \"In vivo confirmation that LAR clustering controls phosphatase output at synapses lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro phase separation assays with recombinant proteins, gain-of-function oligomerization mutant, FRAP\",\n      \"pmids\": [\"33761347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phase separation occurs at physiological concentrations in mammalian neurons unconfirmed\", \"Role of liprin-α1 vs. liprin-α2 in phase separation not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"SLiM mutagenesis blocking B56γ binding, rescue experiments showing SLiM-dependence of cell spreading, RNAi of B56γ phenocopying liprin-α1 depletion\",\n      \"pmids\": [\"36171301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"iPSC-derived human neuron quadruple KO with isoform-specific and interaction-defective rescue, electrophysiology, EM\",\n      \"pmids\": [\"38472649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"40484382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4, 14, 28, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 20, 25]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 10, 16, 18, 22, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 27, 30]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 6, 14, 17, 23, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 25]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 5, 21]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12, 18, 21, 22]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [10, 13, 18]}\n    ],\n    \"complexes\": [\n      \"Liprin-α1/ERC1/LL5 leading-edge complex\",\n      \"CASK/Mint-1/MALS presynaptic complex\",\n      \"LAR-RPTP/liprin-α/liprin-β complex\"\n    ],\n    \"partners\": [\n      \"PTPRF\",\n      \"CASK\",\n      \"ERC1\",\n      \"GRIP1\",\n      \"GIT1\",\n      \"KIF1A\",\n      \"PPP2R5C\",\n      \"PPP2R5D\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}