{"gene":"PPFIA1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1995,"finding":"PPFIA1 (LIP.1) physically associates with LAR, PTPδ, and PTPσ transmembrane receptor protein tyrosine phosphatases via its intracellular coiled-coil domain, and was postulated to recruit LAR to focal adhesions.","method":"Co-precipitation / biochemical association assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct biochemical association shown across multiple RPTPs, single lab, replicated across three phosphatase family members","pmids":["8524829"],"is_preprint":false},{"year":2005,"finding":"Liprin-α1 (PPFIA1) autophosphorylates and phosphorylation of liprin-α1 is required for its binding to LAR; dephosphorylation by calf intestinal phosphatase weakens the liprin–LAR interaction, and liprin binds ATP-agarose in an ATP-competable manner.","method":"In vitro phosphorylation assay with purified protein from Sf-9 cells, co-precipitation with recombinant GST-LAR, ATP-agarose binding competition, [32P]-orthophosphate labeling in vivo","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution with purified protein plus in vivo labeling, single lab with multiple orthogonal methods","pmids":["16313174"],"is_preprint":false},{"year":2002,"finding":"Liprin-α (PPFIA1 family) interacts with the multi-PDZ protein GRIP, and dominant-negative constructs that interfere with the GRIP–liprin interaction disrupt surface expression and dendritic clustering of AMPA receptors in cultured neurons. Liprin-α and LAR-RPTP coimmunoprecipitate with GRIP and AMPA receptors from neurons.","method":"Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, immunofluorescence","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from brain, dominant-negative functional rescue, replicated across labs in related work","pmids":["11931740"],"is_preprint":false},{"year":2003,"finding":"Liprin-α1 (PPFIA1) directly interacts with GIT1 (an ARF-GAP); dominant-negative constructs interfering with the GIT1–liprin-α1 interaction selectively reduce dendritic and surface clustering of AMPA receptors, and GIT1 forms a complex with liprin-α1, GRIP, and AMPA receptors in brain.","method":"Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, electron microscopy of GIT1 distribution","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, dominant-negative with defined readout, electron microscopy, multiple orthogonal methods","pmids":["12629171"],"is_preprint":false},{"year":2003,"finding":"Liprin-α1 (PPFIA1) interacts with the kinesin motor KIF1A; KIF1A co-accumulates with liprin-α1 in ligated sciatic nerves and co-immunoprecipitates with liprin-α1 and associated proteins (AMPA receptors, GRIP/ABP, RIM, GIT1, βPIX), suggesting liprin-α functions as a KIF1A receptor for axonal transport.","method":"Co-immunoprecipitation, sciatic nerve ligation, co-fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo nerve ligation, single lab","pmids":["12522103"],"is_preprint":false},{"year":2003,"finding":"Liprin-α1 (PPFIA1) directly interacts with ERC/CAST proteins (ERC2/CAST and ERC1b); coexpression of ERC2 with liprin-α1 in cultured neurons redistributes liprin-α1 to synaptic sites, and liprin-α1–ERC2 complex is detected in brain by co-immunoprecipitation.","method":"In vitro direct binding assay, co-immunoprecipitation from brain, coexpression in cultured neurons with immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown in vitro plus Co-IP from brain and cellular redistribution, single lab","pmids":["12923177"],"is_preprint":false},{"year":2005,"finding":"MALS/Veli proteins form a presynaptic complex with liprin-α (PPFIA1 family); mice lacking all three MALS isoforms die perinatally with reduced excitatory synaptic transmission due to a presynaptic vesicle cycling deficit. Liprin-α was identified as a major component of the MALS complex purified from brain.","method":"Affinity purification from brain, triple knockout mouse analysis, autaptic electrophysiology","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical purification plus genetic knockout with defined electrophysiological phenotype, multiple orthogonal methods","pmids":["16186258"],"is_preprint":false},{"year":2007,"finding":"PPFIA1 (liprin-α1) interacts with ING4 (inhibitor of growth 4); the two proteins colocalize at lamellipodia near vinculin. Overexpressed liprin-α1 enhances cell spreading and migration, while knockdown suppresses cell motility. ING4-mediated suppression of cell motility requires liprin-α1, as ING4 does not further suppress motility when liprin-α1 is knocked down.","method":"Co-immunoprecipitation, RNAi knockdown, overexpression, wound healing / migration assay, immunofluorescence colocalization","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus epistatic RNAi rescue, single lab, multiple functional readouts","pmids":["17363573"],"is_preprint":false},{"year":2007,"finding":"Liprin-α1 (PPFIA1) interacts with PP2A B56γ regulatory subunit; B56γ–liprin-α1 complexes are biochemically distinct from PP2A complexes. Suppression of liprin-α1 alters cell morphology.","method":"Tandem affinity purification / mass spectrometry, co-immunoprecipitation, RNAi knockdown","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — TAP-MS identification plus Co-IP, single lab, limited functional follow-up","pmids":["18235218"],"is_preprint":false},{"year":2009,"finding":"Liprin-α1 (PPFIA1) is stably associated with the cell membrane and is required for cell spreading on fibronectin; depletion inhibits lamellipodia formation, while overexpression enhances spreading and focal adhesion formation. The effects of liprin-α1 on spreading (but not cell-edge reorganization) require its interaction with LAR-type RPTPs. Cooperation between liprin-α1 and talin is required for spreading.","method":"RNAi knockdown, overexpression, cell spreading assay on fibronectin, immunofluorescence, membrane fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotype, LAR-dependence tested with interaction mutants, single lab","pmids":["19690048"],"is_preprint":false},{"year":2009,"finding":"mAChR-LTD in hippocampus requires interactions among GluA2, GRIP, and liprin-α (PPFIA1 family); peptides that block GRIP–GluA2 or GRIP–liprin-α binding specifically block mAChR-LTD but not mGluR-LTD, linking these interactions to AMPA receptor endocytosis during LTD.","method":"Peptide inhibition of protein–protein interaction in hippocampal slice electrophysiology, LTD induction","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide interference with defined LTD readout, selective for mAChR vs mGluR pathway, single lab","pmids":["19534762"],"is_preprint":false},{"year":2010,"finding":"Liprin-α1 (PPFIA1) overexpression inhibits antibody-induced β1 integrin internalization and stabilizes integrin receptors at the cell surface; depletion of liprin-α1 by siRNA increases the rate of integrin internalization, affecting focal adhesion size and distribution of inactive β1 integrins.","method":"siRNA knockdown, overexpression, antibody-induced internalization assay, immunofluorescence, focal adhesion measurement","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined integrin trafficking readout, single lab","pmids":["20096687"],"is_preprint":false},{"year":2010,"finding":"Liprin-α1 (PPFIA1) is required for migration and invasion of highly invasive MDA-MB-231 breast cancer cells; its depletion causes lamellipodia instability, reduces invadopodium lifetime and ECM degradation per invadopodium, while overexpression enhances these processes.","method":"siRNA knockdown, overexpression, time-lapse microscopy, invasion assay, ECM degradation assay, cortactin-GFP tracking of invadopodia","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with multiple defined cellular phenotypes, single lab","pmids":["21151172"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of liprin-α2/CASK complex shows that the three SAM domains of liprin-α form an integrated supramodule binding the CASK kinase-like domain; this interaction is unique to vertebrates. Three X-linked mental retardation CASK mutants are defective in binding liprin-α. Crystal structure of the liprin-α/liprin-β SAM domain complex reveals the mechanism of liprin heterodimerization, and a CASK/liprin-α/liprin-β ternary complex can form.","method":"X-ray crystallography, biochemical binding assays, mutagenesis of CASK disease alleles, cellular studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of two complexes with functional mutagenesis validation and disease-mutant analysis","pmids":["21855798"],"is_preprint":false},{"year":2011,"finding":"Liprin-α1 (PPFIA1) functionally interacts with GIT1 to regulate cell spreading and migration: GIT1 depletion phenocopies liprin-α1 depletion in lamellipodia formation, and liprin-α1 may compete with paxillin for GIT1 binding. GIT1 and liprin-α1 reciprocally regulate each other's subcellular localization at focal adhesions and cell edge.","method":"siRNA knockdown, dominant-negative (liprin-ΔCC3), co-immunoprecipitation, immunofluorescence, haptotactic migration assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutual depletion epistasis and dominant-negative with defined spreading/migration phenotypes, single lab","pmids":["21695141"],"is_preprint":false},{"year":2012,"finding":"Liprin-α (PPFIA1 family) binds mDia (a Rho-effector actin nucleator) through the central region of liprin-α and the DID-DD domains of mDia, competing with the DAD autoregulatory domain. Liprin-α overexpression decreases mDia membrane localization and attenuates Rho-mDia-mediated stress fiber formation; liprin-α depletion by RNAi increases mDia in the membrane fraction and enhances stress fiber formation.","method":"Pulldown identifying liprin-α as mDia-binding protein, domain mapping, competition binding assay, RNAi knockdown, overexpression, membrane fractionation, immunofluorescence of stress fibers","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — pulldown with domain mapping, bidirectional functional manipulation, competition assay, multiple orthogonal methods","pmids":["22266902"],"is_preprint":false},{"year":2014,"finding":"PPFIA1 (liprin-α1) forms a complex with ERC1a and LL5 proteins to drive cell migration; depletion of any component reduces migration, invasion, lamellipodial persistence, and internalization of active β1 integrin at the cell front. The complex defines polarized cytoplasmic structures at the protruding cell edge.","method":"siRNA knockdown, live-cell microscopy, invasion assay, integrin internalization assay, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-component depletion with multiple cellular phenotypes, single lab","pmids":["24982445"],"is_preprint":false},{"year":2014,"finding":"PPFIA1 (liprin-α1) interacts with PP2A and Kif7, and the PPFIA1–PP2A complex promotes dephosphorylation of Kif7, triggering Kif7 trafficking to the tips of primary cilia and promoting Gli transcriptional activity downstream of Hedgehog signaling.","method":"Mass spectrometry identification of Kif7 interactors, Co-IP, siRNA knockdown of PPFIA1 and PP2A, immunofluorescence of cilia, Hedgehog reporter assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactomics plus Co-IP and functional knockdown with pathway readout, single lab","pmids":["25492966"],"is_preprint":false},{"year":2015,"finding":"Liprin-α3 binds to the mDia1 N-terminal DID domain and allosterically inhibits mDia1 activation by RhoA·GTP; liprin-α3 competes with DAD for a highly overlapping binding site on mDiaN, lowers RhoA and DAD regulatory potency, and regulates actin polymerization.","method":"Reconstituted in vitro binding and competition assays, ITC thermodynamics, mutagenesis, cellular actin filament content measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with thermodynamic characterization and domain/competition mapping, single lab","pmids":["25911102"],"is_preprint":false},{"year":2016,"finding":"PPFIA1 interacts with active α5β1 integrin (via direct interaction shown by Co-IP) and localizes near endothelial cell adhesions where post-Golgi carriers are targeted. PPFIA1 is required for fibronectin polymerization-dependent vascular morphogenesis both in vitro and in developing zebrafish. PPFIA1 acts downstream of Rab11B and PTPRF in a pathway (PI4KB→AP-1A→Rab11B→PTPRF→PPFIA1) that funnels FN secretion and recycling of active α5β1 integrin from the TGN to the cell surface.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, zebrafish morpholino knockdown, vesicle trafficking assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction with active integrin, pathway ordering by knockdown, in vivo zebrafish validation, multiple orthogonal methods","pmids":["27876801"],"is_preprint":false},{"year":2016,"finding":"Liprin-α1 (PPFIA1) and ERC1 promote focal adhesion turnover at the cell edge; displacement of ERC1 from the cell edge (by dominant-negative liprin-N) inhibits disassembly of focal adhesions. Liprin-α1 and ERC1 colocalize with active integrin β1 clusters distinct from cytoplasmic FA proteins and influence localization of peripheral Rab7-positive endosomes.","method":"Dominant-negative expression (liprin-N fragment), siRNA knockdown, immunofluorescence, focal adhesion turnover assay, Rab7 endosome localization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative plus siRNA with FA turnover readout, single lab","pmids":["27659488"],"is_preprint":false},{"year":2016,"finding":"CASK stabilizes neurexin1β and creates a structural link to liprin-α at the presynaptic active zone; liprin-α and Mint1 compete for CASK binding, but neurexin1β eliminates this competition, enabling a four-protein complex. CASK phosphorylation of neurexin1β modulates the interaction of liprin-α with the CASK–neurexin1β–Mint1 complex.","method":"Co-immunoprecipitation, in vitro binding/competition assays, neuronal culture, phosphorylation assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and cellular binding competition with phosphorylation regulation, single lab","pmids":["27015872"],"is_preprint":false},{"year":2018,"finding":"Liprin-α/TANC2 capture KIF1A-transported dense core vesicles at dendritic spines; liprin-α is not part of the KIF1A-cargo complex itself but acts as a capture/recruitment factor at postsynaptic sites. Calcium acting via calmodulin enhances KIF1A binding to DCVs and increases vesicle motility.","method":"KIF1A interactome by mass spectrometry, co-immunoprecipitation, live imaging of DCV transport, neuronal knockdown","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus Co-IP and live imaging, single lab","pmids":["30021165"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of LAR D1D2 in complex with liprin-α3 SAM repeats at 1.91 Å reveals a conserved two-site binding mode involving the D2 phosphatase domain. Liprin-α promotes LAR clustering in cells via both the liprin-α/LAR interaction and liprin-α oligomerization; LAR forms homophilic D1/D1 interactions that are disrupted by liprin-α-promoted clustering, and this D1/D1 disruption increases LAR phosphatase activity. LAR binding to liprin-α allosterically regulates the liprin-α/liprin-β interaction.","method":"X-ray crystallography, structure-based mutagenesis, cellular clustering assays, phosphatase activity assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation in vitro and in cellulo, phosphatase activity measurement","pmids":["31924785"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of mouse PTPδ D2 domain in complex with liprin-α3 tSAM at 1.91 Å shows PTPδ D2 interacts with the N-terminal helix and SAM1/SAM2 of liprin-α3; structure-based mutations of SAM1 and SAM2 contacts abolish binding and synaptogenic activity in cellulo.","method":"X-ray crystallography, structure-based mutagenesis, synaptogenic co-culture assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis in vitro and in cellulo","pmids":["32005855"],"is_preprint":false},{"year":2021,"finding":"Liprin-α proteins oligomerize via the N-terminal coiled-coil region; oligomerized liprin-α2 drives phase separation of ELKS N-terminal segments through multivalent interactions, and liprin-α2 controls protein distribution between ELKS and RIM/RIM-BP condensates. A gain-of-function mutation in the coiled-coil disrupts intramolecular inhibition and promotes intermolecular interactions.","method":"Structural and biochemical characterization of coiled-coil oligomerization, phase separation assays in cells, gain-of-function mutation analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural + biochemical reconstitution of phase separation mechanism with mutagenesis, single lab with multiple orthogonal methods","pmids":["33761347"],"is_preprint":false},{"year":2022,"finding":"Liprin-α1 (PPFIA1) contains an LxxIxE short linear motif in its N-terminal dimerization domain that mediates interaction with the B56γ regulatory subunit of PP2A. B56γ mediates recruitment of the PP2A holoenzyme to liprin-α1. Liprin-α1 recruits B56γ to plasma membrane-associated platforms (PMAPs) at the edge of migrating MDA-MB-231 cells; silencing of B56γ inhibits cell spreading, invasion and lamellipodia dynamics similarly to liprin-α1 silencing, and this requires an intact SLiM.","method":"Co-immunoprecipitation, point mutagenesis of SLiM, siRNA knockdown, cell spreading/invasion/lamellipodia assays, immunofluorescence","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — motif mutagenesis abolishing interaction plus bidirectional functional assays with rescue, multiple orthogonal methods","pmids":["36171301"],"is_preprint":false},{"year":2022,"finding":"CASK CaMK domain missense variants from MICPCH patients selectively weaken binding to liprin-α2; CASK suppresses liprin-α2 phase condensate formation in HEK293T cells and primary neurons, and this suppression is associated with altered liprin-α2 phosphorylation. The p.E115K variant fails to suppress condensate formation, correlating with the severe MICPCH phenotype.","method":"Co-immunoprecipitation with patient-derived CASK variants, condensate formation assay in HEK293T and neurons, phosphorylation analysis","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function with disease alleles and cellular phase separation readout, single lab","pmids":["36137748"],"is_preprint":false},{"year":2024,"finding":"In human neurons lacking all four liprin-α isoforms (including PPFIA1), nascent synaptic contacts form normally but recruitment of active zone components and accumulation of synaptic vesicles is fully blocked ('empty' boutons), abolishing synaptic transmission. LAR-RPTP family adhesion molecules and neurexin–CASK interactions are required to localize liprin-α to nascent synaptic sites; liprin-α then recruits presynaptic components via direct interaction with ELKS proteins, establishing a hierarchical assembly sequence.","method":"CRISPR/Cas9 quadruple knockout of all four liprin-α isoforms in human neurons, electrophysiology, electron microscopy, immunofluorescence, interaction studies","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete genetic ablation in human neurons with defined ultrastructural and electrophysiological phenotype, multiple orthogonal methods, clear epistasis","pmids":["38472649"],"is_preprint":false},{"year":2024,"finding":"Depletion of liprin-α1 (PPFIA1) in cancer cells leads to increased phospho-ERK1/2 levels and more pronounced RAS protein redistribution to the cell membrane, regardless of KRAS mutational status, indicating liprin-α1 negatively regulates MAPK/ERK oncogenic signaling.","method":"siRNA knockdown, Western blot for p-ERK1/2, pharmacological ERK inhibitor screen (trametinib), immunofluorescence of RAS membrane localization","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined signaling readout across multiple cell lines, single lab, mechanism not fully resolved","pmids":["38264964"],"is_preprint":false},{"year":2024,"finding":"PPP2R5D (B56δ) PP2A holoenzyme interacts with liprin-α1 via an LxxIxE SLiM in its N-terminal dimerization domain; mutation of SLiM or knockout of PPP2R5D increases liprin-α1 LLPS in HEK293 cells. Phospho-mimetic S763E mutation drives liprin-α1 LLPS, and B56δ-PP2A inhibits LLPS by dephosphorylation at S763 and other sites. Liprin-α1/β1 heterodimerization is decreased under conditions promoting LLPS, and liprin-β1 itself inhibits liprin-α1 LLPS. PPP2R5D E420K variant (Houge-Janssens Syndrome) compromises suppression of liprin-α1 LLPS.","method":"MS-based interactomics, co-immunoprecipitation, PPP2R5D knockout HEK293 cells, phospho-mimetic and SLiM mutagenesis, phospho-specific antibody, LLPS assay in live cells, domain-mapping","journal":"The Journal of biological chemistry (and preprint bioRxiv)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (interactomics, KO, mutagenesis, phospho-specific antibody, disease variant), single lab with peer-reviewed publication","pmids":["40484382","38948786"],"is_preprint":false}],"current_model":"PPFIA1 (liprin-α1) is a multi-domain scaffolding protein that physically bridges LAR-family receptor protein tyrosine phosphatases (via phosphorylation-dependent SAM domain interactions) to cytoplasmic effectors including GRIP, GIT1, ERC1, CASK, ELKS, and PP2A/B56 complexes; at presynaptic terminals it acts as a hierarchical master organizer—recruited by LAR-RPTPs and neurexin–CASK contacts to nascent synaptic sites where it recruits ELKS and other active zone components for vesicle docking and release—while in non-neuronal cells it localizes to plasma membrane-associated platforms at the leading edge to drive integrin recycling (active α5β1 via a PTPRF–PPFIA1 axis), focal adhesion turnover, and actin regulation through negative control of mDia; its activity state and higher-order assembly are regulated by autophosphorylation, PKC/SAD-kinase-triggered phosphorylation promoting liquid-liquid phase separation, and PP2A-B56δ-mediated dephosphorylation that dissolves condensates and promotes heterodimerization with liprin-β."},"narrative":{"mechanistic_narrative":"PPFIA1 (liprin-α1) is a multidomain scaffolding protein that organizes membrane-associated signaling platforms in both neuronal and non-neuronal cells by bridging LAR-family receptor protein tyrosine phosphatases to a defined set of cytoplasmic effectors [PMID:8524829, PMID:31924785]. It associates with LAR, PTPδ, and PTPσ through its intracellular region, an interaction that depends on liprin-α1 autophosphorylation and is weakened by dephosphorylation [PMID:8524829, PMID:16313174]; structurally, the liprin-α tandem SAM domains engage the LAR D1D2 phosphatase region in a conserved two-site mode, and liprin-α–driven clustering of LAR disrupts homophilic D1/D1 contacts to increase phosphatase activity [PMID:31924785, PMID:32005855]. The same SAM supramodule binds the CASK kinase-like domain and mediates liprin-α/liprin-β heterodimerization, enabling assembly of higher-order CASK–liprin complexes [PMID:21855798]. At presynaptic terminals liprin-α acts as a hierarchical master organizer: recruited to nascent synaptic contacts by LAR-RPTP and neurexin–CASK interactions, it then recruits ELKS and other active-zone components to enable vesicle accumulation and release, and loss of all liprin-α isoforms produces structurally normal but functionally 'empty' boutons [PMID:38472649, PMID:16186258, PMID:27015872]. In non-neuronal cells liprin-α1 builds plasma-membrane-associated platforms at the protruding cell edge together with ERC1 and LL5, driving cell spreading, lamellipodial persistence, focal adhesion turnover, and recycling of active α5β1 integrin from the TGN to the surface through a Rab11B–PTPRF–PPFIA1 axis [PMID:24982445, PMID:19690048, PMID:27659488, PMID:27876801]. It links these platforms to actin regulation by negatively controlling the formin mDia—binding the mDia DID domain in competition with the DAD autoinhibitory segment to restrain RhoA-driven actin polymerization [PMID:22266902, PMID:25911102]—and to GIT1/ARF-GAP and PP2A-B56 activities [PMID:21695141, PMID:18235218, PMID:36171301]. Liprin-α1 higher-order assembly is governed by phosphorylation-driven liquid–liquid phase separation: an LxxIxE SLiM recruits the B56δ/B56γ PP2A holoenzyme, and PP2A-mediated dephosphorylation (including at S763) dissolves condensates and favors liprin-α/liprin-β heterodimerization [PMID:40484382, PMID:38948786, PMID:36171301, PMID:33761347]. Functionally, liprin-α1 promotes breast cancer cell migration and invasion and negatively regulates MAPK/ERK signaling, while CASK disease variants that weaken liprin binding implicate this axis in MICPCH and X-linked intellectual disability [PMID:21151172, PMID:38264964, PMID:36137748, PMID:21855798].","teleology":[{"year":1995,"claim":"Established the founding molecular link of PPFIA1, showing it physically associates with LAR-family receptor tyrosine phosphatases and might recruit them to focal adhesions.","evidence":"Co-precipitation of LIP.1 with LAR, PTPδ, PTPσ via its coiled-coil domain","pmids":["8524829"],"confidence":"Medium","gaps":["Did not resolve which liprin domain contacts the phosphatase at atomic level","Recruitment to focal adhesions postulated, not demonstrated functionally","No measure of effect on phosphatase activity"]},{"year":2002,"claim":"Connected liprin-α to postsynaptic receptor organization by showing the GRIP–liprin interaction controls AMPA receptor surface clustering.","evidence":"Co-IP from brain plus dominant-negative disruption in cultured neurons","pmids":["11931740"],"confidence":"High","gaps":["Did not separate liprin-α1 from other liprin-α isoforms","Mechanism of clustering downstream of GRIP binding unresolved"]},{"year":2003,"claim":"Expanded the liprin effector network to GIT1, ERC/CAST, and the kinesin KIF1A, framing liprin-α as both a synaptic scaffold and a motor cargo adaptor.","evidence":"Co-IP from brain, dominant-negative neuronal expression, sciatic nerve ligation, in vitro binding and coexpression redistribution","pmids":["12629171","12522103","12923177"],"confidence":"High","gaps":["Direct versus indirect nature of some interactions not uniformly established","Whether liprin is true KIF1A receptor or capture factor unresolved at this stage"]},{"year":2005,"claim":"Defined the biochemical requirement for liprin phosphorylation in LAR binding and placed liprin-α in a presynaptic MALS/Veli complex essential for vesicle cycling.","evidence":"In vitro autophosphorylation and ATP-agarose competition with purified protein; MALS triple-knockout mice with autaptic electrophysiology","pmids":["16313174","16186258"],"confidence":"High","gaps":["Kinase responsible for liprin autophosphorylation in vivo not identified","MALS knockout phenotype not isoform-specific to PPFIA1"]},{"year":2007,"claim":"Implicated liprin-α1 in cell motility through ING4 and PP2A B56γ associations, linking the scaffold to migration control beyond neurons.","evidence":"Co-IP, RNAi epistasis, migration assays; TAP-MS identification of B56γ","pmids":["17363573","18235218"],"confidence":"Medium","gaps":["Mechanism by which ING4 acts through liprin-α1 not resolved","Functional consequence of B56γ association limited to morphology"]},{"year":2009,"claim":"Demonstrated that membrane-associated liprin-α1 drives cell spreading and lamellipodia formation, partly through LAR-RPTP interaction and talin cooperation.","evidence":"RNAi and overexpression with fibronectin spreading assays, interaction mutants, membrane fractionation","pmids":["19690048"],"confidence":"Medium","gaps":["LAR-independent cell-edge function mechanistically undefined","Nature of talin cooperation not molecularly mapped"]},{"year":2010,"claim":"Showed liprin-α1 stabilizes integrin at the surface and supports invadopodium-mediated ECM degradation, tying the scaffold to integrin trafficking and invasion.","evidence":"siRNA/overexpression integrin internalization assays; time-lapse invadopodia and ECM degradation tracking in MDA-MB-231 cells","pmids":["20096687","21151172"],"confidence":"Medium","gaps":["Direct integrin binding not yet shown at this stage","Molecular link between liprin and the internalization machinery undefined"]},{"year":2011,"claim":"Provided structural and functional mechanism for liprin SAM-domain interactions with CASK and liprin-β, and tied them to X-linked intellectual disability CASK mutants.","evidence":"Crystal structures of liprin-α/CASK and liprin-α/liprin-β SAM complexes with disease-allele mutagenesis; GIT1 functional epistasis in spreading","pmids":["21855798","21695141"],"confidence":"High","gaps":["In vivo consequence of disrupted ternary complex not tested","Regulation of SAM-domain availability not addressed"]},{"year":2012,"claim":"Identified liprin-α as a negative regulator of the formin mDia, connecting the scaffold to RhoA-driven actin dynamics.","evidence":"mDia pulldown, domain mapping, DAD-competition binding, bidirectional RNAi/overexpression of stress fibers","pmids":["22266902"],"confidence":"High","gaps":["Spatial coordination of mDia inhibition at the cell edge not resolved","Whether inhibition is isoform-specific not addressed here"]},{"year":2014,"claim":"Defined a liprin-α1–ERC1–LL5 platform driving polarized migration and active-integrin internalization, and showed PPFIA1–PP2A dephosphorylates Kif7 to control ciliary Hedgehog signaling.","evidence":"Multi-component siRNA with live imaging and invasion assays; Kif7 interactome MS, Co-IP, knockdowns and Hedgehog reporters","pmids":["24982445","25492966"],"confidence":"Medium","gaps":["Structural basis of the ERC1–LL5 platform unresolved","Direct versus PP2A-bridged action on Kif7 not separated"]},{"year":2015,"claim":"Resolved the biophysical mechanism of mDia inhibition, showing liprin allosterically blocks RhoA·GTP activation by competing for the DAD site.","evidence":"Reconstituted in vitro binding, ITC, mutagenesis, cellular actin content with liprin-α3","pmids":["25911102"],"confidence":"High","gaps":["Demonstrated with liprin-α3; PPFIA1-specific affinity not directly measured","In vivo relevance at migrating cell edge not tested"]},{"year":2016,"claim":"Established PPFIA1 as a direct active-α5β1-integrin partner acting downstream of Rab11B/PTPRF to funnel integrin recycling and fibronectin secretion, with in vivo vascular relevance, and showed it drives focal adhesion turnover with ERC1.","evidence":"Co-IP, knockdowns, pathway ordering, zebrafish morpholino; dominant-negative liprin-N with FA turnover and Rab7 endosome readouts; CASK–neurexin1β presynaptic complex characterization","pmids":["27876801","27659488","27015872"],"confidence":"High","gaps":["Stoichiometry of the TGN-to-surface trafficking complex unresolved","Coupling of FA turnover to integrin recycling not mechanistically unified"]},{"year":2018,"claim":"Refined liprin-α's role in transport, showing it acts as a capture/recruitment factor (not core cargo) for KIF1A-delivered dense core vesicles at dendritic spines.","evidence":"KIF1A interactome MS, Co-IP, live DCV imaging, neuronal knockdown","pmids":["30021165"],"confidence":"Medium","gaps":["Molecular trigger linking liprin capture to vesicle release undefined","PPFIA1-specific contribution among isoforms not isolated"]},{"year":2020,"claim":"Provided atomic-resolution mechanism for liprin-α engagement of LAR and PTPδ phosphatase domains and showed liprin-driven LAR clustering activates phosphatase activity and allosterically tunes liprin heterodimerization.","evidence":"Crystal structures of LAR D1D2 and PTPδ D2 with liprin SAM repeats, structure-based mutagenesis, clustering, phosphatase and synaptogenic assays","pmids":["31924785","32005855"],"confidence":"High","gaps":["Conformational coupling between LAR binding and effector recruitment not fully resolved","Cellular consequences of altered LAR phosphatase activity not mapped"]},{"year":2021,"claim":"Showed liprin-α oligomerizes via its coiled-coil to drive multivalent phase separation of active-zone proteins and partition components between ELKS and RIM/RIM-BP condensates.","evidence":"Coiled-coil oligomerization analysis, cellular phase-separation assays, gain-of-function mutation","pmids":["33761347"],"confidence":"High","gaps":["Demonstrated with liprin-α2; PPFIA1-specific condensate behavior inferred","Physiological regulation of intramolecular inhibition not addressed here"]},{"year":2022,"claim":"Defined an LxxIxE SLiM in liprin-α1 that recruits the PP2A-B56γ holoenzyme to plasma-membrane platforms for migration, and linked CASK disease variants to defective suppression of liprin condensates.","evidence":"SLiM point mutagenesis, Co-IP, knockdown rescue with spreading/invasion assays; patient CASK variants with condensate and phosphorylation assays","pmids":["36171301","36137748"],"confidence":"High","gaps":["Direct PP2A substrates at the migrating edge not identified","Mechanism of CASK suppression of condensates partially defined"]},{"year":2024,"claim":"Established liprin-α (including PPFIA1) as the hierarchical organizer of presynaptic active-zone assembly downstream of LAR-RPTP/neurexin–CASK adhesion, and identified it as a negative regulator of MAPK/ERK oncogenic signaling.","evidence":"CRISPR quadruple liprin-α knockout in human neurons with electrophysiology and EM; cancer cell siRNA with p-ERK and RAS localization analysis","pmids":["38472649","38264964"],"confidence":"High","gaps":["Mechanism linking liprin-α1 to RAS/ERK suppression not resolved","Contribution of individual liprin-α isoforms to active-zone assembly not separated"]},{"year":2024,"claim":"Resolved the phosphorylation switch controlling liprin-α1 phase separation, showing B56δ-PP2A dephosphorylates S763 to dissolve condensates and promote liprin-α/β heterodimerization, with a disease variant compromising this control.","evidence":"MS interactomics, PPP2R5D knockout, phospho-mimetic and SLiM mutagenesis, phospho-specific antibody, live-cell LLPS assays","pmids":["40484382","38948786"],"confidence":"High","gaps":["Upstream kinases setting the S763 phospho-state in vivo not defined","How condensate state controls specific downstream functions not fully mapped"]},{"year":null,"claim":"How the phosphorylation/phase-separation state of liprin-α1 is dynamically integrated with its distinct neuronal active-zone and non-neuronal migration functions in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vivo demonstration linking condensate state to specific physiological output","Isoform-specific roles of PPFIA1 versus other liprin-α genes not delineated","Upstream kinases controlling the autophosphorylation/LLPS switch unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,13,16,23,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,18,23,30]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[15,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,16,19,26]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,12,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,30]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[19,11,20]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,28,2]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[19,16,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,29]}],"complexes":["liprin-α/CASK/neurexin1β presynaptic complex","liprin-α1–ERC1–LL5 plasma-membrane-associated platform","MALS/Veli presynaptic complex","PP2A-B56 holoenzyme (liprin-recruited)"],"partners":["PTPRF","ERC1","GIT1","CASK","PPP2R5D","GRIP1","KIF1A","DIAPH1"],"other_free_text":[]}},"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. 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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 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United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct biochemical association shown across multiple RPTPs, single lab, replicated across three phosphatase family members\",\n      \"pmids\": [\"8524829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Liprin-α1 (PPFIA1) autophosphorylates and phosphorylation of liprin-α1 is required for its binding to LAR; dephosphorylation by calf intestinal phosphatase weakens the liprin–LAR interaction, and liprin binds ATP-agarose in an ATP-competable manner.\",\n      \"method\": \"In vitro phosphorylation assay with purified protein from Sf-9 cells, co-precipitation with recombinant GST-LAR, ATP-agarose binding competition, [32P]-orthophosphate labeling in vivo\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution with purified protein plus in vivo labeling, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16313174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Liprin-α (PPFIA1 family) interacts with the multi-PDZ protein GRIP, and dominant-negative constructs that interfere with the GRIP–liprin interaction disrupt surface expression and dendritic clustering of AMPA receptors in cultured neurons. Liprin-α and LAR-RPTP coimmunoprecipitate with GRIP and AMPA receptors from neurons.\",\n      \"method\": \"Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, immunofluorescence\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from brain, dominant-negative functional rescue, replicated across labs in related work\",\n      \"pmids\": [\"11931740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Liprin-α1 (PPFIA1) directly interacts with GIT1 (an ARF-GAP); dominant-negative constructs interfering with the GIT1–liprin-α1 interaction selectively reduce dendritic and surface clustering of AMPA receptors, and GIT1 forms a complex with liprin-α1, GRIP, and AMPA receptors in brain.\",\n      \"method\": \"Co-immunoprecipitation from brain, dominant-negative expression in cultured neurons, electron microscopy of GIT1 distribution\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, dominant-negative with defined readout, electron microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"12629171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Liprin-α1 (PPFIA1) interacts with the kinesin motor KIF1A; KIF1A co-accumulates with liprin-α1 in ligated sciatic nerves and co-immunoprecipitates with liprin-α1 and associated proteins (AMPA receptors, GRIP/ABP, RIM, GIT1, βPIX), suggesting liprin-α functions as a KIF1A receptor for axonal transport.\",\n      \"method\": \"Co-immunoprecipitation, sciatic nerve ligation, co-fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo nerve ligation, single lab\",\n      \"pmids\": [\"12522103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Liprin-α1 (PPFIA1) directly interacts with ERC/CAST proteins (ERC2/CAST and ERC1b); coexpression of ERC2 with liprin-α1 in cultured neurons redistributes liprin-α1 to synaptic sites, and liprin-α1–ERC2 complex is detected in brain by co-immunoprecipitation.\",\n      \"method\": \"In vitro direct binding assay, co-immunoprecipitation from brain, coexpression in cultured neurons with immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown in vitro plus Co-IP from brain and cellular redistribution, single lab\",\n      \"pmids\": [\"12923177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MALS/Veli proteins form a presynaptic complex with liprin-α (PPFIA1 family); mice lacking all three MALS isoforms die perinatally with reduced excitatory synaptic transmission due to a presynaptic vesicle cycling deficit. Liprin-α was identified as a major component of the MALS complex purified from brain.\",\n      \"method\": \"Affinity purification from brain, triple knockout mouse analysis, autaptic electrophysiology\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical purification plus genetic knockout with defined electrophysiological phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"16186258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PPFIA1 (liprin-α1) interacts with ING4 (inhibitor of growth 4); the two proteins colocalize at lamellipodia near vinculin. Overexpressed liprin-α1 enhances cell spreading and migration, while knockdown suppresses cell motility. ING4-mediated suppression of cell motility requires liprin-α1, as ING4 does not further suppress motility when liprin-α1 is knocked down.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, overexpression, wound healing / migration assay, immunofluorescence colocalization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus epistatic RNAi rescue, single lab, multiple functional readouts\",\n      \"pmids\": [\"17363573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Liprin-α1 (PPFIA1) interacts with PP2A B56γ regulatory subunit; B56γ–liprin-α1 complexes are biochemically distinct from PP2A complexes. Suppression of liprin-α1 alters cell morphology.\",\n      \"method\": \"Tandem affinity purification / mass spectrometry, co-immunoprecipitation, RNAi knockdown\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — TAP-MS identification plus Co-IP, single lab, limited functional follow-up\",\n      \"pmids\": [\"18235218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Liprin-α1 (PPFIA1) is stably associated with the cell membrane and is required for cell spreading on fibronectin; depletion inhibits lamellipodia formation, while overexpression enhances spreading and focal adhesion formation. The effects of liprin-α1 on spreading (but not cell-edge reorganization) require its interaction with LAR-type RPTPs. Cooperation between liprin-α1 and talin is required for spreading.\",\n      \"method\": \"RNAi knockdown, overexpression, cell spreading assay on fibronectin, immunofluorescence, membrane fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotype, LAR-dependence tested with interaction mutants, single lab\",\n      \"pmids\": [\"19690048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"mAChR-LTD in hippocampus requires interactions among GluA2, GRIP, and liprin-α (PPFIA1 family); peptides that block GRIP–GluA2 or GRIP–liprin-α binding specifically block mAChR-LTD but not mGluR-LTD, linking these interactions to AMPA receptor endocytosis during LTD.\",\n      \"method\": \"Peptide inhibition of protein–protein interaction in hippocampal slice electrophysiology, LTD induction\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide interference with defined LTD readout, selective for mAChR vs mGluR pathway, single lab\",\n      \"pmids\": [\"19534762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Liprin-α1 (PPFIA1) overexpression inhibits antibody-induced β1 integrin internalization and stabilizes integrin receptors at the cell surface; depletion of liprin-α1 by siRNA increases the rate of integrin internalization, affecting focal adhesion size and distribution of inactive β1 integrins.\",\n      \"method\": \"siRNA knockdown, overexpression, antibody-induced internalization assay, immunofluorescence, focal adhesion measurement\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined integrin trafficking readout, single lab\",\n      \"pmids\": [\"20096687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Liprin-α1 (PPFIA1) is required for migration and invasion of highly invasive MDA-MB-231 breast cancer cells; its depletion causes lamellipodia instability, reduces invadopodium lifetime and ECM degradation per invadopodium, while overexpression enhances these processes.\",\n      \"method\": \"siRNA knockdown, overexpression, time-lapse microscopy, invasion assay, ECM degradation assay, cortactin-GFP tracking of invadopodia\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"21151172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of liprin-α2/CASK complex shows that the three SAM domains of liprin-α form an integrated supramodule binding the CASK kinase-like domain; this interaction is unique to vertebrates. Three X-linked mental retardation CASK mutants are defective in binding liprin-α. Crystal structure of the liprin-α/liprin-β SAM domain complex reveals the mechanism of liprin heterodimerization, and a CASK/liprin-α/liprin-β ternary complex can form.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, mutagenesis of CASK disease alleles, cellular studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of two complexes with functional mutagenesis validation and disease-mutant analysis\",\n      \"pmids\": [\"21855798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Liprin-α1 (PPFIA1) functionally interacts with GIT1 to regulate cell spreading and migration: GIT1 depletion phenocopies liprin-α1 depletion in lamellipodia formation, and liprin-α1 may compete with paxillin for GIT1 binding. GIT1 and liprin-α1 reciprocally regulate each other's subcellular localization at focal adhesions and cell edge.\",\n      \"method\": \"siRNA knockdown, dominant-negative (liprin-ΔCC3), co-immunoprecipitation, immunofluorescence, haptotactic migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutual depletion epistasis and dominant-negative with defined spreading/migration phenotypes, single lab\",\n      \"pmids\": [\"21695141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Liprin-α (PPFIA1 family) binds mDia (a Rho-effector actin nucleator) through the central region of liprin-α and the DID-DD domains of mDia, competing with the DAD autoregulatory domain. Liprin-α overexpression decreases mDia membrane localization and attenuates Rho-mDia-mediated stress fiber formation; liprin-α depletion by RNAi increases mDia in the membrane fraction and enhances stress fiber formation.\",\n      \"method\": \"Pulldown identifying liprin-α as mDia-binding protein, domain mapping, competition binding assay, RNAi knockdown, overexpression, membrane fractionation, immunofluorescence of stress fibers\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pulldown with domain mapping, bidirectional functional manipulation, competition assay, multiple orthogonal methods\",\n      \"pmids\": [\"22266902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PPFIA1 (liprin-α1) forms a complex with ERC1a and LL5 proteins to drive cell migration; depletion of any component reduces migration, invasion, lamellipodial persistence, and internalization of active β1 integrin at the cell front. The complex defines polarized cytoplasmic structures at the protruding cell edge.\",\n      \"method\": \"siRNA knockdown, live-cell microscopy, invasion assay, integrin internalization assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-component depletion with multiple cellular phenotypes, single lab\",\n      \"pmids\": [\"24982445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PPFIA1 (liprin-α1) interacts with PP2A and Kif7, and the PPFIA1–PP2A complex promotes dephosphorylation of Kif7, triggering Kif7 trafficking to the tips of primary cilia and promoting Gli transcriptional activity downstream of Hedgehog signaling.\",\n      \"method\": \"Mass spectrometry identification of Kif7 interactors, Co-IP, siRNA knockdown of PPFIA1 and PP2A, immunofluorescence of cilia, Hedgehog reporter assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactomics plus Co-IP and functional knockdown with pathway readout, single lab\",\n      \"pmids\": [\"25492966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Liprin-α3 binds to the mDia1 N-terminal DID domain and allosterically inhibits mDia1 activation by RhoA·GTP; liprin-α3 competes with DAD for a highly overlapping binding site on mDiaN, lowers RhoA and DAD regulatory potency, and regulates actin polymerization.\",\n      \"method\": \"Reconstituted in vitro binding and competition assays, ITC thermodynamics, mutagenesis, cellular actin filament content measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with thermodynamic characterization and domain/competition mapping, single lab\",\n      \"pmids\": [\"25911102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PPFIA1 interacts with active α5β1 integrin (via direct interaction shown by Co-IP) and localizes near endothelial cell adhesions where post-Golgi carriers are targeted. PPFIA1 is required for fibronectin polymerization-dependent vascular morphogenesis both in vitro and in developing zebrafish. PPFIA1 acts downstream of Rab11B and PTPRF in a pathway (PI4KB→AP-1A→Rab11B→PTPRF→PPFIA1) that funnels FN secretion and recycling of active α5β1 integrin from the TGN to the cell surface.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, zebrafish morpholino knockdown, vesicle trafficking assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction with active integrin, pathway ordering by knockdown, in vivo zebrafish validation, multiple orthogonal methods\",\n      \"pmids\": [\"27876801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Liprin-α1 (PPFIA1) and ERC1 promote focal adhesion turnover at the cell edge; displacement of ERC1 from the cell edge (by dominant-negative liprin-N) inhibits disassembly of focal adhesions. Liprin-α1 and ERC1 colocalize with active integrin β1 clusters distinct from cytoplasmic FA proteins and influence localization of peripheral Rab7-positive endosomes.\",\n      \"method\": \"Dominant-negative expression (liprin-N fragment), siRNA knockdown, immunofluorescence, focal adhesion turnover assay, Rab7 endosome localization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative plus siRNA with FA turnover readout, single lab\",\n      \"pmids\": [\"27659488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CASK stabilizes neurexin1β and creates a structural link to liprin-α at the presynaptic active zone; liprin-α and Mint1 compete for CASK binding, but neurexin1β eliminates this competition, enabling a four-protein complex. CASK phosphorylation of neurexin1β modulates the interaction of liprin-α with the CASK–neurexin1β–Mint1 complex.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding/competition assays, neuronal culture, phosphorylation assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and cellular binding competition with phosphorylation regulation, single lab\",\n      \"pmids\": [\"27015872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Liprin-α/TANC2 capture KIF1A-transported dense core vesicles at dendritic spines; liprin-α is not part of the KIF1A-cargo complex itself but acts as a capture/recruitment factor at postsynaptic sites. Calcium acting via calmodulin enhances KIF1A binding to DCVs and increases vesicle motility.\",\n      \"method\": \"KIF1A interactome by mass spectrometry, co-immunoprecipitation, live imaging of DCV transport, neuronal knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus Co-IP and live imaging, single lab\",\n      \"pmids\": [\"30021165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of LAR D1D2 in complex with liprin-α3 SAM repeats at 1.91 Å reveals a conserved two-site binding mode involving the D2 phosphatase domain. Liprin-α promotes LAR clustering in cells via both the liprin-α/LAR interaction and liprin-α oligomerization; LAR forms homophilic D1/D1 interactions that are disrupted by liprin-α-promoted clustering, and this D1/D1 disruption increases LAR phosphatase activity. LAR binding to liprin-α allosterically regulates the liprin-α/liprin-β interaction.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, cellular clustering assays, phosphatase activity assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation in vitro and in cellulo, phosphatase activity measurement\",\n      \"pmids\": [\"31924785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of mouse PTPδ D2 domain in complex with liprin-α3 tSAM at 1.91 Å shows PTPδ D2 interacts with the N-terminal helix and SAM1/SAM2 of liprin-α3; structure-based mutations of SAM1 and SAM2 contacts abolish binding and synaptogenic activity in cellulo.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, synaptogenic co-culture assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis in vitro and in cellulo\",\n      \"pmids\": [\"32005855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Liprin-α proteins oligomerize via the N-terminal coiled-coil region; oligomerized liprin-α2 drives phase separation of ELKS N-terminal segments through multivalent interactions, and liprin-α2 controls protein distribution between ELKS and RIM/RIM-BP condensates. A gain-of-function mutation in the coiled-coil disrupts intramolecular inhibition and promotes intermolecular interactions.\",\n      \"method\": \"Structural and biochemical characterization of coiled-coil oligomerization, phase separation assays in cells, gain-of-function mutation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural + biochemical reconstitution of phase separation mechanism with mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33761347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Liprin-α1 (PPFIA1) contains an LxxIxE short linear motif in its N-terminal dimerization domain that mediates interaction with the B56γ regulatory subunit of PP2A. B56γ mediates recruitment of the PP2A holoenzyme to liprin-α1. Liprin-α1 recruits B56γ to plasma membrane-associated platforms (PMAPs) at the edge of migrating MDA-MB-231 cells; silencing of B56γ inhibits cell spreading, invasion and lamellipodia dynamics similarly to liprin-α1 silencing, and this requires an intact SLiM.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis of SLiM, siRNA knockdown, cell spreading/invasion/lamellipodia assays, immunofluorescence\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — motif mutagenesis abolishing interaction plus bidirectional functional assays with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"36171301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CASK CaMK domain missense variants from MICPCH patients selectively weaken binding to liprin-α2; CASK suppresses liprin-α2 phase condensate formation in HEK293T cells and primary neurons, and this suppression is associated with altered liprin-α2 phosphorylation. The p.E115K variant fails to suppress condensate formation, correlating with the severe MICPCH phenotype.\",\n      \"method\": \"Co-immunoprecipitation with patient-derived CASK variants, condensate formation assay in HEK293T and neurons, phosphorylation analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function with disease alleles and cellular phase separation readout, single lab\",\n      \"pmids\": [\"36137748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In human neurons lacking all four liprin-α isoforms (including PPFIA1), nascent synaptic contacts form normally but recruitment of active zone components and accumulation of synaptic vesicles is fully blocked ('empty' boutons), abolishing synaptic transmission. LAR-RPTP family adhesion molecules and neurexin–CASK interactions are required to localize liprin-α to nascent synaptic sites; liprin-α then recruits presynaptic components via direct interaction with ELKS proteins, establishing a hierarchical assembly sequence.\",\n      \"method\": \"CRISPR/Cas9 quadruple knockout of all four liprin-α isoforms in human neurons, electrophysiology, electron microscopy, immunofluorescence, interaction studies\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete genetic ablation in human neurons with defined ultrastructural and electrophysiological phenotype, multiple orthogonal methods, clear epistasis\",\n      \"pmids\": [\"38472649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of liprin-α1 (PPFIA1) in cancer cells leads to increased phospho-ERK1/2 levels and more pronounced RAS protein redistribution to the cell membrane, regardless of KRAS mutational status, indicating liprin-α1 negatively regulates MAPK/ERK oncogenic signaling.\",\n      \"method\": \"siRNA knockdown, Western blot for p-ERK1/2, pharmacological ERK inhibitor screen (trametinib), immunofluorescence of RAS membrane localization\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined signaling readout across multiple cell lines, single lab, mechanism not fully resolved\",\n      \"pmids\": [\"38264964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPP2R5D (B56δ) PP2A holoenzyme interacts with liprin-α1 via an LxxIxE SLiM in its N-terminal dimerization domain; mutation of SLiM or knockout of PPP2R5D increases liprin-α1 LLPS in HEK293 cells. Phospho-mimetic S763E mutation drives liprin-α1 LLPS, and B56δ-PP2A inhibits LLPS by dephosphorylation at S763 and other sites. Liprin-α1/β1 heterodimerization is decreased under conditions promoting LLPS, and liprin-β1 itself inhibits liprin-α1 LLPS. PPP2R5D E420K variant (Houge-Janssens Syndrome) compromises suppression of liprin-α1 LLPS.\",\n      \"method\": \"MS-based interactomics, co-immunoprecipitation, PPP2R5D knockout HEK293 cells, phospho-mimetic and SLiM mutagenesis, phospho-specific antibody, LLPS assay in live cells, domain-mapping\",\n      \"journal\": \"The Journal of biological chemistry (and preprint bioRxiv)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (interactomics, KO, mutagenesis, phospho-specific antibody, disease variant), single lab with peer-reviewed publication\",\n      \"pmids\": [\"40484382\", \"38948786\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPFIA1 (liprin-α1) is a multi-domain scaffolding protein that physically bridges LAR-family receptor protein tyrosine phosphatases (via phosphorylation-dependent SAM domain interactions) to cytoplasmic effectors including GRIP, GIT1, ERC1, CASK, ELKS, and PP2A/B56 complexes; at presynaptic terminals it acts as a hierarchical master organizer—recruited by LAR-RPTPs and neurexin–CASK contacts to nascent synaptic sites where it recruits ELKS and other active zone components for vesicle docking and release—while in non-neuronal cells it localizes to plasma membrane-associated platforms at the leading edge to drive integrin recycling (active α5β1 via a PTPRF–PPFIA1 axis), focal adhesion turnover, and actin regulation through negative control of mDia; its activity state and higher-order assembly are regulated by autophosphorylation, PKC/SAD-kinase-triggered phosphorylation promoting liquid-liquid phase separation, and PP2A-B56δ-mediated dephosphorylation that dissolves condensates and promotes heterodimerization with liprin-β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPFIA1 (liprin-\\u03b11) is a multidomain scaffolding protein that organizes membrane-associated signaling platforms in both neuronal and non-neuronal cells by bridging LAR-family receptor protein tyrosine phosphatases to a defined set of cytoplasmic effectors [#0, #23]. It associates with LAR, PTP\\u03b4, and PTP\\u03c3 through its intracellular region, an interaction that depends on liprin-\\u03b11 autophosphorylation and is weakened by dephosphorylation [#0, #1]; structurally, the liprin-\\u03b1 tandem SAM domains engage the LAR D1D2 phosphatase region in a conserved two-site mode, and liprin-\\u03b1\\u2013driven clustering of LAR disrupts homophilic D1/D1 contacts to increase phosphatase activity [#23, #24]. The same SAM supramodule binds the CASK kinase-like domain and mediates liprin-\\u03b1/liprin-\\u03b2 heterodimerization, enabling assembly of higher-order CASK\\u2013liprin complexes [#13]. At presynaptic terminals liprin-\\u03b1 acts as a hierarchical master organizer: recruited to nascent synaptic contacts by LAR-RPTP and neurexin\\u2013CASK interactions, it then recruits ELKS and other active-zone components to enable vesicle accumulation and release, and loss of all liprin-\\u03b1 isoforms produces structurally normal but functionally 'empty' boutons [#28, #6, #21]. In non-neuronal cells liprin-\\u03b11 builds plasma-membrane-associated platforms at the protruding cell edge together with ERC1 and LL5, driving cell spreading, lamellipodial persistence, focal adhesion turnover, and recycling of active \\u03b15\\u03b21 integrin from the TGN to the surface through a Rab11B\\u2013PTPRF\\u2013PPFIA1 axis [#16, #9, #20, #19]. It links these platforms to actin regulation by negatively controlling the formin mDia\\u2014binding the mDia DID domain in competition with the DAD autoinhibitory segment to restrain RhoA-driven actin polymerization [#15, #18]\\u2014and to GIT1/ARF-GAP and PP2A-B56 activities [#14, #8, #26]. Liprin-\\u03b11 higher-order assembly is governed by phosphorylation-driven liquid\\u2013liquid phase separation: an LxxIxE SLiM recruits the B56\\u03b4/B56\\u03b3 PP2A holoenzyme, and PP2A-mediated dephosphorylation (including at S763) dissolves condensates and favors liprin-\\u03b1/liprin-\\u03b2 heterodimerization [#30, #26, #25]. Functionally, liprin-\\u03b11 promotes breast cancer cell migration and invasion and negatively regulates MAPK/ERK signaling, while CASK disease variants that weaken liprin binding implicate this axis in MICPCH and X-linked intellectual disability [#12, #29, #27, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding molecular link of PPFIA1, showing it physically associates with LAR-family receptor tyrosine phosphatases and might recruit them to focal adhesions.\",\n      \"evidence\": \"Co-precipitation of LIP.1 with LAR, PTP\\u03b4, PTP\\u03c3 via its coiled-coil domain\",\n      \"pmids\": [\"8524829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve which liprin domain contacts the phosphatase at atomic level\", \"Recruitment to focal adhesions postulated, not demonstrated functionally\", \"No measure of effect on phosphatase activity\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected liprin-\\u03b1 to postsynaptic receptor organization by showing the GRIP\\u2013liprin interaction controls AMPA receptor surface clustering.\",\n      \"evidence\": \"Co-IP from brain plus dominant-negative disruption in cultured neurons\",\n      \"pmids\": [\"11931740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate liprin-\\u03b11 from other liprin-\\u03b1 isoforms\", \"Mechanism of clustering downstream of GRIP binding unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Expanded the liprin effector network to GIT1, ERC/CAST, and the kinesin KIF1A, framing liprin-\\u03b1 as both a synaptic scaffold and a motor cargo adaptor.\",\n      \"evidence\": \"Co-IP from brain, dominant-negative neuronal expression, sciatic nerve ligation, in vitro binding and coexpression redistribution\",\n      \"pmids\": [\"12629171\", \"12522103\", \"12923177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect nature of some interactions not uniformly established\", \"Whether liprin is true KIF1A receptor or capture factor unresolved at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the biochemical requirement for liprin phosphorylation in LAR binding and placed liprin-\\u03b1 in a presynaptic MALS/Veli complex essential for vesicle cycling.\",\n      \"evidence\": \"In vitro autophosphorylation and ATP-agarose competition with purified protein; MALS triple-knockout mice with autaptic electrophysiology\",\n      \"pmids\": [\"16313174\", \"16186258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for liprin autophosphorylation in vivo not identified\", \"MALS knockout phenotype not isoform-specific to PPFIA1\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Implicated liprin-\\u03b11 in cell motility through ING4 and PP2A B56\\u03b3 associations, linking the scaffold to migration control beyond neurons.\",\n      \"evidence\": \"Co-IP, RNAi epistasis, migration assays; TAP-MS identification of B56\\u03b3\",\n      \"pmids\": [\"17363573\", \"18235218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ING4 acts through liprin-\\u03b11 not resolved\", \"Functional consequence of B56\\u03b3 association limited to morphology\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that membrane-associated liprin-\\u03b11 drives cell spreading and lamellipodia formation, partly through LAR-RPTP interaction and talin cooperation.\",\n      \"evidence\": \"RNAi and overexpression with fibronectin spreading assays, interaction mutants, membrane fractionation\",\n      \"pmids\": [\"19690048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LAR-independent cell-edge function mechanistically undefined\", \"Nature of talin cooperation not molecularly mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed liprin-\\u03b11 stabilizes integrin at the surface and supports invadopodium-mediated ECM degradation, tying the scaffold to integrin trafficking and invasion.\",\n      \"evidence\": \"siRNA/overexpression integrin internalization assays; time-lapse invadopodia and ECM degradation tracking in MDA-MB-231 cells\",\n      \"pmids\": [\"20096687\", \"21151172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct integrin binding not yet shown at this stage\", \"Molecular link between liprin and the internalization machinery undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural and functional mechanism for liprin SAM-domain interactions with CASK and liprin-\\u03b2, and tied them to X-linked intellectual disability CASK mutants.\",\n      \"evidence\": \"Crystal structures of liprin-\\u03b1/CASK and liprin-\\u03b1/liprin-\\u03b2 SAM complexes with disease-allele mutagenesis; GIT1 functional epistasis in spreading\",\n      \"pmids\": [\"21855798\", \"21695141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of disrupted ternary complex not tested\", \"Regulation of SAM-domain availability not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified liprin-\\u03b1 as a negative regulator of the formin mDia, connecting the scaffold to RhoA-driven actin dynamics.\",\n      \"evidence\": \"mDia pulldown, domain mapping, DAD-competition binding, bidirectional RNAi/overexpression of stress fibers\",\n      \"pmids\": [\"22266902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial coordination of mDia inhibition at the cell edge not resolved\", \"Whether inhibition is isoform-specific not addressed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a liprin-\\u03b11\\u2013ERC1\\u2013LL5 platform driving polarized migration and active-integrin internalization, and showed PPFIA1\\u2013PP2A dephosphorylates Kif7 to control ciliary Hedgehog signaling.\",\n      \"evidence\": \"Multi-component siRNA with live imaging and invasion assays; Kif7 interactome MS, Co-IP, knockdowns and Hedgehog reporters\",\n      \"pmids\": [\"24982445\", \"25492966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the ERC1\\u2013LL5 platform unresolved\", \"Direct versus PP2A-bridged action on Kif7 not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the biophysical mechanism of mDia inhibition, showing liprin allosterically blocks RhoA\\u00b7GTP activation by competing for the DAD site.\",\n      \"evidence\": \"Reconstituted in vitro binding, ITC, mutagenesis, cellular actin content with liprin-\\u03b13\",\n      \"pmids\": [\"25911102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated with liprin-\\u03b13; PPFIA1-specific affinity not directly measured\", \"In vivo relevance at migrating cell edge not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established PPFIA1 as a direct active-\\u03b15\\u03b21-integrin partner acting downstream of Rab11B/PTPRF to funnel integrin recycling and fibronectin secretion, with in vivo vascular relevance, and showed it drives focal adhesion turnover with ERC1.\",\n      \"evidence\": \"Co-IP, knockdowns, pathway ordering, zebrafish morpholino; dominant-negative liprin-N with FA turnover and Rab7 endosome readouts; CASK\\u2013neurexin1\\u03b2 presynaptic complex characterization\",\n      \"pmids\": [\"27876801\", \"27659488\", \"27015872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the TGN-to-surface trafficking complex unresolved\", \"Coupling of FA turnover to integrin recycling not mechanistically unified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined liprin-\\u03b1's role in transport, showing it acts as a capture/recruitment factor (not core cargo) for KIF1A-delivered dense core vesicles at dendritic spines.\",\n      \"evidence\": \"KIF1A interactome MS, Co-IP, live DCV imaging, neuronal knockdown\",\n      \"pmids\": [\"30021165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger linking liprin capture to vesicle release undefined\", \"PPFIA1-specific contribution among isoforms not isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided atomic-resolution mechanism for liprin-\\u03b1 engagement of LAR and PTP\\u03b4 phosphatase domains and showed liprin-driven LAR clustering activates phosphatase activity and allosterically tunes liprin heterodimerization.\",\n      \"evidence\": \"Crystal structures of LAR D1D2 and PTP\\u03b4 D2 with liprin SAM repeats, structure-based mutagenesis, clustering, phosphatase and synaptogenic assays\",\n      \"pmids\": [\"31924785\", \"32005855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational coupling between LAR binding and effector recruitment not fully resolved\", \"Cellular consequences of altered LAR phosphatase activity not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed liprin-\\u03b1 oligomerizes via its coiled-coil to drive multivalent phase separation of active-zone proteins and partition components between ELKS and RIM/RIM-BP condensates.\",\n      \"evidence\": \"Coiled-coil oligomerization analysis, cellular phase-separation assays, gain-of-function mutation\",\n      \"pmids\": [\"33761347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated with liprin-\\u03b12; PPFIA1-specific condensate behavior inferred\", \"Physiological regulation of intramolecular inhibition not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an LxxIxE SLiM in liprin-\\u03b11 that recruits the PP2A-B56\\u03b3 holoenzyme to plasma-membrane platforms for migration, and linked CASK disease variants to defective suppression of liprin condensates.\",\n      \"evidence\": \"SLiM point mutagenesis, Co-IP, knockdown rescue with spreading/invasion assays; patient CASK variants with condensate and phosphorylation assays\",\n      \"pmids\": [\"36171301\", \"36137748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PP2A substrates at the migrating edge not identified\", \"Mechanism of CASK suppression of condensates partially defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established liprin-\\u03b1 (including PPFIA1) as the hierarchical organizer of presynaptic active-zone assembly downstream of LAR-RPTP/neurexin\\u2013CASK adhesion, and identified it as a negative regulator of MAPK/ERK oncogenic signaling.\",\n      \"evidence\": \"CRISPR quadruple liprin-\\u03b1 knockout in human neurons with electrophysiology and EM; cancer cell siRNA with p-ERK and RAS localization analysis\",\n      \"pmids\": [\"38472649\", \"38264964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking liprin-\\u03b11 to RAS/ERK suppression not resolved\", \"Contribution of individual liprin-\\u03b1 isoforms to active-zone assembly not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the phosphorylation switch controlling liprin-\\u03b11 phase separation, showing B56\\u03b4-PP2A dephosphorylates S763 to dissolve condensates and promote liprin-\\u03b1/\\u03b2 heterodimerization, with a disease variant compromising this control.\",\n      \"evidence\": \"MS interactomics, PPP2R5D knockout, phospho-mimetic and SLiM mutagenesis, phospho-specific antibody, live-cell LLPS assays\",\n      \"pmids\": [\"40484382\", \"38948786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream kinases setting the S763 phospho-state in vivo not defined\", \"How condensate state controls specific downstream functions not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the phosphorylation/phase-separation state of liprin-\\u03b11 is dynamically integrated with its distinct neuronal active-zone and non-neuronal migration functions in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo demonstration linking condensate state to specific physiological output\", \"Isoform-specific roles of PPFIA1 versus other liprin-\\u03b1 genes not delineated\", \"Upstream kinases controlling the autophosphorylation/LLPS switch unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 13, 16, 23, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 18, 23, 30]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [15, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 16, 19, 26]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 12, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [19, 11, 20]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 28, 2]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [19, 16, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 29]}\n    ],\n    \"complexes\": [\n      \"liprin-\\u03b1/CASK/neurexin1\\u03b2 presynaptic complex\",\n      \"liprin-\\u03b11\\u2013ERC1\\u2013LL5 plasma-membrane-associated platform\",\n      \"MALS/Veli presynaptic complex\",\n      \"PP2A-B56 holoenzyme (liprin-recruited)\"\n    ],\n    \"partners\": [\n      \"PTPRF\",\n      \"ERC1\",\n      \"GIT1\",\n      \"CASK\",\n      \"PPP2R5D\",\n      \"GRIP1\",\n      \"KIF1A\",\n      \"DIAPH1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}