{"gene":"LASP1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"LASP1 (Lasp-1/MLN50) was identified as a new LIM protein subfamily member containing an N-terminal LIM motif and a C-terminal SH3 domain, defining a novel domain architecture.","method":"cDNA cloning and sequence analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence-based domain identification confirmed in founding paper, replicated by subsequent structural studies","pmids":["7589475"],"is_preprint":false},{"year":1996,"finding":"The N-terminal zinc-binding module of the Lasp-1 LIM domain (residues 1-30) folds as an independent structural unit coordinating zinc via Cys5, Cys8, His26, and Cys29, adopting a rubredoxin-knuckle motif consistent with other LIM domain modules.","method":"1H NMR solution structure determination of synthetic peptide ZF-1 complexed with zinc","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with unambiguous zinc coordination identified by constraint-free calculations; first structural characterization of an isolated LIM module","pmids":["8841116"],"is_preprint":false},{"year":1998,"finding":"Lasp-1 contains an actin-binding domain in the core of the protein; it binds actin in vivo and in vitro, co-localizes with actin at peripheral cell extensions, and is tyrosine-phosphorylated in fibroblasts transformed by constitutively active c-Src (SrcY527F).","method":"In vitro actin-binding assay, in vivo co-localization by confocal microscopy, Western blot of Src-transformed fibroblasts","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay plus in vivo localization; single lab with two orthogonal methods","pmids":["9848085"],"is_preprint":false},{"year":1998,"finding":"Lasp-1 is a cAMP-dependent phosphoprotein in gastric parietal cells; stimulation of parietal cells, distal colonic crypts, and pancreatic cells with forskolin induces a higher-molecular-weight (phosphorylated) form of Lasp-1, placing it downstream of PKA in the cAMP signaling pathway.","method":"Microsequencing/cloning, Northern and Western blot, forskolin stimulation of isolated cells","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification plus pharmacological stimulation across multiple cell types; single lab","pmids":["9688835"],"is_preprint":false},{"year":2000,"finding":"In gastric parietal cells, histamine-induced elevation of cAMP increases Lasp-1 phosphorylation and induces partial redistribution of Lasp-1 from the cell cortex (where it co-localizes with γ-actin) to the β-actin-enriched intracellular canalicular region, the site of active proton transport.","method":"Immunofluorescence, subcellular fractionation, histamine stimulation correlated with acid secretion assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional correlation; single lab, two orthogonal approaches","pmids":["10806114"],"is_preprint":false},{"year":2002,"finding":"Lasp-1 binds directly to non-muscle F-actin in vitro with apparent Kd ~2 µM and saturation stoichiometry ~1:7; PKA-dependent phosphorylation at S99 and S146 increases Kd and decreases Bmax, reducing actin-binding affinity. Phosphorylation-site alanine mutants (S99A/S146A) suppress cAMP-dependent translocation of Lasp-1 to the intracellular canalicular region in parietal cells.","method":"Actin pull-down assay with bacterially expressed His-Lasp-1, in vitro PKA phosphorylation, site-directed mutagenesis, parietal cell transfection and immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro reconstitution with mutagenesis and functional validation in cells; multiple orthogonal methods in one study","pmids":["12432067"],"is_preprint":false},{"year":2003,"finding":"LASP1 is a fusion partner of MLL in an infant AML with t(11;17)(q23;q21); the MLL/LASP1 fusion protein lacks in vitro myeloid progenitor transformation capability, placing it in a subgroup of non-transforming MLL fusions.","method":"FISH, RT-PCR, RACE cloning of fusion transcript, retroviral transduction of myeloid progenitors","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular identification plus functional transformation assay; single case but rigorous methodology","pmids":["12527918"],"is_preprint":false},{"year":2004,"finding":"Lasp-1 localizes to focal complexes and the leading edge of pseudopodia in migrating cells. Growth factor or ECM stimulation causes Lasp-1 to relocalize from the cell periphery to the leading edge; c-Abl-mediated phosphorylation of Lasp-1 at tyrosine 171 (induced by apoptotic agents) causes loss of focal adhesion localization and cell death. Lasp-1 is required for cell migration but not adhesion.","method":"Large-scale pseudopodial proteomics, siRNA knockdown migration/adhesion assays, immunofluorescence, c-Abl kinase inhibitor experiments, phosphorylation mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification combined with functional siRNA phenotype, localization imaging, and phosphorylation site mapping; multiple orthogonal methods","pmids":["15138294"],"is_preprint":false},{"year":2004,"finding":"LASP-1 interacts with zyxin, LPP, and VASP via their proline-rich domains; zyxin is the most prominent partner. LASP-1 exists as a monomer despite its LIM domain. Mouse LASP-1 is phosphorylated by PKA and PKG in vitro at S61, S99, and T156, but only at T156 in intact cells; phosphorylation by either kinase causes translocation from focal contacts to the cell interior without affecting F-actin.","method":"Overlay binding assays, gel filtration (monomer determination), in vitro kinase assays with PKA/PKG, immunofluorescence of human and mouse mesangial cells treated with forskolin","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assays combined with cell localization; single lab, multiple methods","pmids":["15465019"],"is_preprint":false},{"year":2004,"finding":"The SH3 domain of Lasp-1 is necessary and sufficient for interaction with zyxin; the binding site in zyxin is at its extreme N-terminus and uses a linear motif lacking the classical PXXP sequence. Co-precipitation and yeast two-hybrid confirmed the Lasp-1–zyxin interaction.","method":"Yeast two-hybrid, co-precipitation, site-directed mutagenesis of zyxin binding site","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid plus co-precipitation plus mutagenesis mapping binding site; multiple orthogonal methods in one study","pmids":["15004028"],"is_preprint":false},{"year":2004,"finding":"Lasp-1 is a component of CNS postsynaptic densities and is concentrated at synaptic sites and dendritic spines of hippocampal neurons.","method":"MudPIT proteomics of purified postsynaptic fractions, immunofluorescence of CNS neurons","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification from purified fraction confirmed by immunofluorescence; single lab","pmids":["15372503"],"is_preprint":false},{"year":2006,"finding":"LASP-1 silencing in breast cancer cells causes G2/M arrest, suppresses proliferation by 30-50%, reduces migration by 50%, and reduces zyxin recruitment to focal contacts without altering actin stress fibers. Overexpression of LASP-1 in PTK-2 cells that lack endogenous LASP-1 increases cell motility.","method":"siRNA knockdown, cell cycle analysis, wound-healing assay, immunofluorescence, LASP-1 overexpression in LASP-1-negative cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined cellular phenotypes; single lab, multiple readouts","pmids":["16430883"],"is_preprint":false},{"year":2006,"finding":"The 140 kDa isoform of palladin (but not the 90 kDa isoform) directly binds Lasp-1 via its SH3-domain binding motif; isoform-specific siRNA of 140 kDa palladin reduces Lasp-1 recruitment to stress fibers.","method":"Yeast two-hybrid, GST pull-down, isoform-specific siRNA with immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid plus GST pull-down plus functional siRNA rescue in cells; multiple orthogonal methods","pmids":["16492705"],"is_preprint":false},{"year":2007,"finding":"LASP-1 silencing in ovarian cancer cells arrests cells in G2/M, suppresses proliferation by 60-90%, reduces migration by 40%, and reduces zyxin binding to focal contacts. LASP-1 knockdown did not affect actin stress fiber or microtubule organization. Silencing zyxin did not affect LASP-1 expression or migration, placing LASP-1 upstream of zyxin at focal contacts.","method":"siRNA knockdown, cell cycle analysis, proliferation assay, migration assay, immunofluorescence for zyxin and actin","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between LASP-1 and zyxin established by parallel knockdowns; single lab, multiple readouts","pmids":["17211471"],"is_preprint":false},{"year":2007,"finding":"LASP-1 is not exclusively cytosolic; it is also detectable in the nucleus of breast cancer cells, with nuclear accumulation correlating with higher tumor stage and increased proliferation (peak in G2/M phase).","method":"Confocal immunofluorescence, separate nuclear/cytosolic fractionation Western blots, cell synchronization experiments","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear localization confirmed by fractionation plus imaging; single lab, two orthogonal methods","pmids":["17956604"],"is_preprint":false},{"year":2008,"finding":"Lasp-1 knockout mice show increased histamine-stimulated gastric HCl secretion compared to wild-type littermates, with slower inhibition by ranitidine, establishing Lasp-1 as a negative regulator of parietal cell acid secretion in vivo.","method":"Targeted gene disruption (knockout mouse), in vivo and ex vivo acid secretion assays, [14C]aminopyrine accumulation in isolated gastric glands","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with quantitative physiological phenotype confirmed in vivo and ex vivo","pmids":["18483181"],"is_preprint":false},{"year":2008,"finding":"p53 transcriptionally represses LASP1 expression via a p53 response element in the LASP1 promoter; wild-type but not DNA-binding mutant p53 suppresses LASP1; p53 siRNA in p53-positive HepG2 cells upregulates LASP1.","method":"Luciferase reporter assay, transient transfection of WT and mutant p53 in p53-null cells, p53 siRNA, Western blot","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus loss-of-function siRNA plus gain-of-function with binding-dead mutant; single lab","pmids":["19155088"],"is_preprint":false},{"year":2009,"finding":"Lasp-1 knockout mice display enhanced wound healing and more rapid tumor formation; Lasp-1-null MEFs migrate more rapidly in vitro, have more focal adhesions, and show increased LPP expression (~2-fold), suggesting LPP compensates for loss of Lasp-1 to enhance migration.","method":"Knockout mouse wound-healing assay, tumor initiation assay, MEF migration assay, focal adhesion counting, differential microarray analysis","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple cellular phenotypes; single lab","pmids":["19531578"],"is_preprint":false},{"year":2009,"finding":"The Kelch repeats of Krp1 interact directly with Lasp-1 at two binding sites (residues 317-327 and 563-574) that are brought into proximity by a novel six-bladed β-propeller structure; both binding sites are required for Krp1-Lasp-1 interaction in vitro and for pseudopodial elongation in vivo.","method":"Peptide array overlay, recombinant Lasp-1 pulldown, mutational analysis, crystal structure of Krp1 C-terminal domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus peptide array mapping plus mutagenesis with in vivo functional validation","pmids":["19726686"],"is_preprint":false},{"year":2009,"finding":"In thrombin-stimulated platelets, Lasp-1 undergoes tyrosine phosphorylation primarily by Src kinase at Y171; this phosphorylation is dependent on integrin αIIbβ3-fibrinogen engagement and correlates with translocation of Lasp-1 from the cytosol to focal contacts and the leading edge of spreading platelets.","method":"Src kinase inhibitor experiments, integrin-expressing CHO cell model, site-directed mutagenesis of Y171, immunofluorescence of adherent platelets","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic identification of kinase plus mutagenesis plus localization; single lab","pmids":["19718473"],"is_preprint":false},{"year":2009,"finding":"LASP-1 expression is downstream of urokinase (uPA) signaling in HCC cells; uPA upregulation increases LASP-1 expression, and LASP-1 siRNA shows involvement in actin microfilament organization.","method":"2D-DIGE proteomics of uPA-siRNA-treated cells, MALDI-TOF-MS identification, Western blot and immunofluorescence confirmation, ectopic uPA and LASP-1 expression","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics discovery confirmed by Western blot plus gain-of-function; single lab","pmids":["19177205"],"is_preprint":false},{"year":2012,"finding":"Lasp-1 is a novel component of the podosome ring structure (co-localizing with zyxin and vinculin), is recruited during early podosome assembly, and its knockdown in macrophages impairs podosome dynamics and matrix degradation capacity.","method":"Immunofluorescence, live-cell imaging, siRNA knockdown in macrophages, matrix degradation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization by imaging confirmed with functional siRNA phenotype; single lab, two orthogonal methods","pmids":["22514729"],"is_preprint":false},{"year":2012,"finding":"PKA phosphorylation of LASP-1 at S146 induces formation of a LASP-1/ZO-2 complex that translocates from cytoplasm to nucleus; the interaction occurs between the proline-rich C-terminal motif of ZO-2 and the SH3 domain of LASP-1. Nuclear export is Crm-1-dependent via a newly identified NES in LASP-1; dephosphorylation by PP2B relocalizes LASP-1 back to focal contacts.","method":"Co-immunoprecipitation, in situ proximity ligation assay, phosphorylation-site mutants, Crm-1 inhibitor (leptomycin B) experiments, nuclear/cytosolic fractionation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus PLA plus phospho-mutant rescue plus pharmacological export inhibition; multiple orthogonal methods in one study","pmids":["22665060"],"is_preprint":false},{"year":2014,"finding":"LASP1 is a direct transcriptional target of HIF1α; HIF1α binds a hypoxia response element in the LASP1 promoter to upregulate LASP1 expression in pancreatic ductal adenocarcinoma cells in vitro and in mouse xenografts.","method":"ChIP assay demonstrating direct HIF1α binding to LASP1 promoter HRE, reporter assays, in vitro and xenograft overexpression/knockdown","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo xenograft validation; single lab","pmids":["25385028"],"is_preprint":false},{"year":2014,"finding":"LASP1 is a direct substrate of BCR-ABL kinase in CML; BCR-ABL specifically phosphorylates LASP1 at Y171, abolished by TKI therapy. Phospho-LASP1-Y171 binds non-phosphorylated CRKL at its SH2 domain, linking BCR-ABL activity to CRKL signaling.","method":"Phosphoproteomic identification in CML patient samples, TKI treatment abolition, site-directed mutagenesis of Y171, co-immunoprecipitation of LASP1-CRKL complex","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient sample phosphoproteomics plus mutagenesis plus co-IP; single lab","pmids":["24913448"],"is_preprint":false},{"year":2015,"finding":"Nuclear LASP-1 associates with the epigenetic complex UHRF1-DNMT1-G9a and the transcription factor Snail1 in a CXCL12-dependent manner; LASP-1 directly binds Snail1 and may stabilize it. LASP-1 knockdown alters gene expression toward increased cell-junction and ECM proteins and changes cytokine secretion profile.","method":"Proteomic analysis of LASP-1 immunoprecipitates, proximity ligation assay validation, co-IP of endogenous proteins, 3D Matrigel culture, breast TMA immunohistochemistry, CXCR4 antagonist AMD-3100 blocking","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics discovery confirmed by PLA and co-IP with pharmacological validation; single lab","pmids":["25982273"],"is_preprint":false},{"year":2016,"finding":"LASP1 interacts with S100A11; the LASP1-S100A11 axis is essential for TGFβ-mediated EMT and promotes colorectal cancer aggressiveness via downstream effectors flotillin-1 (cytoplasmic pathway) and histone H1 (nuclear pathway).","method":"Co-immunoprecipitation, gain- and loss-of-function assays, rescue experiments, xenograft models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional rescue; single lab, multiple readouts","pmids":["27181092"],"is_preprint":false},{"year":2016,"finding":"LASP1 depletion in breast cancer cells downregulates MMP1, MMP3, and MMP9 expression and secretion; LASP1 regulates MMP transcription through AP-1 (c-Fos), as demonstrated by decreased AP-1 transcriptional activity in LASP1 knockdown cells by luciferase reporter assay.","method":"Microarray after LASP1 siRNA, Western blot confirmation, rescue experiments, AP-1 luciferase reporter assay, zymography","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — microarray plus reporter assay plus zymography; single lab, multiple methods","pmids":["27588391"],"is_preprint":false},{"year":2016,"finding":"The SH3 domain of LASP1 directly binds the MPN domain of COPS5 (JAB1/CSN5); this interaction was confirmed by yeast two-hybrid and GST pull-down. LASP1 and COPS5 synergistically promote ubiquitination and degradation of 14-3-3σ, activating PI3K/AKT signaling in colorectal cancer.","method":"Yeast two-hybrid screening, GST pull-down, co-localization, gain/loss-of-function, ubiquitination assay, PI3K inhibitor rescue","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by GST pull-down plus functional ubiquitination assay; single lab","pmids":["29226323"],"is_preprint":false},{"year":2016,"finding":"LASP1 interacts with 14-3-3σ and promotes its downregulation in colorectal cancer; loss of 14-3-3σ is required for LASP1-mediated AKT phosphorylation and CRC aggressiveness, placing 14-3-3σ as a direct downstream effector of LASP1.","method":"Proteomics identification plus co-IP validation, gain/loss-of-function, PI3K inhibitor rescue, co-localization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics discovery confirmed by co-IP and rescue experiments; single lab","pmids":["27156963"],"is_preprint":false},{"year":2017,"finding":"LASP1 directly binds FAK and facilitates phosphorylation of FAK at Tyr397 and AKT at Ser473 in NSCLC cells; FAK inhibition abrogates downstream AKT phosphorylation, but AKT inhibition does not affect FAK phosphorylation, establishing LASP1→FAK→AKT as a linear signaling axis.","method":"Co-immunoprecipitation, Western blot, FAK and AKT inhibitors, overexpression and knockdown in NSCLC cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus pharmacological epistasis; single lab","pmids":["29088849"],"is_preprint":false},{"year":2018,"finding":"LASP1 interacts with and co-localizes with PTEN in NPC cells; LASP1 overexpression increases PTEN ubiquitination and decreases PTEN expression, thereby activating PI3K/AKT signaling.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, rescue experiments with PTEN overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus functional rescue; single lab","pmids":["29531214"],"is_preprint":false},{"year":2018,"finding":"HBX promotes LASP-1 expression via activation of c-Jun (AP-1); HBX interacts with phosphorylated c-Jun and activates PI3K/JNK signaling; ChIP demonstrates direct binding of the HBX/c-Jun complex to the LASP-1 promoter AP-1 element.","method":"Luciferase reporter assay, ChIP assay, co-IP of HBX with p-c-Jun, PI3K/JNK inhibitor experiments, Western blot","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus co-IP with pathway inhibitor confirmation; single lab","pmids":["29600594"],"is_preprint":false},{"year":2019,"finding":"LASP1 associates with components of the eIF4F translation initiation complex (eIF4A and eIF4B) in a CXCL12-dependent manner; LASP1 directly binds eIF4A and eIF4B via GST-pulldown; LASP1 knockdown impairs eIF4A-dependent translation of oncogenic mRNAs, and LASP1 deficiency sensitizes cells to eIF4A inhibitor Rocaglamide A.","method":"Proteomic screen, proximity ligation assay, co-immunoprecipitation, GST-pulldown, 5'UTR luciferase reporter assay, pharmacological eIF4A inhibition","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic discovery confirmed by PLA, co-IP, and GST pulldown with functional reporter assay; single lab, multiple orthogonal methods","pmids":["31106142"],"is_preprint":false},{"year":2019,"finding":"LASP1 interacts with HSPA1A (HSP70 family member) in HNSCC; HSPA1A acts as a chaperone for LASP1 and positively regulates LASP1-P-AKT interaction, enhancing malignant behavior.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, gain/loss-of-function assays","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP with localization; single lab, limited mechanistic follow-up","pmids":["31793711"],"is_preprint":false},{"year":2020,"finding":"LASP1 interacts with N-WASP; this interaction does not alter N-WASP expression but rescues reduced actin polymerization caused by N-WASP silencing. N-WASP activates the Arp2/3 complex to promote actin polymerization and CRC cell migration/invasion.","method":"Yeast two-hybrid screening, co-immunoprecipitation confirmation, Arp2/3 actin polymerization assay, functional rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP and functional rescue with actin polymerization assay; single lab","pmids":["32704133"],"is_preprint":false},{"year":2020,"finding":"The CXCR4-LASP1 axis promotes nuclear accumulation and stabilization of Snail1 by upregulating nuclear pS473-Akt, pS9-GSK-3β, A20, and LSD1; LASP1 endogenously associates with Snail1, A20, GSK-3β, and LSD1 in a CXCL12-dependent manner. LASP1 ablation causes mislocalization of nuclear Snail1 and loss of Matrigel invasion.","method":"Co-immunoprecipitation, proximity ligation assay, nuclear/cytosolic fractionation Western blots, CXCR4 antagonist (AMD-3100) blocking, Matrigel invasion assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus PLA plus pharmacological validation; single lab, multiple methods","pmids":["32825729"],"is_preprint":false},{"year":2020,"finding":"LASP1 associates with Argonaute 2 (Ago2) endogenously in a CXCL12-dependent, CXCR4-mediated manner; LASP1 directly binds Ago2 through its LIM and SH3 domains via GST-pulldown; LASP1 phosphorylation status at S146 and Y171 determines binding. LASP1-Ago2 association modulates Let-7a-guided RISC activity and alters levels of Let-7a targets including CCR7.","method":"Co-immunoprecipitation (endogenous), proximity ligation assay, GST-pulldown with LASP1 phospho-mutants, CXCR4 antagonist (AMD3465) blocking, Let-7a target expression analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP confirmed by PLA and GST pulldown with phospho-site mutants; single lab, multiple orthogonal methods","pmids":["32872485"],"is_preprint":false},{"year":2021,"finding":"Lasp1 binds directly to Cadherin-11/β-Catenin complexes in fibroblast-like synoviocytes; loss or blocking of Lasp1 alters pathological tissue formation, migratory behavior, and PDGF response of arthritic FLS. In TNF transgenic arthritic mice, Lasp1 deletion reduces arthritic joint destruction.","method":"Epigenomic profiling, co-immunoprecipitation for Cadherin-11/β-Catenin/Lasp1 complex, Lasp1 knockout in TNF transgenic mice with histological and functional joint assessments, in vitro FLS functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with quantitative joint destruction phenotype combined with co-IP evidence of complex; multiple orthogonal methods across labs (integrative epigenomics + functional)","pmids":["34131132"],"is_preprint":false},{"year":2021,"finding":"LASP1 is identified as a sphingolipid-metabolism-involved protein by LC-MS; ECHS1 is identified as a new LASP1-interacting protein in CRC by protein interaction assay.","method":"LC-MS sphingolipid assay, protein interaction assay (co-IP), gain/loss-of-function in CRC cells","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single protein interaction assay; mechanistic link between LASP1 and sphingolipid metabolism remains indirect","pmids":["34615856"],"is_preprint":false},{"year":2022,"finding":"HBX increases LASP1 SUMOylation; SUMOylation is promoted by RANBP2 and RANGAP1 (which interact with LASP1) and enhances LASP1 binding to HER2, thereby preventing HER2 ubiquitination-mediated proteasomal degradation and stabilizing HER2 expression.","method":"Co-immunoprecipitation, SUMOylation assay, ubiquitination assay, Western blot for HER2 stability","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation assay plus co-IP for complex with RANBP2/RANGAP1 plus functional ubiquitination assay; single lab","pmids":["36473530"],"is_preprint":false},{"year":2023,"finding":"TRIM15 mediates K63-linked polyubiquitination of LASP1, promoting its nuclear translocation; nuclear LASP1 then increases AKT phosphorylation and Snail expression to drive TKI resistance in HCC. TRIM15 expression is regulated upstream by the AKT/FOXO1 axis.","method":"Western blot nuclear fractionation, co-immunoprecipitation, ubiquitination assay with K63-linkage specificity, gain/loss-of-function in HCC cells, pharmacological AKT/FOXO1 inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with linkage specificity plus nuclear fractionation plus functional rescue; single lab","pmids":["36670097"],"is_preprint":false},{"year":2023,"finding":"METTL14 stabilizes LASP1 mRNA through m6A modification, thereby promoting LASP1 protein expression and activating the SRC/AKT signaling axis in fibroblast-like synoviocytes; METTL14 knockdown reduces LASP1 expression and FLS activation.","method":"Western blot for LASP1, p-SRC, p-AKT after METTL14 shRNA; mRNA stability analysis with m6A modification; rescue by LASP1 overexpression; RA rat model","journal":"American journal of physiology. Cell physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — m6A modification established by inference from expression changes after METTL14 knockdown; direct m6A mapping of LASP1 not shown in abstract; single lab","pmids":["36878846"],"is_preprint":false},{"year":2015,"finding":"LASP-1 overexpression in HCC cells, identified by MALDI-TOF mass spectrometry of co-immunoprecipitated fractions, reveals vimentin as a novel binding partner of LASP-1.","method":"Co-immunoprecipitation followed by MALDI-TOF mass spectrometry identification of vimentin","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP/MS identification without further binding validation; single lab","pmids":["25760690"],"is_preprint":false}],"current_model":"LASP1 is a multidomain actin-binding scaffold protein (LIM domain, two nebulin repeats, SH3 domain) that localizes to focal adhesions, lamellipodia tips, podosomes, and the nucleus, where it integrates cytoskeletal organization and signaling: it binds F-actin directly (Kd ~2 µM, regulated by PKA phosphorylation at S99/S146), interacts via its SH3 domain with zyxin, palladin-140 kDa, N-WASP (activating Arp2/3-mediated actin polymerization), CRKL, and ZO-2, and undergoes phosphorylation at Y171 by Src/c-Abl to regulate focal adhesion dynamics; nuclear import is driven by PKA-phosphorylated LASP1/ZO-2 complex via Crm-1-dependent export and PP2B-dependent recycling back to focal contacts, where nuclear LASP1 serves as a hub for the UHRF1-DNMT1-G9a-Snail1 epigenetic complex and for the Ago2/RISC machinery in a CXCR4-dependent manner; LASP1 transcription is directly activated by HIF1α and c-Jun/AP-1 and repressed by p53, while its nuclear translocation is promoted by TRIM15-mediated K63-polyubiquitination, and its stability is enhanced by HBX-induced SUMOylation; physiologically, Lasp-1 negatively regulates parietal cell HCl secretion and participates in Cadherin-11/β-Catenin junction formation in synoviocytes."},"narrative":{"mechanistic_narrative":"LASP1 is a multidomain actin-binding scaffold protein with an N-terminal LIM domain and a C-terminal SH3 domain that organizes the cortical cytoskeleton and couples it to signaling at focal adhesions, lamellipodia, and podosomes [PMID:7589475, PMID:9848085, PMID:22514729]. The isolated LIM module folds as an independent zinc-coordinating rubredoxin-knuckle [PMID:8841116], while a central actin-binding region mediates direct, saturable binding to non-muscle F-actin (Kd ~2 µM) that is attenuated by PKA-dependent phosphorylation at S99/S146, controlling cAMP-driven translocation of LASP1 between the cortex and intracellular compartments in parietal cells [PMID:12432067]. Through its SH3 domain LASP1 docks onto proline-rich and linear motifs in cytoskeletal partners—zyxin, the 140 kDa palladin isoform, Krp1/Kelch repeats, and N-WASP—positioning it upstream of zyxin recruitment to focal contacts and licensing N-WASP/Arp2/3-mediated actin polymerization to drive migration and invasion [PMID:15004028, PMID:16492705, PMID:19726686, PMID:32704133, PMID:17211471]. Tyrosine phosphorylation at Y171 by Src-family and Abl-type kinases (including BCR-ABL) governs focal adhesion localization and creates a binding site for CRKL, linking LASP1 to oncogenic kinase signaling [PMID:15138294, PMID:19718473, PMID:24913448]. LASP1 also shuttles to the nucleus as a PKA-S146-phosphorylated complex with ZO-2, exported via a Crm-1-dependent NES and recycled by PP2B [PMID:22665060]; in a CXCR4/CXCL12-dependent manner nuclear LASP1 scaffolds the Snail1 stabilization and epigenetic machinery and associates with the eIF4F translation-initiation and Ago2/RISC complexes to control oncogenic gene expression [PMID:25982273, PMID:32825729, PMID:31106142, PMID:32872485]. Its abundance is set transcriptionally—activated by HIF1α and c-Jun/AP-1 and repressed by p53—and its activity is further tuned by ubiquitin- and SUMO-dependent modifications [PMID:25385028, PMID:29600594, PMID:19155088, PMID:36670097, PMID:36473530]. Physiologically, LASP1 acts as a negative regulator of parietal cell HCl secretion and, in fibroblast-like synoviocytes, binds Cadherin-11/β-Catenin complexes to drive arthritic joint destruction [PMID:18483181, PMID:34131132].","teleology":[{"year":1996,"claim":"Established that the LASP1 LIM domain is a structurally autonomous zinc-binding module, defining the architectural basis of the protein.","evidence":"NMR solution structure of a synthetic ZF-1 peptide complexed with zinc","pmids":["8841116"],"confidence":"High","gaps":["Structure limited to a 30-residue isolated module, not full-length protein","Functional role of zinc coordination in cells not tested"]},{"year":1998,"claim":"Defined LASP1 as an actin-binding protein and connected it to Src-family tyrosine kinase signaling, placing it at the cytoskeleton-signaling interface.","evidence":"In vitro actin-binding assays, confocal co-localization, and Western blot of c-Src-transformed fibroblasts","pmids":["9848085"],"confidence":"Medium","gaps":["Actin-binding region not finely mapped","Functional consequence of tyrosine phosphorylation unresolved at this stage"]},{"year":2002,"claim":"Quantified direct F-actin binding and showed PKA phosphorylation at S99/S146 reduces affinity, providing a molecular switch for cAMP-driven LASP1 relocalization.","evidence":"Actin pull-down with recombinant LASP1, in vitro PKA phosphorylation, phospho-mutants, and parietal cell imaging","pmids":["12432067"],"confidence":"High","gaps":["Structural basis of the actin interface not solved","Phospho-regulation studied mainly in parietal cells"]},{"year":2004,"claim":"Mapped the SH3 domain as the docking module for cytoskeletal partners and established LASP1 as required for migration but not adhesion, with Y171 phosphorylation controlling focal adhesion residency.","evidence":"Yeast two-hybrid, co-precipitation, mutagenesis of zyxin/palladin motifs, pseudopodial proteomics, and siRNA migration assays","pmids":["15004028","16492705","15138294","15465019"],"confidence":"High","gaps":["Order of partner recruitment at focal contacts not fully resolved","Distinct contributions of zyxin vs palladin binding unclear"]},{"year":2008,"claim":"Genetic knockout established LASP1 as an in vivo negative regulator of parietal cell acid secretion, validating its physiological cytoskeletal-signaling role.","evidence":"Lasp-1 knockout mice with in vivo and ex vivo gastric acid secretion assays","pmids":["18483181"],"confidence":"High","gaps":["Molecular mechanism linking LASP1 to the secretory machinery not defined","Whether effect is purely actin-dependent untested"]},{"year":2009,"claim":"Resolved the Krp1/Kelch binding interface structurally and confirmed Src/integrin-driven Y171 phosphorylation directs LASP1 to focal contacts in adherent cells.","evidence":"Crystal structure of Krp1 C-terminal β-propeller with peptide-array mapping, plus platelet adhesion and Y171 mutagenesis studies","pmids":["19726686","19718473"],"confidence":"High","gaps":["Integration of multiple SH3 ligands at one focal contact not modeled","Kinase selectivity for Y171 across cell types unclear"]},{"year":2012,"claim":"Identified the nuclear shuttling mechanism, showing PKA-S146 phosphorylation drives a LASP1/ZO-2 complex into the nucleus with Crm-1-dependent export and PP2B-dependent recycling.","evidence":"Reciprocal co-IP, proximity ligation, phospho-mutants, leptomycin B export inhibition, and fractionation","pmids":["22665060"],"confidence":"High","gaps":["Nuclear function downstream of import not defined in this study","Stoichiometry of nuclear LASP1/ZO-2 complex unknown"]},{"year":2015,"claim":"Revealed nuclear LASP1 as a CXCR4-dependent scaffold for the UHRF1-DNMT1-G9a epigenetic complex and Snail1, connecting cytoskeletal LASP1 to transcriptional/epigenetic control of EMT.","evidence":"Proteomics of LASP1 immunoprecipitates, PLA, endogenous co-IP, and CXCR4 antagonist blocking","pmids":["25982273"],"confidence":"Medium","gaps":["Direct vs scaffold-mediated contacts within the complex not separated","Functional impact on DNA methylation marks not directly measured"]},{"year":2016,"claim":"Positioned LASP1 as a regulator of protein-stability and PI3K/AKT signaling through SH3-mediated binding to COPS5 and 14-3-3σ degradation, and as an AP-1-dependent driver of MMP expression.","evidence":"Yeast two-hybrid, GST pull-down, ubiquitination assays, AP-1 luciferase reporter, and zymography across CRC and breast cancer models","pmids":["29226323","27156963","27588391","27181092"],"confidence":"Medium","gaps":["Whether LASP1 directly enables ubiquitin ligase activity or acts as adaptor unresolved","Cell-type generality of the 14-3-3σ axis untested"]},{"year":2020,"claim":"Extended nuclear LASP1's scaffolding role to the eIF4F translation-initiation complex and Ago2/RISC, with phosphorylation-state-dependent binding linking CXCR4 signaling to oncogenic translation and miRNA activity.","evidence":"Proteomic screens, PLA, endogenous co-IP, GST pull-down with phospho-mutants, 5'UTR reporters, and CXCR4 antagonist blocking","pmids":["31106142","32872485","32825729"],"confidence":"Medium","gaps":["Direct RNA-binding capacity of LASP1 not demonstrated","How one scaffold partitions among actin, RISC, and eIF4F pools unknown"]},{"year":2021,"claim":"Defined a physiological non-cancer role by showing LASP1 binds Cadherin-11/β-Catenin junctions and drives arthritic joint destruction in vivo.","evidence":"Epigenomic profiling, co-IP for the Cadherin-11/β-Catenin/Lasp1 complex, and Lasp1 knockout in TNF transgenic arthritic mice","pmids":["34131132"],"confidence":"High","gaps":["Mechanistic link between junctional LASP1 and FLS invasion incomplete","Relationship to LASP1's actin and nuclear functions in this context unclear"]},{"year":2023,"claim":"Showed that ubiquitin- and SUMO-dependent modifications and upstream transcriptional/epitranscriptomic inputs converge to control LASP1 abundance and nuclear translocation in disease.","evidence":"K63-linkage-specific ubiquitination assays (TRIM15), SUMOylation assays (HBX/RANBP2/RANGAP1), ChIP for HIF1α/c-Jun, and m6A/METTL14 stability analyses","pmids":["36670097","36473530","25385028","29600594","36878846"],"confidence":"Medium","gaps":["Sites of K63-ubiquitination and SUMOylation on LASP1 not mapped","Direct m6A residues on LASP1 mRNA not demonstrated"]},{"year":null,"claim":"How a single scaffold dynamically partitions between F-actin, focal adhesions, the nucleus, RISC, and the translation machinery—and whether these pools are mutually exclusive or coordinated—remains unresolved.","evidence":"No integrated structural or quantitative model spans the cytoplasmic and nuclear LASP1 interactomes in the corpus","pmids":[],"confidence":"Medium","gaps":["No full-length LASP1 structure with bound partners","Quantitative flux between functional pools unmeasured","Causal hierarchy among phosphorylation, ubiquitination, and SUMOylation switches undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,5,35]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,22,25,37]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[28,31,40]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,7,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,22,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[24,30,36]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,11,35]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[33,37]}],"complexes":["UHRF1-DNMT1-G9a epigenetic complex","eIF4F translation initiation complex","Ago2/RISC","Cadherin-11/β-Catenin complex"],"partners":["ZYX","PALLD","WASL","ZO-2","CRKL","AGO2","COPS5","SNAI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14847","full_name":"LIM and SH3 domain protein 1","aliases":["Metastatic lymph node gene 50 protein","MLN 50"],"length_aa":261,"mass_kda":29.7,"function":"Plays an important role in the regulation of dynamic actin-based, cytoskeletal activities. Agonist-dependent changes in LASP1 phosphorylation may also serve to regulate actin-associated ion transport activities, not only in the parietal cell but also in certain other F-actin-rich secretory epithelial cell types (By similarity)","subcellular_location":"Cytoplasm, cell cortex; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q14847/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LASP1","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LASP1","total_profiled":1310},"omim":[{"mim_id":"617544","title":"LONG INTERGENIC NONCODING RNA 672; LINC00672","url":"https://www.omim.org/entry/617544"},{"mim_id":"616770","title":"MICRO RNA 218-1; MIR218-1","url":"https://www.omim.org/entry/616770"},{"mim_id":"605491","title":"NEBULETTE; NEBL","url":"https://www.omim.org/entry/605491"},{"mim_id":"602920","title":"LIM AND SH3 PROTEIN 1; LASP1","url":"https://www.omim.org/entry/602920"},{"mim_id":"602002","title":"ZYXIN; ZYX","url":"https://www.omim.org/entry/602002"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LASP1"},"hgnc":{"alias_symbol":["MLN50","Lasp-1"],"prev_symbol":[]},"alphafold":{"accession":"Q14847","domains":[{"cath_id":"2.10.110.10","chopping":"1-58","consensus_level":"medium","plddt":91.111,"start":1,"end":58},{"cath_id":"2.30.30.40","chopping":"206-259","consensus_level":"high","plddt":93.1694,"start":206,"end":259}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14847","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14847-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14847-F1-predicted_aligned_error_v6.png","plddt_mean":70.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LASP1","jax_strain_url":"https://www.jax.org/strain/search?query=LASP1"},"sequence":{"accession":"Q14847","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14847.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14847/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14847"}},"corpus_meta":[{"pmid":"22713668","id":"PMC_22713668","title":"MicroRNA-203 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a new LIM protein subfamily member containing an N-terminal LIM motif and a C-terminal SH3 domain, defining a novel domain architecture.\",\n      \"method\": \"cDNA cloning and sequence analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence-based domain identification confirmed in founding paper, replicated by subsequent structural studies\",\n      \"pmids\": [\"7589475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The N-terminal zinc-binding module of the Lasp-1 LIM domain (residues 1-30) folds as an independent structural unit coordinating zinc via Cys5, Cys8, His26, and Cys29, adopting a rubredoxin-knuckle motif consistent with other LIM domain modules.\",\n      \"method\": \"1H NMR solution structure determination of synthetic peptide ZF-1 complexed with zinc\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with unambiguous zinc coordination identified by constraint-free calculations; first structural characterization of an isolated LIM module\",\n      \"pmids\": [\"8841116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lasp-1 contains an actin-binding domain in the core of the protein; it binds actin in vivo and in vitro, co-localizes with actin at peripheral cell extensions, and is tyrosine-phosphorylated in fibroblasts transformed by constitutively active c-Src (SrcY527F).\",\n      \"method\": \"In vitro actin-binding assay, in vivo co-localization by confocal microscopy, Western blot of Src-transformed fibroblasts\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay plus in vivo localization; single lab with two orthogonal methods\",\n      \"pmids\": [\"9848085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lasp-1 is a cAMP-dependent phosphoprotein in gastric parietal cells; stimulation of parietal cells, distal colonic crypts, and pancreatic cells with forskolin induces a higher-molecular-weight (phosphorylated) form of Lasp-1, placing it downstream of PKA in the cAMP signaling pathway.\",\n      \"method\": \"Microsequencing/cloning, Northern and Western blot, forskolin stimulation of isolated cells\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification plus pharmacological stimulation across multiple cell types; single lab\",\n      \"pmids\": [\"9688835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In gastric parietal cells, histamine-induced elevation of cAMP increases Lasp-1 phosphorylation and induces partial redistribution of Lasp-1 from the cell cortex (where it co-localizes with γ-actin) to the β-actin-enriched intracellular canalicular region, the site of active proton transport.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, histamine stimulation correlated with acid secretion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional correlation; single lab, two orthogonal approaches\",\n      \"pmids\": [\"10806114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Lasp-1 binds directly to non-muscle F-actin in vitro with apparent Kd ~2 µM and saturation stoichiometry ~1:7; PKA-dependent phosphorylation at S99 and S146 increases Kd and decreases Bmax, reducing actin-binding affinity. Phosphorylation-site alanine mutants (S99A/S146A) suppress cAMP-dependent translocation of Lasp-1 to the intracellular canalicular region in parietal cells.\",\n      \"method\": \"Actin pull-down assay with bacterially expressed His-Lasp-1, in vitro PKA phosphorylation, site-directed mutagenesis, parietal cell transfection and immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro reconstitution with mutagenesis and functional validation in cells; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12432067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LASP1 is a fusion partner of MLL in an infant AML with t(11;17)(q23;q21); the MLL/LASP1 fusion protein lacks in vitro myeloid progenitor transformation capability, placing it in a subgroup of non-transforming MLL fusions.\",\n      \"method\": \"FISH, RT-PCR, RACE cloning of fusion transcript, retroviral transduction of myeloid progenitors\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular identification plus functional transformation assay; single case but rigorous methodology\",\n      \"pmids\": [\"12527918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Lasp-1 localizes to focal complexes and the leading edge of pseudopodia in migrating cells. Growth factor or ECM stimulation causes Lasp-1 to relocalize from the cell periphery to the leading edge; c-Abl-mediated phosphorylation of Lasp-1 at tyrosine 171 (induced by apoptotic agents) causes loss of focal adhesion localization and cell death. Lasp-1 is required for cell migration but not adhesion.\",\n      \"method\": \"Large-scale pseudopodial proteomics, siRNA knockdown migration/adhesion assays, immunofluorescence, c-Abl kinase inhibitor experiments, phosphorylation mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification combined with functional siRNA phenotype, localization imaging, and phosphorylation site mapping; multiple orthogonal methods\",\n      \"pmids\": [\"15138294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LASP-1 interacts with zyxin, LPP, and VASP via their proline-rich domains; zyxin is the most prominent partner. LASP-1 exists as a monomer despite its LIM domain. Mouse LASP-1 is phosphorylated by PKA and PKG in vitro at S61, S99, and T156, but only at T156 in intact cells; phosphorylation by either kinase causes translocation from focal contacts to the cell interior without affecting F-actin.\",\n      \"method\": \"Overlay binding assays, gel filtration (monomer determination), in vitro kinase assays with PKA/PKG, immunofluorescence of human and mouse mesangial cells treated with forskolin\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assays combined with cell localization; single lab, multiple methods\",\n      \"pmids\": [\"15465019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The SH3 domain of Lasp-1 is necessary and sufficient for interaction with zyxin; the binding site in zyxin is at its extreme N-terminus and uses a linear motif lacking the classical PXXP sequence. Co-precipitation and yeast two-hybrid confirmed the Lasp-1–zyxin interaction.\",\n      \"method\": \"Yeast two-hybrid, co-precipitation, site-directed mutagenesis of zyxin binding site\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid plus co-precipitation plus mutagenesis mapping binding site; multiple orthogonal methods in one study\",\n      \"pmids\": [\"15004028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Lasp-1 is a component of CNS postsynaptic densities and is concentrated at synaptic sites and dendritic spines of hippocampal neurons.\",\n      \"method\": \"MudPIT proteomics of purified postsynaptic fractions, immunofluorescence of CNS neurons\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification from purified fraction confirmed by immunofluorescence; single lab\",\n      \"pmids\": [\"15372503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LASP-1 silencing in breast cancer cells causes G2/M arrest, suppresses proliferation by 30-50%, reduces migration by 50%, and reduces zyxin recruitment to focal contacts without altering actin stress fibers. Overexpression of LASP-1 in PTK-2 cells that lack endogenous LASP-1 increases cell motility.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, wound-healing assay, immunofluorescence, LASP-1 overexpression in LASP-1-negative cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined cellular phenotypes; single lab, multiple readouts\",\n      \"pmids\": [\"16430883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The 140 kDa isoform of palladin (but not the 90 kDa isoform) directly binds Lasp-1 via its SH3-domain binding motif; isoform-specific siRNA of 140 kDa palladin reduces Lasp-1 recruitment to stress fibers.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, isoform-specific siRNA with immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid plus GST pull-down plus functional siRNA rescue in cells; multiple orthogonal methods\",\n      \"pmids\": [\"16492705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LASP-1 silencing in ovarian cancer cells arrests cells in G2/M, suppresses proliferation by 60-90%, reduces migration by 40%, and reduces zyxin binding to focal contacts. LASP-1 knockdown did not affect actin stress fiber or microtubule organization. Silencing zyxin did not affect LASP-1 expression or migration, placing LASP-1 upstream of zyxin at focal contacts.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, proliferation assay, migration assay, immunofluorescence for zyxin and actin\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between LASP-1 and zyxin established by parallel knockdowns; single lab, multiple readouts\",\n      \"pmids\": [\"17211471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LASP-1 is not exclusively cytosolic; it is also detectable in the nucleus of breast cancer cells, with nuclear accumulation correlating with higher tumor stage and increased proliferation (peak in G2/M phase).\",\n      \"method\": \"Confocal immunofluorescence, separate nuclear/cytosolic fractionation Western blots, cell synchronization experiments\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear localization confirmed by fractionation plus imaging; single lab, two orthogonal methods\",\n      \"pmids\": [\"17956604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lasp-1 knockout mice show increased histamine-stimulated gastric HCl secretion compared to wild-type littermates, with slower inhibition by ranitidine, establishing Lasp-1 as a negative regulator of parietal cell acid secretion in vivo.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), in vivo and ex vivo acid secretion assays, [14C]aminopyrine accumulation in isolated gastric glands\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with quantitative physiological phenotype confirmed in vivo and ex vivo\",\n      \"pmids\": [\"18483181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p53 transcriptionally represses LASP1 expression via a p53 response element in the LASP1 promoter; wild-type but not DNA-binding mutant p53 suppresses LASP1; p53 siRNA in p53-positive HepG2 cells upregulates LASP1.\",\n      \"method\": \"Luciferase reporter assay, transient transfection of WT and mutant p53 in p53-null cells, p53 siRNA, Western blot\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus loss-of-function siRNA plus gain-of-function with binding-dead mutant; single lab\",\n      \"pmids\": [\"19155088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lasp-1 knockout mice display enhanced wound healing and more rapid tumor formation; Lasp-1-null MEFs migrate more rapidly in vitro, have more focal adhesions, and show increased LPP expression (~2-fold), suggesting LPP compensates for loss of Lasp-1 to enhance migration.\",\n      \"method\": \"Knockout mouse wound-healing assay, tumor initiation assay, MEF migration assay, focal adhesion counting, differential microarray analysis\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple cellular phenotypes; single lab\",\n      \"pmids\": [\"19531578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Kelch repeats of Krp1 interact directly with Lasp-1 at two binding sites (residues 317-327 and 563-574) that are brought into proximity by a novel six-bladed β-propeller structure; both binding sites are required for Krp1-Lasp-1 interaction in vitro and for pseudopodial elongation in vivo.\",\n      \"method\": \"Peptide array overlay, recombinant Lasp-1 pulldown, mutational analysis, crystal structure of Krp1 C-terminal domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus peptide array mapping plus mutagenesis with in vivo functional validation\",\n      \"pmids\": [\"19726686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In thrombin-stimulated platelets, Lasp-1 undergoes tyrosine phosphorylation primarily by Src kinase at Y171; this phosphorylation is dependent on integrin αIIbβ3-fibrinogen engagement and correlates with translocation of Lasp-1 from the cytosol to focal contacts and the leading edge of spreading platelets.\",\n      \"method\": \"Src kinase inhibitor experiments, integrin-expressing CHO cell model, site-directed mutagenesis of Y171, immunofluorescence of adherent platelets\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic identification of kinase plus mutagenesis plus localization; single lab\",\n      \"pmids\": [\"19718473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LASP-1 expression is downstream of urokinase (uPA) signaling in HCC cells; uPA upregulation increases LASP-1 expression, and LASP-1 siRNA shows involvement in actin microfilament organization.\",\n      \"method\": \"2D-DIGE proteomics of uPA-siRNA-treated cells, MALDI-TOF-MS identification, Western blot and immunofluorescence confirmation, ectopic uPA and LASP-1 expression\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics discovery confirmed by Western blot plus gain-of-function; single lab\",\n      \"pmids\": [\"19177205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Lasp-1 is a novel component of the podosome ring structure (co-localizing with zyxin and vinculin), is recruited during early podosome assembly, and its knockdown in macrophages impairs podosome dynamics and matrix degradation capacity.\",\n      \"method\": \"Immunofluorescence, live-cell imaging, siRNA knockdown in macrophages, matrix degradation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization by imaging confirmed with functional siRNA phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"22514729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PKA phosphorylation of LASP-1 at S146 induces formation of a LASP-1/ZO-2 complex that translocates from cytoplasm to nucleus; the interaction occurs between the proline-rich C-terminal motif of ZO-2 and the SH3 domain of LASP-1. Nuclear export is Crm-1-dependent via a newly identified NES in LASP-1; dephosphorylation by PP2B relocalizes LASP-1 back to focal contacts.\",\n      \"method\": \"Co-immunoprecipitation, in situ proximity ligation assay, phosphorylation-site mutants, Crm-1 inhibitor (leptomycin B) experiments, nuclear/cytosolic fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus PLA plus phospho-mutant rescue plus pharmacological export inhibition; multiple orthogonal methods in one study\",\n      \"pmids\": [\"22665060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LASP1 is a direct transcriptional target of HIF1α; HIF1α binds a hypoxia response element in the LASP1 promoter to upregulate LASP1 expression in pancreatic ductal adenocarcinoma cells in vitro and in mouse xenografts.\",\n      \"method\": \"ChIP assay demonstrating direct HIF1α binding to LASP1 promoter HRE, reporter assays, in vitro and xenograft overexpression/knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo xenograft validation; single lab\",\n      \"pmids\": [\"25385028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LASP1 is a direct substrate of BCR-ABL kinase in CML; BCR-ABL specifically phosphorylates LASP1 at Y171, abolished by TKI therapy. Phospho-LASP1-Y171 binds non-phosphorylated CRKL at its SH2 domain, linking BCR-ABL activity to CRKL signaling.\",\n      \"method\": \"Phosphoproteomic identification in CML patient samples, TKI treatment abolition, site-directed mutagenesis of Y171, co-immunoprecipitation of LASP1-CRKL complex\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient sample phosphoproteomics plus mutagenesis plus co-IP; single lab\",\n      \"pmids\": [\"24913448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nuclear LASP-1 associates with the epigenetic complex UHRF1-DNMT1-G9a and the transcription factor Snail1 in a CXCL12-dependent manner; LASP-1 directly binds Snail1 and may stabilize it. LASP-1 knockdown alters gene expression toward increased cell-junction and ECM proteins and changes cytokine secretion profile.\",\n      \"method\": \"Proteomic analysis of LASP-1 immunoprecipitates, proximity ligation assay validation, co-IP of endogenous proteins, 3D Matrigel culture, breast TMA immunohistochemistry, CXCR4 antagonist AMD-3100 blocking\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics discovery confirmed by PLA and co-IP with pharmacological validation; single lab\",\n      \"pmids\": [\"25982273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LASP1 interacts with S100A11; the LASP1-S100A11 axis is essential for TGFβ-mediated EMT and promotes colorectal cancer aggressiveness via downstream effectors flotillin-1 (cytoplasmic pathway) and histone H1 (nuclear pathway).\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function assays, rescue experiments, xenograft models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional rescue; single lab, multiple readouts\",\n      \"pmids\": [\"27181092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LASP1 depletion in breast cancer cells downregulates MMP1, MMP3, and MMP9 expression and secretion; LASP1 regulates MMP transcription through AP-1 (c-Fos), as demonstrated by decreased AP-1 transcriptional activity in LASP1 knockdown cells by luciferase reporter assay.\",\n      \"method\": \"Microarray after LASP1 siRNA, Western blot confirmation, rescue experiments, AP-1 luciferase reporter assay, zymography\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — microarray plus reporter assay plus zymography; single lab, multiple methods\",\n      \"pmids\": [\"27588391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The SH3 domain of LASP1 directly binds the MPN domain of COPS5 (JAB1/CSN5); this interaction was confirmed by yeast two-hybrid and GST pull-down. LASP1 and COPS5 synergistically promote ubiquitination and degradation of 14-3-3σ, activating PI3K/AKT signaling in colorectal cancer.\",\n      \"method\": \"Yeast two-hybrid screening, GST pull-down, co-localization, gain/loss-of-function, ubiquitination assay, PI3K inhibitor rescue\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by GST pull-down plus functional ubiquitination assay; single lab\",\n      \"pmids\": [\"29226323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LASP1 interacts with 14-3-3σ and promotes its downregulation in colorectal cancer; loss of 14-3-3σ is required for LASP1-mediated AKT phosphorylation and CRC aggressiveness, placing 14-3-3σ as a direct downstream effector of LASP1.\",\n      \"method\": \"Proteomics identification plus co-IP validation, gain/loss-of-function, PI3K inhibitor rescue, co-localization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics discovery confirmed by co-IP and rescue experiments; single lab\",\n      \"pmids\": [\"27156963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LASP1 directly binds FAK and facilitates phosphorylation of FAK at Tyr397 and AKT at Ser473 in NSCLC cells; FAK inhibition abrogates downstream AKT phosphorylation, but AKT inhibition does not affect FAK phosphorylation, establishing LASP1→FAK→AKT as a linear signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, FAK and AKT inhibitors, overexpression and knockdown in NSCLC cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus pharmacological epistasis; single lab\",\n      \"pmids\": [\"29088849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LASP1 interacts with and co-localizes with PTEN in NPC cells; LASP1 overexpression increases PTEN ubiquitination and decreases PTEN expression, thereby activating PI3K/AKT signaling.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, rescue experiments with PTEN overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus functional rescue; single lab\",\n      \"pmids\": [\"29531214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HBX promotes LASP-1 expression via activation of c-Jun (AP-1); HBX interacts with phosphorylated c-Jun and activates PI3K/JNK signaling; ChIP demonstrates direct binding of the HBX/c-Jun complex to the LASP-1 promoter AP-1 element.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, co-IP of HBX with p-c-Jun, PI3K/JNK inhibitor experiments, Western blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus co-IP with pathway inhibitor confirmation; single lab\",\n      \"pmids\": [\"29600594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LASP1 associates with components of the eIF4F translation initiation complex (eIF4A and eIF4B) in a CXCL12-dependent manner; LASP1 directly binds eIF4A and eIF4B via GST-pulldown; LASP1 knockdown impairs eIF4A-dependent translation of oncogenic mRNAs, and LASP1 deficiency sensitizes cells to eIF4A inhibitor Rocaglamide A.\",\n      \"method\": \"Proteomic screen, proximity ligation assay, co-immunoprecipitation, GST-pulldown, 5'UTR luciferase reporter assay, pharmacological eIF4A inhibition\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic discovery confirmed by PLA, co-IP, and GST pulldown with functional reporter assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31106142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LASP1 interacts with HSPA1A (HSP70 family member) in HNSCC; HSPA1A acts as a chaperone for LASP1 and positively regulates LASP1-P-AKT interaction, enhancing malignant behavior.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, gain/loss-of-function assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP with localization; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"31793711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LASP1 interacts with N-WASP; this interaction does not alter N-WASP expression but rescues reduced actin polymerization caused by N-WASP silencing. N-WASP activates the Arp2/3 complex to promote actin polymerization and CRC cell migration/invasion.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation confirmation, Arp2/3 actin polymerization assay, functional rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP and functional rescue with actin polymerization assay; single lab\",\n      \"pmids\": [\"32704133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CXCR4-LASP1 axis promotes nuclear accumulation and stabilization of Snail1 by upregulating nuclear pS473-Akt, pS9-GSK-3β, A20, and LSD1; LASP1 endogenously associates with Snail1, A20, GSK-3β, and LSD1 in a CXCL12-dependent manner. LASP1 ablation causes mislocalization of nuclear Snail1 and loss of Matrigel invasion.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, nuclear/cytosolic fractionation Western blots, CXCR4 antagonist (AMD-3100) blocking, Matrigel invasion assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus PLA plus pharmacological validation; single lab, multiple methods\",\n      \"pmids\": [\"32825729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LASP1 associates with Argonaute 2 (Ago2) endogenously in a CXCL12-dependent, CXCR4-mediated manner; LASP1 directly binds Ago2 through its LIM and SH3 domains via GST-pulldown; LASP1 phosphorylation status at S146 and Y171 determines binding. LASP1-Ago2 association modulates Let-7a-guided RISC activity and alters levels of Let-7a targets including CCR7.\",\n      \"method\": \"Co-immunoprecipitation (endogenous), proximity ligation assay, GST-pulldown with LASP1 phospho-mutants, CXCR4 antagonist (AMD3465) blocking, Let-7a target expression analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP confirmed by PLA and GST pulldown with phospho-site mutants; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32872485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lasp1 binds directly to Cadherin-11/β-Catenin complexes in fibroblast-like synoviocytes; loss or blocking of Lasp1 alters pathological tissue formation, migratory behavior, and PDGF response of arthritic FLS. In TNF transgenic arthritic mice, Lasp1 deletion reduces arthritic joint destruction.\",\n      \"method\": \"Epigenomic profiling, co-immunoprecipitation for Cadherin-11/β-Catenin/Lasp1 complex, Lasp1 knockout in TNF transgenic mice with histological and functional joint assessments, in vitro FLS functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with quantitative joint destruction phenotype combined with co-IP evidence of complex; multiple orthogonal methods across labs (integrative epigenomics + functional)\",\n      \"pmids\": [\"34131132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LASP1 is identified as a sphingolipid-metabolism-involved protein by LC-MS; ECHS1 is identified as a new LASP1-interacting protein in CRC by protein interaction assay.\",\n      \"method\": \"LC-MS sphingolipid assay, protein interaction assay (co-IP), gain/loss-of-function in CRC cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single protein interaction assay; mechanistic link between LASP1 and sphingolipid metabolism remains indirect\",\n      \"pmids\": [\"34615856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBX increases LASP1 SUMOylation; SUMOylation is promoted by RANBP2 and RANGAP1 (which interact with LASP1) and enhances LASP1 binding to HER2, thereby preventing HER2 ubiquitination-mediated proteasomal degradation and stabilizing HER2 expression.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, ubiquitination assay, Western blot for HER2 stability\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation assay plus co-IP for complex with RANBP2/RANGAP1 plus functional ubiquitination assay; single lab\",\n      \"pmids\": [\"36473530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM15 mediates K63-linked polyubiquitination of LASP1, promoting its nuclear translocation; nuclear LASP1 then increases AKT phosphorylation and Snail expression to drive TKI resistance in HCC. TRIM15 expression is regulated upstream by the AKT/FOXO1 axis.\",\n      \"method\": \"Western blot nuclear fractionation, co-immunoprecipitation, ubiquitination assay with K63-linkage specificity, gain/loss-of-function in HCC cells, pharmacological AKT/FOXO1 inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with linkage specificity plus nuclear fractionation plus functional rescue; single lab\",\n      \"pmids\": [\"36670097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 stabilizes LASP1 mRNA through m6A modification, thereby promoting LASP1 protein expression and activating the SRC/AKT signaling axis in fibroblast-like synoviocytes; METTL14 knockdown reduces LASP1 expression and FLS activation.\",\n      \"method\": \"Western blot for LASP1, p-SRC, p-AKT after METTL14 shRNA; mRNA stability analysis with m6A modification; rescue by LASP1 overexpression; RA rat model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — m6A modification established by inference from expression changes after METTL14 knockdown; direct m6A mapping of LASP1 not shown in abstract; single lab\",\n      \"pmids\": [\"36878846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LASP-1 overexpression in HCC cells, identified by MALDI-TOF mass spectrometry of co-immunoprecipitated fractions, reveals vimentin as a novel binding partner of LASP-1.\",\n      \"method\": \"Co-immunoprecipitation followed by MALDI-TOF mass spectrometry identification of vimentin\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP/MS identification without further binding validation; single lab\",\n      \"pmids\": [\"25760690\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LASP1 is a multidomain actin-binding scaffold protein (LIM domain, two nebulin repeats, SH3 domain) that localizes to focal adhesions, lamellipodia tips, podosomes, and the nucleus, where it integrates cytoskeletal organization and signaling: it binds F-actin directly (Kd ~2 µM, regulated by PKA phosphorylation at S99/S146), interacts via its SH3 domain with zyxin, palladin-140 kDa, N-WASP (activating Arp2/3-mediated actin polymerization), CRKL, and ZO-2, and undergoes phosphorylation at Y171 by Src/c-Abl to regulate focal adhesion dynamics; nuclear import is driven by PKA-phosphorylated LASP1/ZO-2 complex via Crm-1-dependent export and PP2B-dependent recycling back to focal contacts, where nuclear LASP1 serves as a hub for the UHRF1-DNMT1-G9a-Snail1 epigenetic complex and for the Ago2/RISC machinery in a CXCR4-dependent manner; LASP1 transcription is directly activated by HIF1α and c-Jun/AP-1 and repressed by p53, while its nuclear translocation is promoted by TRIM15-mediated K63-polyubiquitination, and its stability is enhanced by HBX-induced SUMOylation; physiologically, Lasp-1 negatively regulates parietal cell HCl secretion and participates in Cadherin-11/β-Catenin junction formation in synoviocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LASP1 is a multidomain actin-binding scaffold protein with an N-terminal LIM domain and a C-terminal SH3 domain that organizes the cortical cytoskeleton and couples it to signaling at focal adhesions, lamellipodia, and podosomes [#0, #2, #21]. The isolated LIM module folds as an independent zinc-coordinating rubredoxin-knuckle [#1], while a central actin-binding region mediates direct, saturable binding to non-muscle F-actin (Kd ~2 µM) that is attenuated by PKA-dependent phosphorylation at S99/S146, controlling cAMP-driven translocation of LASP1 between the cortex and intracellular compartments in parietal cells [#5]. Through its SH3 domain LASP1 docks onto proline-rich and linear motifs in cytoskeletal partners—zyxin, the 140 kDa palladin isoform, Krp1/Kelch repeats, and N-WASP—positioning it upstream of zyxin recruitment to focal contacts and licensing N-WASP/Arp2/3-mediated actin polymerization to drive migration and invasion [#9, #12, #18, #35, #13]. Tyrosine phosphorylation at Y171 by Src-family and Abl-type kinases (including BCR-ABL) governs focal adhesion localization and creates a binding site for CRKL, linking LASP1 to oncogenic kinase signaling [#7, #19, #24]. LASP1 also shuttles to the nucleus as a PKA-S146-phosphorylated complex with ZO-2, exported via a Crm-1-dependent NES and recycled by PP2B [#22]; in a CXCR4/CXCL12-dependent manner nuclear LASP1 scaffolds the Snail1 stabilization and epigenetic machinery and associates with the eIF4F translation-initiation and Ago2/RISC complexes to control oncogenic gene expression [#25, #36, #33, #37]. Its abundance is set transcriptionally—activated by HIF1α and c-Jun/AP-1 and repressed by p53—and its activity is further tuned by ubiquitin- and SUMO-dependent modifications [#23, #32, #16, #41, #40]. Physiologically, LASP1 acts as a negative regulator of parietal cell HCl secretion and, in fibroblast-like synoviocytes, binds Cadherin-11/β-Catenin complexes to drive arthritic joint destruction [#15, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the LASP1 LIM domain is a structurally autonomous zinc-binding module, defining the architectural basis of the protein.\",\n      \"evidence\": \"NMR solution structure of a synthetic ZF-1 peptide complexed with zinc\",\n      \"pmids\": [\"8841116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to a 30-residue isolated module, not full-length protein\", \"Functional role of zinc coordination in cells not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined LASP1 as an actin-binding protein and connected it to Src-family tyrosine kinase signaling, placing it at the cytoskeleton-signaling interface.\",\n      \"evidence\": \"In vitro actin-binding assays, confocal co-localization, and Western blot of c-Src-transformed fibroblasts\",\n      \"pmids\": [\"9848085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Actin-binding region not finely mapped\", \"Functional consequence of tyrosine phosphorylation unresolved at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantified direct F-actin binding and showed PKA phosphorylation at S99/S146 reduces affinity, providing a molecular switch for cAMP-driven LASP1 relocalization.\",\n      \"evidence\": \"Actin pull-down with recombinant LASP1, in vitro PKA phosphorylation, phospho-mutants, and parietal cell imaging\",\n      \"pmids\": [\"12432067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the actin interface not solved\", \"Phospho-regulation studied mainly in parietal cells\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the SH3 domain as the docking module for cytoskeletal partners and established LASP1 as required for migration but not adhesion, with Y171 phosphorylation controlling focal adhesion residency.\",\n      \"evidence\": \"Yeast two-hybrid, co-precipitation, mutagenesis of zyxin/palladin motifs, pseudopodial proteomics, and siRNA migration assays\",\n      \"pmids\": [\"15004028\", \"16492705\", \"15138294\", \"15465019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of partner recruitment at focal contacts not fully resolved\", \"Distinct contributions of zyxin vs palladin binding unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic knockout established LASP1 as an in vivo negative regulator of parietal cell acid secretion, validating its physiological cytoskeletal-signaling role.\",\n      \"evidence\": \"Lasp-1 knockout mice with in vivo and ex vivo gastric acid secretion assays\",\n      \"pmids\": [\"18483181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking LASP1 to the secretory machinery not defined\", \"Whether effect is purely actin-dependent untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the Krp1/Kelch binding interface structurally and confirmed Src/integrin-driven Y171 phosphorylation directs LASP1 to focal contacts in adherent cells.\",\n      \"evidence\": \"Crystal structure of Krp1 C-terminal β-propeller with peptide-array mapping, plus platelet adhesion and Y171 mutagenesis studies\",\n      \"pmids\": [\"19726686\", \"19718473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple SH3 ligands at one focal contact not modeled\", \"Kinase selectivity for Y171 across cell types unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the nuclear shuttling mechanism, showing PKA-S146 phosphorylation drives a LASP1/ZO-2 complex into the nucleus with Crm-1-dependent export and PP2B-dependent recycling.\",\n      \"evidence\": \"Reciprocal co-IP, proximity ligation, phospho-mutants, leptomycin B export inhibition, and fractionation\",\n      \"pmids\": [\"22665060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear function downstream of import not defined in this study\", \"Stoichiometry of nuclear LASP1/ZO-2 complex unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed nuclear LASP1 as a CXCR4-dependent scaffold for the UHRF1-DNMT1-G9a epigenetic complex and Snail1, connecting cytoskeletal LASP1 to transcriptional/epigenetic control of EMT.\",\n      \"evidence\": \"Proteomics of LASP1 immunoprecipitates, PLA, endogenous co-IP, and CXCR4 antagonist blocking\",\n      \"pmids\": [\"25982273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold-mediated contacts within the complex not separated\", \"Functional impact on DNA methylation marks not directly measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned LASP1 as a regulator of protein-stability and PI3K/AKT signaling through SH3-mediated binding to COPS5 and 14-3-3σ degradation, and as an AP-1-dependent driver of MMP expression.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, ubiquitination assays, AP-1 luciferase reporter, and zymography across CRC and breast cancer models\",\n      \"pmids\": [\"29226323\", \"27156963\", \"27588391\", \"27181092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LASP1 directly enables ubiquitin ligase activity or acts as adaptor unresolved\", \"Cell-type generality of the 14-3-3σ axis untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended nuclear LASP1's scaffolding role to the eIF4F translation-initiation complex and Ago2/RISC, with phosphorylation-state-dependent binding linking CXCR4 signaling to oncogenic translation and miRNA activity.\",\n      \"evidence\": \"Proteomic screens, PLA, endogenous co-IP, GST pull-down with phospho-mutants, 5'UTR reporters, and CXCR4 antagonist blocking\",\n      \"pmids\": [\"31106142\", \"32872485\", \"32825729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding capacity of LASP1 not demonstrated\", \"How one scaffold partitions among actin, RISC, and eIF4F pools unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a physiological non-cancer role by showing LASP1 binds Cadherin-11/β-Catenin junctions and drives arthritic joint destruction in vivo.\",\n      \"evidence\": \"Epigenomic profiling, co-IP for the Cadherin-11/β-Catenin/Lasp1 complex, and Lasp1 knockout in TNF transgenic arthritic mice\",\n      \"pmids\": [\"34131132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between junctional LASP1 and FLS invasion incomplete\", \"Relationship to LASP1's actin and nuclear functions in this context unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that ubiquitin- and SUMO-dependent modifications and upstream transcriptional/epitranscriptomic inputs converge to control LASP1 abundance and nuclear translocation in disease.\",\n      \"evidence\": \"K63-linkage-specific ubiquitination assays (TRIM15), SUMOylation assays (HBX/RANBP2/RANGAP1), ChIP for HIF1α/c-Jun, and m6A/METTL14 stability analyses\",\n      \"pmids\": [\"36670097\", \"36473530\", \"25385028\", \"29600594\", \"36878846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sites of K63-ubiquitination and SUMOylation on LASP1 not mapped\", \"Direct m6A residues on LASP1 mRNA not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold dynamically partitions between F-actin, focal adhesions, the nucleus, RISC, and the translation machinery—and whether these pools are mutually exclusive or coordinated—remains unresolved.\",\n      \"evidence\": \"No integrated structural or quantitative model spans the cytoplasmic and nuclear LASP1 interactomes in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length LASP1 structure with bound partners\", \"Quantitative flux between functional pools unmeasured\", \"Causal hierarchy among phosphorylation, ubiquitination, and SUMOylation switches undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 5, 35]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 22, 25, 37]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [28, 31, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 7, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 22, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [24, 30, 36]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 11, 35]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [33, 37]}\n    ],\n    \"complexes\": [\"UHRF1-DNMT1-G9a epigenetic complex\", \"eIF4F translation initiation complex\", \"Ago2/RISC\", \"Cadherin-11/β-Catenin complex\"],\n    \"partners\": [\"ZYX\", \"PALLD\", \"WASL\", \"ZO-2\", \"CRKL\", \"AGO2\", \"COPS5\", \"SNAI1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}