{"gene":"LPP","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1996,"finding":"LPP (lipoma preferred partner) was identified as a novel LIM domain protein with a proline-rich N-terminal region containing a leucine-zipper motif and three LIM domains at its carboxy-terminus, and is the preferred fusion partner of HMGIC in lipomas due to recurrent t(3;12)(q13-15;q27-28) translocations.","method":"3'-RACE analysis, CASH, FISH, Northern blot, cDNA cloning, nucleotide sequence analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — original molecular characterization with multiple orthogonal methods establishing domain architecture and chromosomal fusion","pmids":["8812423"],"is_preprint":false},{"year":2000,"finding":"LPP localizes to focal adhesions and cell-to-cell contacts, binds VASP (a protein involved in actin organization), accumulates in the nucleus upon CRM1 inhibition by leptomycin B, contains a leucine-rich nuclear export signal (NES) in its N-terminal region, and displays transcriptional activation capacity as measured by GAL4-based assays.","method":"Immunofluorescence localization, co-immunoprecipitation/binding assays, leptomycin B treatment, GAL4-luciferase reporter assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in single study establishing localization, NES function, protein-protein interaction, and transcriptional activity","pmids":["10637295"],"is_preprint":false},{"year":2002,"finding":"The LIM domains of LPP are the primary focal adhesion targeting elements and cooperate to provide robust targeting; the linker between LIM domains 1 and 2 is pivotal for this targeting. The proline-rich pre-LIM region (containing alpha-actinin and VASP binding sites) has weak targeting capacity to focal adhesions and stress fibers. LIM domains are dispensable for nuclear targeting of LPP.","method":"Domain deletion/mutation analysis, fluorescence microscopy, overexpression of LIM domain fragments to deplete endogenous LPP and vinculin from focal adhesions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — systematic domain analysis with multiple constructs and functional readouts, single lab with multiple orthogonal approaches","pmids":["12441356"],"is_preprint":false},{"year":2005,"finding":"LPP interacts with the tumor suppressor protein Scrib (human homologue of Drosophila scribble); this interaction is mediated by the PDZ domains of Scrib and the carboxy-terminus of LPP. Both proteins co-localize at cell-cell contacts, linking LPP to Scrib-associated functions and providing a communication pathway between cell-cell contacts and the nucleus.","method":"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence co-localization, domain deletion analysis","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding confirmed by multiple methods, domain mapping performed","pmids":["15649318"],"is_preprint":false},{"year":2006,"finding":"LPP acts as a transcriptional coactivator for the ETS domain transcription factor PEA3: LPP forms a complex with PEA3, is found associated with PEA3-regulated promoters by ChIP, has intrinsic transactivation capacity, and upregulates PEA3 transactivation. LPP also functionally interacts similarly with related family member ER81.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assays, siRNA knockdown/overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP on endogenous promoters, functional reporter assays with gain/loss of function","pmids":["16738319"],"is_preprint":false},{"year":2006,"finding":"Zyxin and LPP promote the rate of early cell-cell junction assembly through their VASP-binding ActA (FPPPPP) repeat region; the LIM domain region acts as a regulatory domain that inhibits this function. Deletion of LIM domains drives adhesion and increases VASP levels in detergent-insoluble cadherin-actin networks. Dominant-negative zyxin/LPP mutants reduce adhesion rate and allow capping protein accumulation at cell-cell contacts.","method":"Quantitative cell-cell adhesion assay, dominant-negative constructs, detergent fractionation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — quantitative functional assay with domain mutants and multiple readouts","pmids":["16613855"],"is_preprint":false},{"year":2003,"finding":"LPP is highly and selectively expressed in vascular and visceral smooth muscle cells, colocalizes with vinculin at focal adhesions (peripheral dense bodies) in smooth muscle cells, and overexpression of LPP increases EGF-stimulated migration of vascular smooth muscle cells. Rho-kinase inhibition dissociates focal adhesions/LPP peripheral staining and enhances nuclear accumulation of LPP induced by leptomycin B, indicating a Rho-kinase-sensitive nucleocytoplasmic shuttling mechanism.","method":"Immunofluorescence microscopy, Western blot, Transwell migration assay, Y-27632 Rho-kinase inhibitor treatment, leptomycin B treatment","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, direct localization with functional consequence, and pharmacological dissection of pathway","pmids":["12760907"],"is_preprint":false},{"year":2006,"finding":"LPP expression in smooth muscle cells (SMCs) is regulated by myocardin and RhoA/Rho-kinase (ROK) signaling. LPP silencing with siRNA significantly decreases SMC migration. LPP expression is decreased in focal adhesion kinase (FAK)-null cells and rescued by inducible FAK re-expression; LPP expression in FAK-null fibroblasts enhances cell spreading.","method":"siRNA knockdown, adenovirus overexpression, FAK-null cell lines, Transwell migration assays, cell spreading assays, RT-PCR","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function (siRNA, FAK-null cells) with specific phenotypic readouts and pathway placement","pmids":["16397143"],"is_preprint":false},{"year":2008,"finding":"LPP (zebrafish ortholog) is required for convergence and extension (C&E) movements during gastrulation, acting in the non-canonical Wnt/PCP signaling pathway. Morpholino knockdown of lpp phenocopies Wnt signaling mutants; lpp expression depends on Wnt11 and Rho-kinase 2. LPP interacts with the PCP protein Scrib in zebrafish and cooperates with Scrib for C&E mediation.","method":"Morpholino knockdown, time-lapse imaging, epistasis with Wnt11 morphants, dominant-negative Rho-kinase 2 overexpression, co-immunoprecipitation (LPP-Scrib interaction in zebrafish)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in zebrafish, time-lapse quantification, protein interaction confirmed by Co-IP, multiple orthogonal approaches","pmids":["18582857"],"is_preprint":false},{"year":2010,"finding":"LPP (and TRIP6) associate with the shelterin telomere protection complex, co-immunoprecipitate with POT1, TRF2, and TIN2 in human cells, are detected at telomeres by ChIP, and are required for repressing the DNA damage response at telomeres (as shown by siRNA-mediated depletion causing telomere dysfunction-induced foci, TIFs).","method":"Yeast two-hybrid screen, co-immunoprecipitation, ChIP, siRNA knockdown with immunofluorescence TIF assay","journal":"Aging","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with multiple shelterin components, ChIP, and functional siRNA phenotype","pmids":["20634563"],"is_preprint":false},{"year":2011,"finding":"LPP and TRIP6 (but not zyxin) are detected at a subset of telomeres in human cells by immunofluorescence, confirming specificity of LIM protein recruitment to telomeres, likely at critically short telomeres.","method":"Immunofluorescence at telomeres, comparison across zyxin family members","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 — single imaging method, single lab, extends prior finding without new functional readout","pmids":["21519191"],"is_preprint":false},{"year":2008,"finding":"Alpha-actinin links LPP (but not zyxin) to cadherin-based cell-cell junctions; the alpha-actinin binding site of LPP is required for LPP localization and function at cell-cell contacts. Perturbation of LPP function (not zyxin) changes anchoring of alpha-actinin to detergent-insoluble networks at cell-cell contacts.","method":"Domain fragment targeting assays, detergent fractionation, immunofluorescence, functional adhesion perturbation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain dissection with functional consequence, single lab, moderate evidence","pmids":["18413140"],"is_preprint":false},{"year":2013,"finding":"LPP is an indispensable regulator of TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. Upon TGFβ stimulation, LPP re-localizes to focal adhesion complexes and mediates focal adhesion turnover. The interaction between LPP and alpha-actinin is necessary for TGFβ-induced migration and invasion.","method":"siRNA knockdown, live-cell imaging of focal adhesion dynamics, co-immunoprecipitation, Transwell invasion/migration assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific phenotypic readouts, protein interaction validated by Co-IP, mechanistic link to focal adhesion turnover","pmids":["23447672"],"is_preprint":false},{"year":2015,"finding":"LPP, together with its functional partner Etv5, directly transcriptionally activates MMP-15, which in turn degrades the extracellular domain of N-cadherin. Loss of LPP increases N-cadherin-dependent collective cell migration (CCM) in 3D collagen invasion assays and promotes in vivo dissemination of lung cancer cells.","method":"siRNA knockdown, 3D collagen invasion assay, orthotopic mouse model, RT-PCR, immunohistochemistry, luciferase reporter (MMP-15 promoter), direct N-cadherin cleavage by MMP-15","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined molecular mechanism (LPP/Etv5→MMP-15→N-cadherin cleavage), validated in vivo","pmids":["26028032"],"is_preprint":false},{"year":2017,"finding":"LPP localizes to invadopodia along with Tks5/actin at sites of matrix degradation and is required for invadopodia formation. LPP is phosphorylated by Src at specific tyrosine residues (Y245/301/302), and this Src-mediated phosphorylation is critical for invadopodia formation, breast cancer cell invasion, and lung metastasis. Invadopodia formation also requires an intact LPP LIM domain and LPP-alpha-actinin interaction.","method":"siRNA knockdown, domain/point mutants, intravital imaging (CAM model), Src kinase phosphorylation assay, in vitro invasion assay, mouse lung metastasis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — identified phosphorylation sites by mutagenesis, in vivo metastasis model, intravital imaging, multiple orthogonal methods","pmids":["28436416"],"is_preprint":false},{"year":2017,"finding":"CAFs upregulate LPP in microvascular endothelial cells via a calcium-dependent MFAP5→FAK→ERK→LPP signaling pathway. Endothelial LPP increases focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in vivo decreases intratumoral microvessel leakiness and improves paclitaxel delivery to tumor cells.","method":"siRNA knockdown, co-culture (CAF/endothelial cells), pathway inhibitor studies, in vivo siRNA treatment in tumor-bearing mice, permeability assays, drug delivery measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — defined upstream signaling pathway by pharmacological dissection, in vivo siRNA with functional vascular readouts","pmids":["29251630"],"is_preprint":false},{"year":2005,"finding":"The HMGA2/LPP fusion protein retains the transcriptional activation functions of the LPP LIM domains, activates transcription from PRDII and BAT-1 elements, and is augmented by co-expressed wild-type HMGA2. This supports a model where HMGA2/LPP functions as a transcription factor in lipomagenesis.","method":"GAL4-based and promoter-based luciferase reporter assays, co-transfection, RT-PCR in lipoma samples","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vitro reporter assays with defined promoter elements, single lab","pmids":["15755872"],"is_preprint":false},{"year":2012,"finding":"LPP acts as a regulatory partner of ETV5 transcription factor, sensing extracellular signals to promote epithelial-to-mesenchymal transition (EMT) and tumor invasion in endometrial carcinoma cells. ETV5 modulates Zeb1 and E-cadherin repression, and LPP cooperates with ETV5 to promote migratory and invasive capabilities.","method":"Co-immunoprecipitation, siRNA knockdown, reporter assays, invasion/migration assays, molecular profiling","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — protein interaction confirmed by Co-IP, functional loss-of-function assays, single lab","pmids":["22266854"],"is_preprint":false},{"year":2013,"finding":"Treatment of control fibroblasts with gliadin peptide P31-43 mimics a celiac disease cellular phenotype, including altered LPP sub-cellular distribution (redistribution away from focal adhesions), altered cell shape, actin organization, and increased focal adhesion number, linking LPP localization changes to celiac disease pathogenesis.","method":"Immunofluorescence, cell shape analysis, focal adhesion quantification, peptide treatment of fibroblasts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — single imaging method with pharmacological perturbation, mechanistic link is correlative but direct","pmids":["24278174"],"is_preprint":false},{"year":2023,"finding":"UBE2S interacts with TRIM21 E3 ligase and jointly induces K11-linked polyubiquitination of LPP (not K48- or K63-linked), leading to LPP degradation. LPP silencing rescues the anti-metastatic phenotypes and inhibits EMT caused by UBE2S knockdown in bladder cancer cells, placing LPP downstream of the UBE2S-TRIM21 ubiquitin axis in lymphatic metastasis.","method":"Co-immunoprecipitation, ubiquitination assay with K11/K48/K63 mutant ubiquitin, siRNA knockdown, in vivo lymphatic metastasis model, organoid experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — biochemically defined ubiquitin linkage type, epistasis by siRNA rescue, in vivo validation","pmids":["37422473"],"is_preprint":false},{"year":2009,"finding":"LPP expression in SMCs is regulated by TGF-β1 in a Rho-kinase (ROK)-dependent manner during differentiation and migration of bone marrow-derived smooth muscle progenitor cells; siRNA silencing of LPP significantly decreases SMC migration.","method":"siRNA knockdown, ROK inhibitor treatment, RT-PCR, migration assay","journal":"Journal of Huazhong University of Science and Technology","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with migration phenotype and pharmacological pathway dissection, single lab","pmids":["22886954"],"is_preprint":false}],"current_model":"LPP (lipoma preferred partner) is a multi-domain LIM protein that shuttles between focal adhesions/cell-cell contacts and the nucleus via a CRM1-dependent NES; at adhesion sites it interacts with VASP (via FPPPPP motifs) and alpha-actinin to regulate actin dynamics, focal adhesion turnover, and cell migration, while in the nucleus it acts as a transcriptional coactivator (e.g., for PEA3/ETV5) to regulate genes including MMP-15; Src phosphorylates LPP at Y245/301/302 to drive invadopodia formation and metastasis, and LPP protein stability is controlled by UBE2S/TRIM21-mediated K11-linked polyubiquitination."},"narrative":{"teleology":[{"year":1996,"claim":"The identity and domain architecture of LPP were established, revealing it as a novel LIM-domain protein and the preferred translocation partner of HMGIC in lipomas, thus framing the gene as relevant to mesenchymal tumorigenesis.","evidence":"3'-RACE, FISH, cDNA cloning from lipoma translocation breakpoints","pmids":["8812423"],"confidence":"High","gaps":["No functional data on LPP protein activity","No subcellular localization determined","Role of individual domains unknown"]},{"year":2000,"claim":"LPP was shown to be a nucleocytoplasmic shuttling protein that localizes to focal adhesions and cell-cell contacts, binds VASP, possesses a CRM1-dependent nuclear export signal, and has intrinsic transcriptional activation capacity — establishing its dual-compartment biology.","evidence":"Immunofluorescence, co-immunoprecipitation, leptomycin B treatment, GAL4-luciferase reporter assay in mammalian cells","pmids":["10637295"],"confidence":"High","gaps":["Mechanism of nuclear function unknown","Whether shuttling is regulated by signaling pathways not addressed","Identity of transcriptional targets unknown"]},{"year":2002,"claim":"Systematic domain dissection resolved that the three LIM domains cooperatively target LPP to focal adhesions (with the LIM1-LIM2 linker being critical), while the pre-LIM proline-rich region mediates weaker adhesion targeting through alpha-actinin and VASP binding, clarifying the modular logic of LPP localization.","evidence":"Deletion/mutation constructs with fluorescence microscopy, dominant-negative displacement of endogenous LPP from focal adhesions","pmids":["12441356"],"confidence":"High","gaps":["Structural basis of LIM domain targeting not resolved","Whether LIM domains mediate protein-protein interactions at adhesions or lipid binding unknown"]},{"year":2003,"claim":"LPP was found to be highly expressed in vascular smooth muscle cells and to promote EGF-stimulated SMC migration, with Rho-kinase activity controlling both focal adhesion retention and nuclear accumulation of LPP, placing LPP under RhoA/ROCK signaling control.","evidence":"Immunofluorescence, Transwell migration, Y-27632 and leptomycin B pharmacological treatments in SMCs","pmids":["12760907"],"confidence":"High","gaps":["Direct phosphorylation by Rho-kinase not shown","Whether nuclear LPP contributes to migration phenotype unclear"]},{"year":2005,"claim":"Identification of Scrib as a direct binding partner of LPP at cell-cell contacts, mediated by Scrib PDZ domains and the LPP C-terminus, provided a molecular link between LPP and the polarity/tumor suppressor machinery.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, immunofluorescence co-localization, domain deletion mapping","pmids":["15649318"],"confidence":"High","gaps":["Functional consequence of LPP-Scrib interaction on polarity or proliferation not tested","Whether Scrib regulates LPP shuttling unknown"]},{"year":2006,"claim":"Multiple studies converged to define LPP's transcriptional and adhesion functions: LPP was identified as a coactivator of PEA3/ER81 ETS transcription factors on endogenous promoters, shown to promote early cell-cell junction assembly through its VASP-binding repeats with LIM domains acting as an auto-inhibitory module, and placed downstream of FAK and myocardin/Rho-kinase signaling for SMC migration.","evidence":"ChIP on PEA3-regulated promoters, co-immunoprecipitation, luciferase reporters, quantitative adhesion assays with dominant-negative constructs, siRNA in SMCs, FAK-null cell reconstitution","pmids":["16738319","16613855","16397143"],"confidence":"High","gaps":["Direct transcriptional target genes of LPP/PEA3 not comprehensively identified","Structural basis of LIM domain auto-inhibition of VASP-mediated adhesion not resolved"]},{"year":2008,"claim":"In vivo genetic evidence from zebrafish established that LPP functions in non-canonical Wnt/PCP signaling during gastrulation convergence and extension, acting downstream of Wnt11 and Rho-kinase 2 in cooperation with Scrib, extending LPP's roles beyond adhesion/migration to developmental morphogenesis. Separately, alpha-actinin was shown to specifically link LPP (not zyxin) to cadherin-based junctions.","evidence":"Morpholino knockdown with epistasis analysis and time-lapse imaging in zebrafish; domain targeting and detergent fractionation in mammalian cells","pmids":["18582857","18413140"],"confidence":"High","gaps":["Whether Wnt/PCP role is conserved in mammalian development not tested","Direct molecular mechanism by which LPP affects PCP downstream of Scrib unknown"]},{"year":2010,"claim":"The unexpected finding that LPP associates with shelterin components (POT1, TRF2, TIN2) at telomeres and is required to suppress telomere dysfunction-induced foci revealed a chromatin-associated protective function distinct from adhesion or transcription.","evidence":"Yeast two-hybrid, co-immunoprecipitation with multiple shelterin proteins, ChIP at telomeres, siRNA depletion causing TIF formation in human cells","pmids":["20634563"],"confidence":"High","gaps":["Which LPP domain mediates shelterin interaction unknown","Whether telomere function requires LPP shuttling or is constitutively nuclear unclear","Mechanism by which LPP suppresses DNA damage response at telomeres not defined"]},{"year":2013,"claim":"LPP was shown to be indispensable for TGFβ-induced migration and invasion in ErbB2-positive breast cancer cells by mediating focal adhesion turnover through its alpha-actinin interaction, mechanistically linking LPP to oncogenic signal-dependent invasion programs.","evidence":"siRNA knockdown, live-cell focal adhesion dynamics imaging, co-immunoprecipitation, Transwell invasion assays in breast cancer cells","pmids":["23447672"],"confidence":"High","gaps":["How TGFβ signaling triggers LPP relocalization to focal adhesions not defined","Whether nuclear LPP/transcriptional activity contributes to invasion phenotype not separated"]},{"year":2015,"claim":"A complete transcriptional pathway was delineated: LPP cooperates with ETV5 to directly activate MMP-15 transcription, MMP-15 cleaves N-cadherin, and loss of LPP paradoxically increases N-cadherin-dependent collective cell migration and in vivo lung cancer dissemination, revealing context-dependent pro- and anti-migratory roles.","evidence":"siRNA, MMP-15 promoter reporter, 3D collagen invasion, orthotopic mouse model with lung cancer cells","pmids":["26028032"],"confidence":"High","gaps":["Full repertoire of LPP/ETV5 target genes unknown","Whether this pathway operates in non-cancer contexts not addressed"]},{"year":2017,"claim":"Src-mediated phosphorylation of LPP at Y245/Y301/Y302 was identified as the critical switch for invadopodia formation and metastasis, with LPP localizing to invadopodia alongside Tks5; separately, a MFAP5→FAK→ERK→LPP axis in endothelial cells was shown to regulate tumor vascular permeability, broadening LPP's role to the tumor microenvironment.","evidence":"Phospho-site mutagenesis, intravital imaging in CAM model, mouse lung metastasis assay; in vivo siRNA delivery in tumor-bearing mice with permeability measurements","pmids":["28436416","29251630"],"confidence":"High","gaps":["Whether Src phosphorylation affects LPP nuclear functions or transcriptional activity untested","Downstream effectors recruited by phospho-LPP at invadopodia unknown","Structural consequences of Y245/Y301/Y302 phosphorylation unresolved"]},{"year":2023,"claim":"The mechanism controlling LPP protein turnover was defined: UBE2S cooperates with TRIM21 E3 ligase to catalyze K11-linked polyubiquitination of LPP, targeting it for degradation, and LPP acts as the critical downstream effector of UBE2S in promoting EMT and lymphatic metastasis in bladder cancer.","evidence":"Co-immunoprecipitation, ubiquitination assays with linkage-specific ubiquitin mutants, epistatic siRNA rescue, in vivo lymphatic metastasis model","pmids":["37422473"],"confidence":"High","gaps":["Specific lysine residues on LPP targeted for K11-ubiquitination not mapped","Whether TRIM21-mediated degradation is signal-regulated not determined","Relationship between ubiquitin-mediated turnover and phosphorylation-dependent functions unknown"]},{"year":null,"claim":"How the nuclear and cytoplasmic pools of LPP are coordinately regulated — and whether post-translational modifications such as Src phosphorylation or K11-ubiquitination differentially affect adhesion versus transcriptional functions — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of LPP or its LIM domain-mediated interactions exists","Comprehensive identification of LPP/ETV5 transcriptional targets genome-wide has not been performed","Whether telomere-protective and adhesion/transcription functions are mechanistically linked is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,13,16,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,5,11,12,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,6,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2,5,6,12,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,5,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,8,15,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,13,16,17]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,5,11]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[19]}],"complexes":["shelterin-associated complex"],"partners":["VASP","ACTN1","SCRIB","PEA3","ETV5","TRF2","POT1","TRIM21"],"other_free_text":[]},"mechanistic_narrative":"LPP is a zyxin-family LIM domain protein that functions as a dual-compartment signaling hub, integrating cytoskeletal dynamics at focal adhesions and cell-cell contacts with transcriptional regulation in the nucleus. At adhesion sites, LPP is targeted by its three C-terminal LIM domains, where it recruits VASP via N-terminal FPPPPP motifs and binds alpha-actinin to regulate actin organization, focal adhesion turnover, and cell migration; these interactions are essential for TGFβ-induced invasion, invadopodia formation driven by Src phosphorylation at Y245/Y301/Y302, and early cell-cell junction assembly [PMID:10637295, PMID:12441356, PMID:28436416, PMID:16613855, PMID:23447672]. LPP undergoes CRM1-dependent nucleocytoplasmic shuttling regulated by Rho-kinase, and in the nucleus it serves as a transcriptional coactivator for PEA3/ETV5 family ETS factors to drive expression of target genes such as MMP-15, linking adhesion-derived signals to gene programs controlling EMT and invasion [PMID:16738319, PMID:26028032, PMID:22266854]. LPP protein stability is controlled by UBE2S/TRIM21-mediated K11-linked polyubiquitination, and LPP also associates with shelterin components at telomeres where it suppresses telomere dysfunction-induced DNA damage signaling [PMID:37422473, PMID:20634563]."},"prefetch_data":{"uniprot":{"accession":"Q93052","full_name":"Lipoma-preferred partner","aliases":["LIM domain-containing preferred translocation partner in lipoma"],"length_aa":612,"mass_kda":65.7,"function":"May play a structural role at sites of cell adhesion in maintaining cell shape and motility. In addition to these structural functions, it may also be implicated in signaling events and activation of gene transcription. May be involved in signal transduction from cell adhesion sites to the nucleus allowing successful integration of signals arising from soluble factors and cell-cell adhesion sites. Also suggested to serve as a scaffold protein upon which distinct protein complexes are assembled in the cytoplasm and in the nucleus","subcellular_location":"Nucleus; Cytoplasm; Cell junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q93052/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LPP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPP2CA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LPP","total_profiled":1310},"omim":[{"mim_id":"620696","title":"RBPJ-INTERACTING AND TUBULIN-ASSOCIATED PROTEIN 1; RITA1","url":"https://www.omim.org/entry/620696"},{"mim_id":"618743","title":"PHOSPHOLIPID PHOSPHATASE 7; PLPP7","url":"https://www.omim.org/entry/618743"},{"mim_id":"614296","title":"WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT; WFSL","url":"https://www.omim.org/entry/614296"},{"mim_id":"612009","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 11; CELIAC11","url":"https://www.omim.org/entry/612009"},{"mim_id":"610391","title":"PHOSPHOLIPID PHOSPHATASE-RELATED PROTEIN 3; PLPPR3","url":"https://www.omim.org/entry/610391"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":128.4}],"url":"https://www.proteinatlas.org/search/LPP"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q93052","domains":[{"cath_id":"2.10.110.10","chopping":"204-211_408-472","consensus_level":"medium","plddt":84.0566,"start":204,"end":472},{"cath_id":"2.10.110.10","chopping":"474-532","consensus_level":"medium","plddt":93.3153,"start":474,"end":532},{"cath_id":"2.10.110.10","chopping":"535-612","consensus_level":"medium","plddt":88.3609,"start":535,"end":612}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q93052","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q93052-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q93052-F1-predicted_aligned_error_v6.png","plddt_mean":60.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LPP","jax_strain_url":"https://www.jax.org/strain/search?query=LPP"},"sequence":{"accession":"Q93052","fasta_url":"https://rest.uniprot.org/uniprotkb/Q93052.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q93052/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q93052"}},"corpus_meta":[{"pmid":"25030700","id":"PMC_25030700","title":"MicL, 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An examination with the late positive potential (LPP).","date":"2019","source":"Emotion (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/31815498","citation_count":6,"is_preprint":false},{"pmid":"23056290","id":"PMC_23056290","title":"Association study of gene LPP in women with polycystic ovary syndrome.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23056290","citation_count":6,"is_preprint":false},{"pmid":"34163454","id":"PMC_34163454","title":"Membrane Stress Caused by Unprocessed Outer Membrane Lipoprotein Intermediate Pro-Lpp Affects DnaA and Fis-Dependent Growth.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34163454","citation_count":6,"is_preprint":false},{"pmid":"12063392","id":"PMC_12063392","title":"A novel LPP fusion gene indicates the crucial role of truncated LPP proteins in lipomas and pulmonary chondroid hamartomas.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12063392","citation_count":6,"is_preprint":false},{"pmid":"12505264","id":"PMC_12505264","title":"Expression of the HMGA2-LPP fusion transcript in only 1 of 61 karyotypically normal pulmonary chondroid hamartomas.","date":"2002","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12505264","citation_count":5,"is_preprint":false},{"pmid":"22886954","id":"PMC_22886954","title":"TGF-β1-induced LPP expression dependant on Rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells.","date":"2012","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/22886954","citation_count":4,"is_preprint":false},{"pmid":"34908933","id":"PMC_34908933","title":"Attentional Processing of Facial Expressions and Gaze Direction in Depression and First-Episode Psychosis as Reflected by LPP Modulation.","date":"2019","source":"Clinical neuropsychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/34908933","citation_count":3,"is_preprint":false},{"pmid":"31295688","id":"PMC_31295688","title":"3'UTR SNPs in the LPP gene associated with Immunoglobulin A nephropathy risk in the Chinese Han population.","date":"2019","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31295688","citation_count":3,"is_preprint":false},{"pmid":"36084606","id":"PMC_36084606","title":"LPP polymorphisms are risk factors for allergic rhinitis in the Chinese Han population.","date":"2022","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/36084606","citation_count":3,"is_preprint":false},{"pmid":"39062631","id":"PMC_39062631","title":"Association of LPP and ZMIZ1 Gene Polymorphism with Celiac Disease in Subjects from Punjab, Pakistan.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39062631","citation_count":2,"is_preprint":false},{"pmid":"37199315","id":"PMC_37199315","title":"Long Non-Coding RNA LPP-AS2 Plays an Anti-Tumor Role in Thyroid Carcinoma by Regulating the miR-132-3p/OLFM1 Axis.","date":"2023","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/37199315","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45813,"output_tokens":5160,"usd":0.10742},"stage2":{"model":"claude-opus-4-6","input_tokens":8692,"output_tokens":3624,"usd":0.20109},"total_usd":0.30851,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"LPP (lipoma preferred partner) was identified as a novel LIM domain protein with a proline-rich N-terminal region containing a leucine-zipper motif and three LIM domains at its carboxy-terminus, and is the preferred fusion partner of HMGIC in lipomas due to recurrent t(3;12)(q13-15;q27-28) translocations.\",\n      \"method\": \"3'-RACE analysis, CASH, FISH, Northern blot, cDNA cloning, nucleotide sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular characterization with multiple orthogonal methods establishing domain architecture and chromosomal fusion\",\n      \"pmids\": [\"8812423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LPP localizes to focal adhesions and cell-to-cell contacts, binds VASP (a protein involved in actin organization), accumulates in the nucleus upon CRM1 inhibition by leptomycin B, contains a leucine-rich nuclear export signal (NES) in its N-terminal region, and displays transcriptional activation capacity as measured by GAL4-based assays.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation/binding assays, leptomycin B treatment, GAL4-luciferase reporter assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in single study establishing localization, NES function, protein-protein interaction, and transcriptional activity\",\n      \"pmids\": [\"10637295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The LIM domains of LPP are the primary focal adhesion targeting elements and cooperate to provide robust targeting; the linker between LIM domains 1 and 2 is pivotal for this targeting. The proline-rich pre-LIM region (containing alpha-actinin and VASP binding sites) has weak targeting capacity to focal adhesions and stress fibers. LIM domains are dispensable for nuclear targeting of LPP.\",\n      \"method\": \"Domain deletion/mutation analysis, fluorescence microscopy, overexpression of LIM domain fragments to deplete endogenous LPP and vinculin from focal adhesions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic domain analysis with multiple constructs and functional readouts, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"12441356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LPP interacts with the tumor suppressor protein Scrib (human homologue of Drosophila scribble); this interaction is mediated by the PDZ domains of Scrib and the carboxy-terminus of LPP. Both proteins co-localize at cell-cell contacts, linking LPP to Scrib-associated functions and providing a communication pathway between cell-cell contacts and the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence co-localization, domain deletion analysis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed by multiple methods, domain mapping performed\",\n      \"pmids\": [\"15649318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LPP acts as a transcriptional coactivator for the ETS domain transcription factor PEA3: LPP forms a complex with PEA3, is found associated with PEA3-regulated promoters by ChIP, has intrinsic transactivation capacity, and upregulates PEA3 transactivation. LPP also functionally interacts similarly with related family member ER81.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assays, siRNA knockdown/overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP on endogenous promoters, functional reporter assays with gain/loss of function\",\n      \"pmids\": [\"16738319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Zyxin and LPP promote the rate of early cell-cell junction assembly through their VASP-binding ActA (FPPPPP) repeat region; the LIM domain region acts as a regulatory domain that inhibits this function. Deletion of LIM domains drives adhesion and increases VASP levels in detergent-insoluble cadherin-actin networks. Dominant-negative zyxin/LPP mutants reduce adhesion rate and allow capping protein accumulation at cell-cell contacts.\",\n      \"method\": \"Quantitative cell-cell adhesion assay, dominant-negative constructs, detergent fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative functional assay with domain mutants and multiple readouts\",\n      \"pmids\": [\"16613855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LPP is highly and selectively expressed in vascular and visceral smooth muscle cells, colocalizes with vinculin at focal adhesions (peripheral dense bodies) in smooth muscle cells, and overexpression of LPP increases EGF-stimulated migration of vascular smooth muscle cells. Rho-kinase inhibition dissociates focal adhesions/LPP peripheral staining and enhances nuclear accumulation of LPP induced by leptomycin B, indicating a Rho-kinase-sensitive nucleocytoplasmic shuttling mechanism.\",\n      \"method\": \"Immunofluorescence microscopy, Western blot, Transwell migration assay, Y-27632 Rho-kinase inhibitor treatment, leptomycin B treatment\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, direct localization with functional consequence, and pharmacological dissection of pathway\",\n      \"pmids\": [\"12760907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LPP expression in smooth muscle cells (SMCs) is regulated by myocardin and RhoA/Rho-kinase (ROK) signaling. LPP silencing with siRNA significantly decreases SMC migration. LPP expression is decreased in focal adhesion kinase (FAK)-null cells and rescued by inducible FAK re-expression; LPP expression in FAK-null fibroblasts enhances cell spreading.\",\n      \"method\": \"siRNA knockdown, adenovirus overexpression, FAK-null cell lines, Transwell migration assays, cell spreading assays, RT-PCR\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function (siRNA, FAK-null cells) with specific phenotypic readouts and pathway placement\",\n      \"pmids\": [\"16397143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LPP (zebrafish ortholog) is required for convergence and extension (C&E) movements during gastrulation, acting in the non-canonical Wnt/PCP signaling pathway. Morpholino knockdown of lpp phenocopies Wnt signaling mutants; lpp expression depends on Wnt11 and Rho-kinase 2. LPP interacts with the PCP protein Scrib in zebrafish and cooperates with Scrib for C&E mediation.\",\n      \"method\": \"Morpholino knockdown, time-lapse imaging, epistasis with Wnt11 morphants, dominant-negative Rho-kinase 2 overexpression, co-immunoprecipitation (LPP-Scrib interaction in zebrafish)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in zebrafish, time-lapse quantification, protein interaction confirmed by Co-IP, multiple orthogonal approaches\",\n      \"pmids\": [\"18582857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPP (and TRIP6) associate with the shelterin telomere protection complex, co-immunoprecipitate with POT1, TRF2, and TIN2 in human cells, are detected at telomeres by ChIP, and are required for repressing the DNA damage response at telomeres (as shown by siRNA-mediated depletion causing telomere dysfunction-induced foci, TIFs).\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, ChIP, siRNA knockdown with immunofluorescence TIF assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with multiple shelterin components, ChIP, and functional siRNA phenotype\",\n      \"pmids\": [\"20634563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LPP and TRIP6 (but not zyxin) are detected at a subset of telomeres in human cells by immunofluorescence, confirming specificity of LIM protein recruitment to telomeres, likely at critically short telomeres.\",\n      \"method\": \"Immunofluorescence at telomeres, comparison across zyxin family members\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single imaging method, single lab, extends prior finding without new functional readout\",\n      \"pmids\": [\"21519191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Alpha-actinin links LPP (but not zyxin) to cadherin-based cell-cell junctions; the alpha-actinin binding site of LPP is required for LPP localization and function at cell-cell contacts. Perturbation of LPP function (not zyxin) changes anchoring of alpha-actinin to detergent-insoluble networks at cell-cell contacts.\",\n      \"method\": \"Domain fragment targeting assays, detergent fractionation, immunofluorescence, functional adhesion perturbation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain dissection with functional consequence, single lab, moderate evidence\",\n      \"pmids\": [\"18413140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LPP is an indispensable regulator of TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. Upon TGFβ stimulation, LPP re-localizes to focal adhesion complexes and mediates focal adhesion turnover. The interaction between LPP and alpha-actinin is necessary for TGFβ-induced migration and invasion.\",\n      \"method\": \"siRNA knockdown, live-cell imaging of focal adhesion dynamics, co-immunoprecipitation, Transwell invasion/migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific phenotypic readouts, protein interaction validated by Co-IP, mechanistic link to focal adhesion turnover\",\n      \"pmids\": [\"23447672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LPP, together with its functional partner Etv5, directly transcriptionally activates MMP-15, which in turn degrades the extracellular domain of N-cadherin. Loss of LPP increases N-cadherin-dependent collective cell migration (CCM) in 3D collagen invasion assays and promotes in vivo dissemination of lung cancer cells.\",\n      \"method\": \"siRNA knockdown, 3D collagen invasion assay, orthotopic mouse model, RT-PCR, immunohistochemistry, luciferase reporter (MMP-15 promoter), direct N-cadherin cleavage by MMP-15\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular mechanism (LPP/Etv5→MMP-15→N-cadherin cleavage), validated in vivo\",\n      \"pmids\": [\"26028032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LPP localizes to invadopodia along with Tks5/actin at sites of matrix degradation and is required for invadopodia formation. LPP is phosphorylated by Src at specific tyrosine residues (Y245/301/302), and this Src-mediated phosphorylation is critical for invadopodia formation, breast cancer cell invasion, and lung metastasis. Invadopodia formation also requires an intact LPP LIM domain and LPP-alpha-actinin interaction.\",\n      \"method\": \"siRNA knockdown, domain/point mutants, intravital imaging (CAM model), Src kinase phosphorylation assay, in vitro invasion assay, mouse lung metastasis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identified phosphorylation sites by mutagenesis, in vivo metastasis model, intravital imaging, multiple orthogonal methods\",\n      \"pmids\": [\"28436416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CAFs upregulate LPP in microvascular endothelial cells via a calcium-dependent MFAP5→FAK→ERK→LPP signaling pathway. Endothelial LPP increases focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in vivo decreases intratumoral microvessel leakiness and improves paclitaxel delivery to tumor cells.\",\n      \"method\": \"siRNA knockdown, co-culture (CAF/endothelial cells), pathway inhibitor studies, in vivo siRNA treatment in tumor-bearing mice, permeability assays, drug delivery measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined upstream signaling pathway by pharmacological dissection, in vivo siRNA with functional vascular readouts\",\n      \"pmids\": [\"29251630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The HMGA2/LPP fusion protein retains the transcriptional activation functions of the LPP LIM domains, activates transcription from PRDII and BAT-1 elements, and is augmented by co-expressed wild-type HMGA2. This supports a model where HMGA2/LPP functions as a transcription factor in lipomagenesis.\",\n      \"method\": \"GAL4-based and promoter-based luciferase reporter assays, co-transfection, RT-PCR in lipoma samples\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vitro reporter assays with defined promoter elements, single lab\",\n      \"pmids\": [\"15755872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LPP acts as a regulatory partner of ETV5 transcription factor, sensing extracellular signals to promote epithelial-to-mesenchymal transition (EMT) and tumor invasion in endometrial carcinoma cells. ETV5 modulates Zeb1 and E-cadherin repression, and LPP cooperates with ETV5 to promote migratory and invasive capabilities.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, reporter assays, invasion/migration assays, molecular profiling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — protein interaction confirmed by Co-IP, functional loss-of-function assays, single lab\",\n      \"pmids\": [\"22266854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Treatment of control fibroblasts with gliadin peptide P31-43 mimics a celiac disease cellular phenotype, including altered LPP sub-cellular distribution (redistribution away from focal adhesions), altered cell shape, actin organization, and increased focal adhesion number, linking LPP localization changes to celiac disease pathogenesis.\",\n      \"method\": \"Immunofluorescence, cell shape analysis, focal adhesion quantification, peptide treatment of fibroblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single imaging method with pharmacological perturbation, mechanistic link is correlative but direct\",\n      \"pmids\": [\"24278174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2S interacts with TRIM21 E3 ligase and jointly induces K11-linked polyubiquitination of LPP (not K48- or K63-linked), leading to LPP degradation. LPP silencing rescues the anti-metastatic phenotypes and inhibits EMT caused by UBE2S knockdown in bladder cancer cells, placing LPP downstream of the UBE2S-TRIM21 ubiquitin axis in lymphatic metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K11/K48/K63 mutant ubiquitin, siRNA knockdown, in vivo lymphatic metastasis model, organoid experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemically defined ubiquitin linkage type, epistasis by siRNA rescue, in vivo validation\",\n      \"pmids\": [\"37422473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPP expression in SMCs is regulated by TGF-β1 in a Rho-kinase (ROK)-dependent manner during differentiation and migration of bone marrow-derived smooth muscle progenitor cells; siRNA silencing of LPP significantly decreases SMC migration.\",\n      \"method\": \"siRNA knockdown, ROK inhibitor treatment, RT-PCR, migration assay\",\n      \"journal\": \"Journal of Huazhong University of Science and Technology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with migration phenotype and pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"22886954\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LPP (lipoma preferred partner) is a multi-domain LIM protein that shuttles between focal adhesions/cell-cell contacts and the nucleus via a CRM1-dependent NES; at adhesion sites it interacts with VASP (via FPPPPP motifs) and alpha-actinin to regulate actin dynamics, focal adhesion turnover, and cell migration, while in the nucleus it acts as a transcriptional coactivator (e.g., for PEA3/ETV5) to regulate genes including MMP-15; Src phosphorylates LPP at Y245/301/302 to drive invadopodia formation and metastasis, and LPP protein stability is controlled by UBE2S/TRIM21-mediated K11-linked polyubiquitination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LPP is a zyxin-family LIM domain protein that functions as a dual-compartment signaling hub, integrating cytoskeletal dynamics at focal adhesions and cell-cell contacts with transcriptional regulation in the nucleus. At adhesion sites, LPP is targeted by its three C-terminal LIM domains, where it recruits VASP via N-terminal FPPPPP motifs and binds alpha-actinin to regulate actin organization, focal adhesion turnover, and cell migration; these interactions are essential for TGFβ-induced invasion, invadopodia formation driven by Src phosphorylation at Y245/Y301/Y302, and early cell-cell junction assembly [PMID:10637295, PMID:12441356, PMID:28436416, PMID:16613855, PMID:23447672]. LPP undergoes CRM1-dependent nucleocytoplasmic shuttling regulated by Rho-kinase, and in the nucleus it serves as a transcriptional coactivator for PEA3/ETV5 family ETS factors to drive expression of target genes such as MMP-15, linking adhesion-derived signals to gene programs controlling EMT and invasion [PMID:16738319, PMID:26028032, PMID:22266854]. LPP protein stability is controlled by UBE2S/TRIM21-mediated K11-linked polyubiquitination, and LPP also associates with shelterin components at telomeres where it suppresses telomere dysfunction-induced DNA damage signaling [PMID:37422473, PMID:20634563].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The identity and domain architecture of LPP were established, revealing it as a novel LIM-domain protein and the preferred translocation partner of HMGIC in lipomas, thus framing the gene as relevant to mesenchymal tumorigenesis.\",\n      \"evidence\": \"3'-RACE, FISH, cDNA cloning from lipoma translocation breakpoints\",\n      \"pmids\": [\"8812423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional data on LPP protein activity\", \"No subcellular localization determined\", \"Role of individual domains unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"LPP was shown to be a nucleocytoplasmic shuttling protein that localizes to focal adhesions and cell-cell contacts, binds VASP, possesses a CRM1-dependent nuclear export signal, and has intrinsic transcriptional activation capacity — establishing its dual-compartment biology.\",\n      \"evidence\": \"Immunofluorescence, co-immunoprecipitation, leptomycin B treatment, GAL4-luciferase reporter assay in mammalian cells\",\n      \"pmids\": [\"10637295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear function unknown\", \"Whether shuttling is regulated by signaling pathways not addressed\", \"Identity of transcriptional targets unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Systematic domain dissection resolved that the three LIM domains cooperatively target LPP to focal adhesions (with the LIM1-LIM2 linker being critical), while the pre-LIM proline-rich region mediates weaker adhesion targeting through alpha-actinin and VASP binding, clarifying the modular logic of LPP localization.\",\n      \"evidence\": \"Deletion/mutation constructs with fluorescence microscopy, dominant-negative displacement of endogenous LPP from focal adhesions\",\n      \"pmids\": [\"12441356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LIM domain targeting not resolved\", \"Whether LIM domains mediate protein-protein interactions at adhesions or lipid binding unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"LPP was found to be highly expressed in vascular smooth muscle cells and to promote EGF-stimulated SMC migration, with Rho-kinase activity controlling both focal adhesion retention and nuclear accumulation of LPP, placing LPP under RhoA/ROCK signaling control.\",\n      \"evidence\": \"Immunofluorescence, Transwell migration, Y-27632 and leptomycin B pharmacological treatments in SMCs\",\n      \"pmids\": [\"12760907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation by Rho-kinase not shown\", \"Whether nuclear LPP contributes to migration phenotype unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of Scrib as a direct binding partner of LPP at cell-cell contacts, mediated by Scrib PDZ domains and the LPP C-terminus, provided a molecular link between LPP and the polarity/tumor suppressor machinery.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, immunofluorescence co-localization, domain deletion mapping\",\n      \"pmids\": [\"15649318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of LPP-Scrib interaction on polarity or proliferation not tested\", \"Whether Scrib regulates LPP shuttling unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Multiple studies converged to define LPP's transcriptional and adhesion functions: LPP was identified as a coactivator of PEA3/ER81 ETS transcription factors on endogenous promoters, shown to promote early cell-cell junction assembly through its VASP-binding repeats with LIM domains acting as an auto-inhibitory module, and placed downstream of FAK and myocardin/Rho-kinase signaling for SMC migration.\",\n      \"evidence\": \"ChIP on PEA3-regulated promoters, co-immunoprecipitation, luciferase reporters, quantitative adhesion assays with dominant-negative constructs, siRNA in SMCs, FAK-null cell reconstitution\",\n      \"pmids\": [\"16738319\", \"16613855\", \"16397143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional target genes of LPP/PEA3 not comprehensively identified\", \"Structural basis of LIM domain auto-inhibition of VASP-mediated adhesion not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"In vivo genetic evidence from zebrafish established that LPP functions in non-canonical Wnt/PCP signaling during gastrulation convergence and extension, acting downstream of Wnt11 and Rho-kinase 2 in cooperation with Scrib, extending LPP's roles beyond adhesion/migration to developmental morphogenesis. Separately, alpha-actinin was shown to specifically link LPP (not zyxin) to cadherin-based junctions.\",\n      \"evidence\": \"Morpholino knockdown with epistasis analysis and time-lapse imaging in zebrafish; domain targeting and detergent fractionation in mammalian cells\",\n      \"pmids\": [\"18582857\", \"18413140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Wnt/PCP role is conserved in mammalian development not tested\", \"Direct molecular mechanism by which LPP affects PCP downstream of Scrib unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The unexpected finding that LPP associates with shelterin components (POT1, TRF2, TIN2) at telomeres and is required to suppress telomere dysfunction-induced foci revealed a chromatin-associated protective function distinct from adhesion or transcription.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation with multiple shelterin proteins, ChIP at telomeres, siRNA depletion causing TIF formation in human cells\",\n      \"pmids\": [\"20634563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which LPP domain mediates shelterin interaction unknown\", \"Whether telomere function requires LPP shuttling or is constitutively nuclear unclear\", \"Mechanism by which LPP suppresses DNA damage response at telomeres not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"LPP was shown to be indispensable for TGFβ-induced migration and invasion in ErbB2-positive breast cancer cells by mediating focal adhesion turnover through its alpha-actinin interaction, mechanistically linking LPP to oncogenic signal-dependent invasion programs.\",\n      \"evidence\": \"siRNA knockdown, live-cell focal adhesion dynamics imaging, co-immunoprecipitation, Transwell invasion assays in breast cancer cells\",\n      \"pmids\": [\"23447672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TGFβ signaling triggers LPP relocalization to focal adhesions not defined\", \"Whether nuclear LPP/transcriptional activity contributes to invasion phenotype not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A complete transcriptional pathway was delineated: LPP cooperates with ETV5 to directly activate MMP-15 transcription, MMP-15 cleaves N-cadherin, and loss of LPP paradoxically increases N-cadherin-dependent collective cell migration and in vivo lung cancer dissemination, revealing context-dependent pro- and anti-migratory roles.\",\n      \"evidence\": \"siRNA, MMP-15 promoter reporter, 3D collagen invasion, orthotopic mouse model with lung cancer cells\",\n      \"pmids\": [\"26028032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of LPP/ETV5 target genes unknown\", \"Whether this pathway operates in non-cancer contexts not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Src-mediated phosphorylation of LPP at Y245/Y301/Y302 was identified as the critical switch for invadopodia formation and metastasis, with LPP localizing to invadopodia alongside Tks5; separately, a MFAP5→FAK→ERK→LPP axis in endothelial cells was shown to regulate tumor vascular permeability, broadening LPP's role to the tumor microenvironment.\",\n      \"evidence\": \"Phospho-site mutagenesis, intravital imaging in CAM model, mouse lung metastasis assay; in vivo siRNA delivery in tumor-bearing mice with permeability measurements\",\n      \"pmids\": [\"28436416\", \"29251630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Src phosphorylation affects LPP nuclear functions or transcriptional activity untested\", \"Downstream effectors recruited by phospho-LPP at invadopodia unknown\", \"Structural consequences of Y245/Y301/Y302 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The mechanism controlling LPP protein turnover was defined: UBE2S cooperates with TRIM21 E3 ligase to catalyze K11-linked polyubiquitination of LPP, targeting it for degradation, and LPP acts as the critical downstream effector of UBE2S in promoting EMT and lymphatic metastasis in bladder cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays with linkage-specific ubiquitin mutants, epistatic siRNA rescue, in vivo lymphatic metastasis model\",\n      \"pmids\": [\"37422473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysine residues on LPP targeted for K11-ubiquitination not mapped\", \"Whether TRIM21-mediated degradation is signal-regulated not determined\", \"Relationship between ubiquitin-mediated turnover and phosphorylation-dependent functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the nuclear and cytoplasmic pools of LPP are coordinately regulated — and whether post-translational modifications such as Src phosphorylation or K11-ubiquitination differentially affect adhesion versus transcriptional functions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of LPP or its LIM domain-mediated interactions exists\", \"Comprehensive identification of LPP/ETV5 transcriptional targets genome-wide has not been performed\", \"Whether telomere-protective and adhesion/transcription functions are mechanistically linked is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 13, 16, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 5, 11, 12, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 6, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2, 5, 6, 12, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 5, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8, 15, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 5, 11]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"shelterin-associated complex\"\n    ],\n    \"partners\": [\n      \"VASP\",\n      \"ACTN1\",\n      \"SCRIB\",\n      \"PEA3\",\n      \"ETV5\",\n      \"TRF2\",\n      \"POT1\",\n      \"TRIM21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}