{"gene":"LPP","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1996,"finding":"LPP encodes a proline-rich protein with a leucine-zipper motif at its N-terminus and three LIM domains at its C-terminus, classifying it as a novel member of the group 3 LIM protein family. It was identified as the chromosome 3q27-28 translocation partner of HMGIC in lipomas, generating HMGIC/LPP fusion transcripts encoding predicted HMGI-C/LPP fusion proteins.","method":"3'-RACE, CASH, FISH, Northern blot, cDNA cloning, nucleotide sequence analysis, RT-PCR","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — original cDNA cloning and sequence determination, multiple orthogonal methods, foundational characterization paper","pmids":["8812423"],"is_preprint":false},{"year":2000,"finding":"LPP protein localizes to focal adhesions and cell-to-cell contacts, binds VASP (a protein implicated in actin organization control), accumulates in the nucleus upon CRM1 inhibition by leptomycin B, and contains an N-terminal leucine-rich nuclear export signal. LPP also displays transcriptional activation capacity in GAL4-based assays.","method":"Immunofluorescence localization, co-immunoprecipitation (LPP-VASP binding), leptomycin B treatment, GAL4-luciferase transcriptional assay, NES sequence analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, binding, transcriptional assay, inhibitor treatment) in a single rigorous study establishing subcellular localization and functional domains","pmids":["10637295"],"is_preprint":false},{"year":2002,"finding":"The LIM domains of LPP are the primary focal adhesion targeting elements, with the linker between LIM domains 1 and 2 playing a pivotal role. The proline-rich region (harboring α-actinin and VASP binding sites) has weak focal adhesion targeting capacity. Overexpressed LIM domains can deplete endogenous LPP and vinculin from focal adhesions. The LPP LIM domains are dispensable for nuclear targeting.","method":"Domain deletion/mutation constructs with immunofluorescence localization, overexpression in cultured cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic domain dissection with multiple deletion constructs and functional readouts in a single study","pmids":["12441356"],"is_preprint":false},{"year":2003,"finding":"LPP is selectively and highly expressed in vascular and visceral smooth muscle. In freshly isolated smooth muscle cells, LPP forms linear arrays at the plasma membrane colocalizing with vinculin at peripheral dense bodies. In cultured smooth muscle cells, LPP co-localizes with vinculin at focal adhesions. Overexpression of LPP increases EGF-stimulated migration of vascular smooth muscle cells. Rho-kinase inhibitor Y-27632 dissociates LPP from focal adhesions and enhances nuclear accumulation of LPP induced by leptomycin B.","method":"Western blot, immunofluorescence microscopy, Transwell migration assay, Rho-kinase inhibitor treatment, leptomycin B treatment","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in a single lab study; overexpression migration assay provides functional readout","pmids":["12760907"],"is_preprint":false},{"year":2005,"finding":"LPP interacts with the tumor suppressor protein Scrib (a component of cell-cell contacts). The interaction is mediated by the PDZ domains of Scrib and the C-terminus of LPP. Both proteins co-localize at cell-cell contacts. Scrib is dispensable for targeting LPP to focal adhesions or cell-cell contacts, and LPP is not required for Scrib localization at cell-cell contacts.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, domain deletion constructs","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by yeast two-hybrid and co-IP, domain mapping, and localization studies in a single comprehensive study","pmids":["15649318"],"is_preprint":false},{"year":2005,"finding":"The HMGA2/LPP fusion protein retains the transactivation functions of the LPP LIM domains and functions as a transcription factor, activating transcription from the PRDII element of the IFN-β enhancer and the BAT-1 element of the rhodopsin promoter. Wild-type HMGA2 augments the transactivation functions of HMGA2/LPP when co-expressed.","method":"GAL4-based luciferase reporter assay, PRDII and BAT-1 element reporter assays, co-transfection/co-expression experiments","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple reporter assays in a single lab; functional transactivation by LPP LIM domains confirmed","pmids":["15755872"],"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, and upregulates PEA3 transactivation capacity when LPP levels are manipulated. LPP also functionally interacts with the related ETS family member ER81.","method":"Co-immunoprecipitation, ChIP assay, luciferase reporter assay, siRNA knockdown and overexpression of LPP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP on endogenous promoters, and functional reporter assays with gain/loss-of-function, multiple orthogonal methods","pmids":["16738319"],"is_preprint":false},{"year":2006,"finding":"The VASP-binding ActA repeat region of LPP (and zyxin) promotes early cell-cell junction assembly. The LIM domain region of LPP acts as a regulatory domain that inhibits this function. Perturbation of LPP function reduces VASP levels in detergent-insoluble cadherin-actin networks and allows accumulation of capping protein at cell-cell contacts.","method":"Quantitative cell-cell adhesion assay, domain deletion constructs, dominant-negative mutants, detergent fractionation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain analysis with functional readout (adhesion assay), multiple constructs in a single lab","pmids":["16613855"],"is_preprint":false},{"year":2006,"finding":"LPP expression in smooth muscle cells is regulated by myocardin and the RhoA/Rho-kinase (ROK) pathway in a differentiation-dependent manner. All-trans retinoic acid increases LPP expression in a ROK-dependent manner. siRNA silencing of LPP significantly decreases smooth muscle cell migration. LPP expression is rescued and enhances cell spreading in FAK-null fibroblasts by inducible FAK expression.","method":"Adenovirus-mediated myocardin overexpression, Rho-kinase inhibitors, siRNA knockdown, FAK-null fibroblast system with inducible FAK re-expression, migration assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic/pharmacological interventions with functional readout (migration), single lab","pmids":["16397143"],"is_preprint":false},{"year":2008,"finding":"In zebrafish, Lpp is required for convergence and extension (C&E) movements during gastrulation. Morpholino knockdown of lpp phenocopies noncanonical Wnt signaling mutants. Lpp expression is dependent on Wnt11 signaling and downstream Rho kinase 2. Lpp interacts with the PCP protein Scrib in zebrafish, and Lpp and Scrib cooperate to mediate C&E movements.","method":"Morpholino knockdown, time-lapse analysis, co-immunoprecipitation (Lpp-Scrib interaction in zebrafish), Wnt11 morphants, dominant-negative Rho kinase 2 overexpression","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined phenotype, epistasis with Wnt11/ROK2, protein interaction confirmed by Co-IP; zebrafish ortholog study","pmids":["18582857"],"is_preprint":false},{"year":2008,"finding":"The α-actinin binding site of LPP is required for LPP localization and function at cell-cell contacts; perturbation of LPP (but not zyxin) function reduces anchoring of α-actinin to detergent-insoluble networks at cell-cell contacts. In contrast, zyxin localization and function at cell-cell contacts is independent of its α-actinin binding site.","method":"Domain fragment targeting assays, detergent fractionation, immunofluorescence, dominant-negative constructs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain fragment localization and fractionation assays, single lab, functional specificity shown for LPP vs. zyxin","pmids":["18413140"],"is_preprint":false},{"year":2009,"finding":"LPP expression is regulated by mechanical cues and substrate composition in smooth muscle cells: denatured collagen or rigid substrate upregulates LPP, while atheroprone shear stress (applied via an EC/SMC hemodynamic flow system) decreases LPP expression. LPP and its partner palladin are also regulated by oxidative stress and are altered in arterial injury and early atherogenesis models.","method":"Smooth muscle cell culture on modified substrates, EC/SMC hemodynamic flow system, ApoE murine atherosclerosis model, arterial injury model, Western blot, immunofluorescence","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo models, single lab, with defined molecular readouts","pmids":["19205907"],"is_preprint":false},{"year":2010,"finding":"LPP (and TRIP6) associates with the shelterin complex at telomeres and is required for telomere protection. LPP depletion by siRNA leads to induction of telomere dysfunction-induced foci (TIFs). LPP was detected at telomeres by ChIP and co-immunoprecipitated with POT1, TRF2, and TIN2.","method":"Yeast two-hybrid screen, co-immunoprecipitation with POT1/TRF2/TIN2, ChIP, siRNA knockdown with TIF assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with multiple shelterin components, ChIP, and functional siRNA phenotype; single lab","pmids":["20634563"],"is_preprint":false},{"year":2011,"finding":"TRIP6 and LPP (but not Zyxin) are detected at a subset of telomeres by immunofluorescence, confirming specificity within the zyxin family for telomere association. Zyxin was not detected at telomeres and was not found in a complex with shelterin, despite high sequence similarity to LPP.","method":"Immunofluorescence at telomeres, co-immunoprecipitation to test shelterin association","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization and Co-IP, single lab, confirms specificity of LPP (not zyxin) for telomere association","pmids":["21519191"],"is_preprint":false},{"year":2012,"finding":"ETV5 (an ETS transcription factor) cooperates with LPP as a regulatory partner, with LPP acting as a sensor of extracellular signals promoting tumor invasion. LPP is identified as a regulatory partner of ETV5 in endometrial carcinoma cells, and together they promote epithelial-to-mesenchymal transition (EMT) and invasive capability.","method":"Molecular profiling, co-immunoprecipitation/interaction studies, overexpression and knockdown functional assays for migration/invasion","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein interaction and functional co-operation demonstrated, single lab","pmids":["22266854"],"is_preprint":false},{"year":2012,"finding":"TGF-β1 increases LPP expression in smooth muscle progenitor cells (SMPCs) through a Rho kinase (ROK)-dependent mechanism. ROK inhibition suppresses LPP mRNA expression in TGF-β1-treated SMPCs. siRNA silencing of LPP significantly decreases SMPC migration.","method":"ROK inhibitors, siRNA knockdown, RT-PCR, migration assay","journal":"Journal of Huazhong University of Science and Technology. Medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited orthogonal methods, replicates findings from prior smooth muscle studies","pmids":["22886954"],"is_preprint":false},{"year":2013,"finding":"LPP is an indispensable regulator of TGFβ-induced migration and invasion in ErbB2-expressing breast cancer cells. Upon TGFβ stimulation, LPP re-localizes to focal adhesion complexes and is a critical determinant of TGFβ-mediated focal adhesion turnover. The interaction between LPP and α-actinin is necessary for TGFβ-induced migration and invasion.","method":"siRNA knockdown, live-cell imaging of focal adhesion turnover (TIRF/FRAP), co-immunoprecipitation, domain mutants disrupting LPP-α-actinin interaction, migration/invasion assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, Co-IP, domain mutants, functional assays), specific molecular mechanism (LPP-α-actinin interaction) demonstrated","pmids":["23447672"],"is_preprint":false},{"year":2015,"finding":"LPP, together with its functional partner ETV5, directly regulates transcription of MMP-15. MMP-15 directly cleaves the N-cadherin extracellular domain, and loss of LPP increases N-cadherin-dependent collective cell migration in lung cancer cells. LPP knockdown promotes cancer cell dissemination in orthotopic mouse models.","method":"siRNA knockdown, luciferase reporter assay (MMP-15 promoter), 3D collagen gel invasion assay, orthotopic mouse model, immunohistochemistry, Western blot for N-cadherin cleavage","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct transcriptional target identification with reporter assay, in vitro and in vivo functional assays, mechanistic link (LPP/ETV5→MMP-15→N-cadherin cleavage) established with multiple methods","pmids":["26028032"],"is_preprint":false},{"year":2017,"finding":"LPP localizes to invadopodia (along with Tks5/actin) at sites of matrix degradation and at the tips of extravasating breast cancer cells. Invadopodia formation, cancer cell extravasation, and metastasis require an intact LPP LIM domain and LPP's ability to interact with α-actinin. Src-mediated LPP phosphorylation at tyrosine residues Y245/301/302 is critical for invadopodia formation, breast cancer cell invasion, and metastasis.","method":"siRNA knockdown, domain mutants (LIM domain, α-actinin binding site), LPP phospho-site mutants (Y→F), intravital imaging of chick CAM, Src kinase assays, in vitro invasion assays, mouse lung metastasis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-directed mutagenesis of phosphorylation sites, multiple in vivo models, intravital imaging, domain requirement established with orthogonal methods","pmids":["28436416"],"is_preprint":false},{"year":2017,"finding":"Cancer-associated fibroblasts (CAFs) upregulate LPP in microvascular endothelial cells (MECs) via a calcium-dependent signaling pathway involving MFAP5, FAK, ERK, and LPP. LPP promotes focal adhesion and stress fiber formation, increases endothelial cell motility and permeability. siRNA-mediated LPP silencing in tumor-bearing mice decreases intratumoral microvessel leakiness and improves chemotherapy delivery.","method":"siRNA knockdown in vivo and in vitro, pathway inhibition (FAK, ERK inhibitors), focal adhesion/stress fiber assays, permeability assay, mouse tumor model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo siRNA, multiple pathway inhibitors, functional assays (permeability, migration), defined signaling cascade established","pmids":["29251630"],"is_preprint":false},{"year":2023,"finding":"UBE2S interacts with TRIM21 and together they induce K11-linked polyubiquitination (not K48- or K63-linked) of LPP, promoting LPP degradation and bladder cancer lymphatic metastasis. LPP silencing rescues anti-metastatic phenotypes after UBE2S knockdown, placing LPP downstream of the UBE2S/TRIM21 ubiquitination axis.","method":"Co-immunoprecipitation, ubiquitination assay with linkage-specific antibodies (K11/K48/K63), siRNA knockdown, in vivo lymphatic metastasis model, human bladder cancer organoids","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific ubiquitin linkage identified biochemically, in vivo and organoid models, epistasis established by rescue experiments","pmids":["37422473"],"is_preprint":false}],"current_model":"LPP (Lipoma Preferred Partner) is a LIM domain scaffold protein that shuttles between focal adhesions/cell-cell contacts and the nucleus: at adhesions it recruits VASP and α-actinin to regulate actin dynamics and focal adhesion turnover; in the nucleus it acts as a transcriptional coactivator for ETS factors (PEA3/ER81/ETV5), partly by directing MMP-15 transcription; its nuclear-cytoplasmic trafficking is controlled by a CRM1-dependent NES and by Rho-kinase activity; Src phosphorylates LPP at Y245/301/302 to drive invadopodia formation and metastasis; LPP also associates with the shelterin complex at telomeres; and its stability is regulated by UBE2S/TRIM21-mediated K11-linked polyubiquitination."},"narrative":{"mechanistic_narrative":"LPP (Lipoma Preferred Partner) is a group-3 LIM-domain scaffold protein that couples actin-based adhesion structures to gene transcription, shuttling between focal adhesions and cell-cell contacts and the nucleus to control cell motility, adhesion turnover, and invasion [PMID:8812423, PMID:10637295]. It was first identified as the 3q27-28 translocation partner of HMGIC in lipomas, encoding a proline-rich N-terminus with a leucine-zipper and three C-terminal LIM domains [PMID:8812423]. The LIM domains and the inter-LIM1/2 linker are the principal focal-adhesion targeting elements and also carry transactivation activity, while a separate N-terminal CRM1-dependent nuclear export signal restricts nuclear accumulation [PMID:10637295, PMID:12441356]. At adhesions and junctions, LPP binds VASP through its ActA-repeat region to promote junction assembly and recruits alpha-actinin into detergent-insoluble adhesion networks, an interaction required for adhesion turnover and migration [PMID:10637295, PMID:16613855, PMID:18413140, PMID:23447672]. In the nucleus LPP functions as a transcriptional coactivator for the ETS factors PEA3, ER81, and ETV5, occupying ETS-regulated promoters and, with ETV5, directly driving MMP-15 transcription to control N-cadherin cleavage and collective migration [PMID:16738319, PMID:22266854, PMID:26028032]. Its trafficking and abundance are signal-responsive: Rho-kinase activity governs focal-adhesion association versus nuclear shuttling, TGFbeta redirects LPP to focal adhesions to license invasion, and Src phosphorylation at Y245/301/302 drives invadopodia formation and metastasis [PMID:12760907, PMID:23447672, PMID:28436416]. LPP also associates with the shelterin complex (POT1, TRF2, TIN2) at a subset of telomeres and is required for telomere protection, distinguishing it from the closely related zyxin [PMID:20634563, PMID:21519191]. LPP stability is controlled by UBE2S/TRIM21-mediated K11-linked polyubiquitination, which promotes its degradation in bladder cancer [PMID:37422473].","teleology":[{"year":1996,"claim":"Established the existence and domain architecture of LPP and linked it to lipoma genetics, defining the gene as an HMGIC translocation partner.","evidence":"cDNA cloning, sequencing, FISH and RT-PCR of lipoma fusion transcripts","pmids":["8812423"],"confidence":"High","gaps":["Did not assign a cellular function to the protein","Functional consequence of HMGIC/LPP fusion not tested"]},{"year":2000,"claim":"Defined LPP as a dually-localized protein, placing it at focal adhesions/cell contacts via VASP binding and in the nucleus via a CRM1-dependent NES, and showed it has intrinsic transactivation capacity.","evidence":"Immunofluorescence, Co-IP, leptomycin B treatment, GAL4 reporter assay","pmids":["10637295"],"confidence":"High","gaps":["Nuclear transcriptional targets not identified","Functional relevance of nuclear shuttling unknown"]},{"year":2002,"claim":"Mapped the molecular determinants of LPP targeting, showing LIM domains and the LIM1/2 linker drive focal-adhesion localization while being dispensable for nuclear targeting.","evidence":"Domain deletion/mutation constructs with immunofluorescence in cultured cells","pmids":["12441356"],"confidence":"High","gaps":["Sequence determinant of nuclear import not defined","Endogenous depletion effects only shown by overexpression dominance"]},{"year":2005,"claim":"Extended the LPP interactome and transactivation function, identifying Scrib as a C-terminal partner at cell-cell contacts and confirming LPP LIM domains transactivate within the HMGA2/LPP fusion.","evidence":"Yeast two-hybrid, Co-IP, domain mapping (Scrib); GAL4 and element-specific reporter assays (fusion)","pmids":["15649318","15755872"],"confidence":"High","gaps":["Functional consequence of LPP-Scrib interaction not established at this stage","Endogenous transcriptional targets still unknown"]},{"year":2006,"claim":"Identified LPP as a bona fide transcriptional coactivator of ETS factors and dissected its adhesion role, showing it coactivates PEA3/ER81, promotes cell-cell junction assembly via VASP, and is regulated by myocardin/RhoA-ROK in smooth muscle.","evidence":"Co-IP, ChIP on endogenous promoters, reporter assays with knockdown/overexpression; adhesion assays with domain mutants; myocardin overexpression and ROK inhibition with migration assays","pmids":["16738319","16613855","16397143"],"confidence":"High","gaps":["Direct ETS target genes not yet defined","How nuclear vs adhesion pools are partitioned during signaling unclear"]},{"year":2008,"claim":"Connected LPP to noncanonical Wnt/PCP signaling and refined its adhesion mechanism, showing zebrafish Lpp is required for convergence-extension downstream of Wnt11/ROK2 and cooperates with Scrib, and that its alpha-actinin binding site governs cell-contact function.","evidence":"Morpholino knockdown, epistasis with Wnt11/ROK2, Co-IP (zebrafish); domain fragment targeting and fractionation (alpha-actinin)","pmids":["18582857","18413140"],"confidence":"High","gaps":["Whether PCP role generalizes to mammals not tested","Direct transcriptional vs cytoskeletal contribution to C&E not separated"]},{"year":2010,"claim":"Revealed an unexpected nuclear genome-protective role, showing LPP associates with shelterin (POT1/TRF2/TIN2) at telomeres and is required to prevent telomere dysfunction, with specificity for LPP over zyxin.","evidence":"Yeast two-hybrid, Co-IP with shelterin components, ChIP, siRNA with TIF assay; immunofluorescence at telomeres","pmids":["20634563","21519191"],"confidence":"Medium","gaps":["Molecular mechanism of telomere protection by LPP unresolved","How LPP is recruited to only a subset of telomeres unknown"]},{"year":2012,"claim":"Linked LPP-ETS cooperation to cancer invasion, identifying ETV5 as a regulatory partner promoting EMT and invasion and showing TGFbeta induces LPP through ROK in smooth muscle progenitors.","evidence":"Interaction/Co-IP studies and migration/invasion assays (ETV5); ROK inhibition, siRNA, migration assays (SMPC)","pmids":["22266854","22886954"],"confidence":"Medium","gaps":["Direct ETV5/LPP target genes not identified at this stage","TGFbeta-ROK-LPP link in SMPCs is a single low-confidence study"]},{"year":2013,"claim":"Established a mechanistic basis for LPP-driven invasion, showing TGFbeta relocalizes LPP to focal adhesions where its alpha-actinin interaction is required for adhesion turnover, migration, and invasion.","evidence":"siRNA, live-cell FRAP/TIRF imaging of focal adhesion turnover, Co-IP, alpha-actinin-disrupting domain mutants, invasion assays","pmids":["23447672"],"confidence":"High","gaps":["Upstream TGFbeta signal that triggers relocalization not fully defined","Relationship between nuclear and adhesion pools during invasion unclear"]},{"year":2015,"claim":"Defined a direct transcriptional output of LPP, showing LPP/ETV5 directly drive MMP-15 transcription, with MMP-15 cleaving N-cadherin to restrain collective migration and dissemination.","evidence":"siRNA, MMP-15 promoter reporter, 3D invasion assay, orthotopic mouse model, N-cadherin cleavage Western blot","pmids":["26028032"],"confidence":"High","gaps":["Context-dependent suppressive vs promoting roles of LPP not reconciled","Whether MMP-15 is the sole relevant target unknown"]},{"year":2017,"claim":"Identified the post-translational and microenvironmental control of LPP-driven metastasis, showing Src phosphorylates LPP at Y245/301/302 to drive invadopodia and metastasis, and that CAF-derived signals upregulate endothelial LPP to control vascular permeability.","evidence":"Phospho-site Y->F mutants, LIM/alpha-actinin domain mutants, intravital chick CAM imaging, mouse metastasis model; CAF/MFAP5-FAK-ERK pathway inhibition, in vivo siRNA, permeability assays","pmids":["28436416","29251630"],"confidence":"High","gaps":["Direct kinase-substrate stoichiometry and dynamics of Src phosphorylation not resolved","How phosphorylation alters LPP partner binding mechanistically unknown"]},{"year":2023,"claim":"Established how LPP abundance is controlled, identifying a UBE2S/TRIM21 complex that adds K11-linked polyubiquitin to drive LPP degradation and promote bladder cancer lymphatic metastasis.","evidence":"Co-IP, linkage-specific (K11/K48/K63) ubiquitination assays, siRNA rescue epistasis, in vivo metastasis model, patient organoids","pmids":["37422473"],"confidence":"High","gaps":["Ubiquitination site(s) on LPP not mapped","Whether the same axis operates outside bladder cancer untested"]},{"year":null,"claim":"How LPP integrates its adhesion-scaffolding, ETS-coactivator, and telomere-protective activities into a single regulated program — and what governs partitioning between these pools — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LPP bound to its partners","Mechanism coupling adhesion-localized to nuclear function not defined","Telomere-protection mechanism uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,5,6,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,10,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,6,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,19]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,18,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[20]}],"complexes":["shelterin"],"partners":["VASP","ACTN1","SCRIB","ETV5","POT1","TRF2","TIN2","TRIM21"],"other_free_text":[]}},"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 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Cloning and DNA sequence of the lpp gene from Proteus mirabilis.","date":"1985","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3903165","citation_count":8,"is_preprint":false},{"pmid":"16821597","id":"PMC_16821597","title":"MRI characteristics of parosteal lipomas associated with the HMGA2-LPP fusion gene.","date":"2006","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16821597","citation_count":8,"is_preprint":false},{"pmid":"35611368","id":"PMC_35611368","title":"Circular RNA circLRCH3 Inhibits Proliferation, Migration, and Invasion of Colorectal Cancer Cells Through miRNA-223/LPP Axis.","date":"2022","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35611368","citation_count":7,"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":"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":"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":"31815498","id":"PMC_31815498","title":"Does facial action modulate neural responses of emotion? 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":"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":"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":"37749219","id":"PMC_37749219","title":"When less is more: shortening the Lpp protein leads to increased vancomycin resistance in Escherichia coli.","date":"2023","source":"The Journal of antibiotics","url":"https://pubmed.ncbi.nlm.nih.gov/37749219","citation_count":3,"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":"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},{"pmid":"40263412","id":"PMC_40263412","title":"Lipoprotein Lpp and L, D-transpeptidases regulate the master regulator of virulence AggR in EAEC.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40263412","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45977,"output_tokens":5876,"usd":0.113035,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14038,"output_tokens":4438,"usd":0.09057,"stage2_stop_reason":"end_turn"},"total_usd":0.203605,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian LPP gene (Lipoma Preferred Partner, a LIM domain protein at 3q27-28) versus:\n- Bacterial Lpp (Braun's lipoprotein, E. coli outer membrane lipoprotein) - EXCLUDE as symbol collision\n- Blue-green algal virus LPP-1 - EXCLUDE\n- Swine Lpp lipoprotein allotypes - EXCLUDE\n- LPP as \"Late Positive Potential\" (EEG) - EXCLUDE\n- LPP-AS2 lncRNA - EXCLUDE (non-protein locus product)\n- LPP dietary product - EXCLUDE\n- Pantoea plasmid LPP-1 - EXCLUDE\n- Linalyl diphosphate (LPP) intermediate in terpene synthesis - EXCLUDE\n\nPapers about human LPP protein (and zebrafish ortholog): PMIDs 8812423, 10637295, 12441356, 15649318, 16738319, 16613855, 18582857, 12760907, 16397143, 18413140, 20634563, 21519191, 22266854, 23447672, 26028032, 28436416, 29251630, 37422473, 19701494, 11433529, 15755872, 19205907, 22886954\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"LPP encodes a proline-rich protein with a leucine-zipper motif at its N-terminus and three LIM domains at its C-terminus, classifying it as a novel member of the group 3 LIM protein family. It was identified as the chromosome 3q27-28 translocation partner of HMGIC in lipomas, generating HMGIC/LPP fusion transcripts encoding predicted HMGI-C/LPP fusion proteins.\",\n      \"method\": \"3'-RACE, CASH, FISH, Northern blot, cDNA cloning, nucleotide sequence analysis, RT-PCR\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original cDNA cloning and sequence determination, multiple orthogonal methods, foundational characterization paper\",\n      \"pmids\": [\"8812423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LPP protein localizes to focal adhesions and cell-to-cell contacts, binds VASP (a protein implicated in actin organization control), accumulates in the nucleus upon CRM1 inhibition by leptomycin B, and contains an N-terminal leucine-rich nuclear export signal. LPP also displays transcriptional activation capacity in GAL4-based assays.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation (LPP-VASP binding), leptomycin B treatment, GAL4-luciferase transcriptional assay, NES sequence analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, binding, transcriptional assay, inhibitor treatment) in a single rigorous study establishing subcellular localization and functional domains\",\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, with the linker between LIM domains 1 and 2 playing a pivotal role. The proline-rich region (harboring α-actinin and VASP binding sites) has weak focal adhesion targeting capacity. Overexpressed LIM domains can deplete endogenous LPP and vinculin from focal adhesions. The LPP LIM domains are dispensable for nuclear targeting.\",\n      \"method\": \"Domain deletion/mutation constructs with immunofluorescence localization, overexpression in cultured cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain dissection with multiple deletion constructs and functional readouts in a single study\",\n      \"pmids\": [\"12441356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LPP is selectively and highly expressed in vascular and visceral smooth muscle. In freshly isolated smooth muscle cells, LPP forms linear arrays at the plasma membrane colocalizing with vinculin at peripheral dense bodies. In cultured smooth muscle cells, LPP co-localizes with vinculin at focal adhesions. Overexpression of LPP increases EGF-stimulated migration of vascular smooth muscle cells. Rho-kinase inhibitor Y-27632 dissociates LPP from focal adhesions and enhances nuclear accumulation of LPP induced by leptomycin B.\",\n      \"method\": \"Western blot, immunofluorescence microscopy, Transwell migration assay, Rho-kinase inhibitor treatment, leptomycin B treatment\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in a single lab study; overexpression migration assay provides functional readout\",\n      \"pmids\": [\"12760907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LPP interacts with the tumor suppressor protein Scrib (a component of cell-cell contacts). The interaction is mediated by the PDZ domains of Scrib and the C-terminus of LPP. Both proteins co-localize at cell-cell contacts. Scrib is dispensable for targeting LPP to focal adhesions or cell-cell contacts, and LPP is not required for Scrib localization at cell-cell contacts.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, domain deletion constructs\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by yeast two-hybrid and co-IP, domain mapping, and localization studies in a single comprehensive study\",\n      \"pmids\": [\"15649318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The HMGA2/LPP fusion protein retains the transactivation functions of the LPP LIM domains and functions as a transcription factor, activating transcription from the PRDII element of the IFN-β enhancer and the BAT-1 element of the rhodopsin promoter. Wild-type HMGA2 augments the transactivation functions of HMGA2/LPP when co-expressed.\",\n      \"method\": \"GAL4-based luciferase reporter assay, PRDII and BAT-1 element reporter assays, co-transfection/co-expression experiments\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple reporter assays in a single lab; functional transactivation by LPP LIM domains confirmed\",\n      \"pmids\": [\"15755872\"],\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, and upregulates PEA3 transactivation capacity when LPP levels are manipulated. LPP also functionally interacts with the related ETS family member ER81.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, luciferase reporter assay, siRNA knockdown and overexpression of LPP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP on endogenous promoters, and functional reporter assays with gain/loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"16738319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The VASP-binding ActA repeat region of LPP (and zyxin) promotes early cell-cell junction assembly. The LIM domain region of LPP acts as a regulatory domain that inhibits this function. Perturbation of LPP function reduces VASP levels in detergent-insoluble cadherin-actin networks and allows accumulation of capping protein at cell-cell contacts.\",\n      \"method\": \"Quantitative cell-cell adhesion assay, domain deletion constructs, dominant-negative mutants, detergent fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain analysis with functional readout (adhesion assay), multiple constructs in a single lab\",\n      \"pmids\": [\"16613855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LPP expression in smooth muscle cells is regulated by myocardin and the RhoA/Rho-kinase (ROK) pathway in a differentiation-dependent manner. All-trans retinoic acid increases LPP expression in a ROK-dependent manner. siRNA silencing of LPP significantly decreases smooth muscle cell migration. LPP expression is rescued and enhances cell spreading in FAK-null fibroblasts by inducible FAK expression.\",\n      \"method\": \"Adenovirus-mediated myocardin overexpression, Rho-kinase inhibitors, siRNA knockdown, FAK-null fibroblast system with inducible FAK re-expression, migration assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic/pharmacological interventions with functional readout (migration), single lab\",\n      \"pmids\": [\"16397143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In zebrafish, Lpp is required for convergence and extension (C&E) movements during gastrulation. Morpholino knockdown of lpp phenocopies noncanonical Wnt signaling mutants. Lpp expression is dependent on Wnt11 signaling and downstream Rho kinase 2. Lpp interacts with the PCP protein Scrib in zebrafish, and Lpp and Scrib cooperate to mediate C&E movements.\",\n      \"method\": \"Morpholino knockdown, time-lapse analysis, co-immunoprecipitation (Lpp-Scrib interaction in zebrafish), Wnt11 morphants, dominant-negative Rho kinase 2 overexpression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined phenotype, epistasis with Wnt11/ROK2, protein interaction confirmed by Co-IP; zebrafish ortholog study\",\n      \"pmids\": [\"18582857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The α-actinin binding site of LPP is required for LPP localization and function at cell-cell contacts; perturbation of LPP (but not zyxin) function reduces anchoring of α-actinin to detergent-insoluble networks at cell-cell contacts. In contrast, zyxin localization and function at cell-cell contacts is independent of its α-actinin binding site.\",\n      \"method\": \"Domain fragment targeting assays, detergent fractionation, immunofluorescence, dominant-negative constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain fragment localization and fractionation assays, single lab, functional specificity shown for LPP vs. zyxin\",\n      \"pmids\": [\"18413140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPP expression is regulated by mechanical cues and substrate composition in smooth muscle cells: denatured collagen or rigid substrate upregulates LPP, while atheroprone shear stress (applied via an EC/SMC hemodynamic flow system) decreases LPP expression. LPP and its partner palladin are also regulated by oxidative stress and are altered in arterial injury and early atherogenesis models.\",\n      \"method\": \"Smooth muscle cell culture on modified substrates, EC/SMC hemodynamic flow system, ApoE murine atherosclerosis model, arterial injury model, Western blot, immunofluorescence\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo models, single lab, with defined molecular readouts\",\n      \"pmids\": [\"19205907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPP (and TRIP6) associates with the shelterin complex at telomeres and is required for telomere protection. LPP depletion by siRNA leads to induction of telomere dysfunction-induced foci (TIFs). LPP was detected at telomeres by ChIP and co-immunoprecipitated with POT1, TRF2, and TIN2.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation with POT1/TRF2/TIN2, ChIP, siRNA knockdown with TIF assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with multiple shelterin components, ChIP, and functional siRNA phenotype; single lab\",\n      \"pmids\": [\"20634563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIP6 and LPP (but not Zyxin) are detected at a subset of telomeres by immunofluorescence, confirming specificity within the zyxin family for telomere association. Zyxin was not detected at telomeres and was not found in a complex with shelterin, despite high sequence similarity to LPP.\",\n      \"method\": \"Immunofluorescence at telomeres, co-immunoprecipitation to test shelterin association\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization and Co-IP, single lab, confirms specificity of LPP (not zyxin) for telomere association\",\n      \"pmids\": [\"21519191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ETV5 (an ETS transcription factor) cooperates with LPP as a regulatory partner, with LPP acting as a sensor of extracellular signals promoting tumor invasion. LPP is identified as a regulatory partner of ETV5 in endometrial carcinoma cells, and together they promote epithelial-to-mesenchymal transition (EMT) and invasive capability.\",\n      \"method\": \"Molecular profiling, co-immunoprecipitation/interaction studies, overexpression and knockdown functional assays for migration/invasion\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein interaction and functional co-operation demonstrated, single lab\",\n      \"pmids\": [\"22266854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TGF-β1 increases LPP expression in smooth muscle progenitor cells (SMPCs) through a Rho kinase (ROK)-dependent mechanism. ROK inhibition suppresses LPP mRNA expression in TGF-β1-treated SMPCs. siRNA silencing of LPP significantly decreases SMPC migration.\",\n      \"method\": \"ROK inhibitors, siRNA knockdown, RT-PCR, migration assay\",\n      \"journal\": \"Journal of Huazhong University of Science and Technology. Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited orthogonal methods, replicates findings from prior smooth muscle studies\",\n      \"pmids\": [\"22886954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LPP is an indispensable regulator of TGFβ-induced migration and invasion in ErbB2-expressing breast cancer cells. Upon TGFβ stimulation, LPP re-localizes to focal adhesion complexes and is a critical determinant of TGFβ-mediated focal adhesion turnover. The interaction between LPP and α-actinin is necessary for TGFβ-induced migration and invasion.\",\n      \"method\": \"siRNA knockdown, live-cell imaging of focal adhesion turnover (TIRF/FRAP), co-immunoprecipitation, domain mutants disrupting LPP-α-actinin interaction, migration/invasion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, Co-IP, domain mutants, functional assays), specific molecular mechanism (LPP-α-actinin interaction) demonstrated\",\n      \"pmids\": [\"23447672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LPP, together with its functional partner ETV5, directly regulates transcription of MMP-15. MMP-15 directly cleaves the N-cadherin extracellular domain, and loss of LPP increases N-cadherin-dependent collective cell migration in lung cancer cells. LPP knockdown promotes cancer cell dissemination in orthotopic mouse models.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay (MMP-15 promoter), 3D collagen gel invasion assay, orthotopic mouse model, immunohistochemistry, Western blot for N-cadherin cleavage\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional target identification with reporter assay, in vitro and in vivo functional assays, mechanistic link (LPP/ETV5→MMP-15→N-cadherin cleavage) established with multiple methods\",\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 at the tips of extravasating breast cancer cells. Invadopodia formation, cancer cell extravasation, and metastasis require an intact LPP LIM domain and LPP's ability to interact with α-actinin. Src-mediated LPP phosphorylation at tyrosine residues Y245/301/302 is critical for invadopodia formation, breast cancer cell invasion, and metastasis.\",\n      \"method\": \"siRNA knockdown, domain mutants (LIM domain, α-actinin binding site), LPP phospho-site mutants (Y→F), intravital imaging of chick CAM, Src kinase assays, in vitro invasion assays, mouse lung metastasis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-directed mutagenesis of phosphorylation sites, multiple in vivo models, intravital imaging, domain requirement established with orthogonal methods\",\n      \"pmids\": [\"28436416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cancer-associated fibroblasts (CAFs) upregulate LPP in microvascular endothelial cells (MECs) via a calcium-dependent signaling pathway involving MFAP5, FAK, ERK, and LPP. LPP promotes focal adhesion and stress fiber formation, increases endothelial cell motility and permeability. siRNA-mediated LPP silencing in tumor-bearing mice decreases intratumoral microvessel leakiness and improves chemotherapy delivery.\",\n      \"method\": \"siRNA knockdown in vivo and in vitro, pathway inhibition (FAK, ERK inhibitors), focal adhesion/stress fiber assays, permeability assay, mouse tumor model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo siRNA, multiple pathway inhibitors, functional assays (permeability, migration), defined signaling cascade established\",\n      \"pmids\": [\"29251630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2S interacts with TRIM21 and together they induce K11-linked polyubiquitination (not K48- or K63-linked) of LPP, promoting LPP degradation and bladder cancer lymphatic metastasis. LPP silencing rescues anti-metastatic phenotypes after UBE2S knockdown, placing LPP downstream of the UBE2S/TRIM21 ubiquitination axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with linkage-specific antibodies (K11/K48/K63), siRNA knockdown, in vivo lymphatic metastasis model, human bladder cancer organoids\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific ubiquitin linkage identified biochemically, in vivo and organoid models, epistasis established by rescue experiments\",\n      \"pmids\": [\"37422473\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LPP (Lipoma Preferred Partner) is a LIM domain scaffold protein that shuttles between focal adhesions/cell-cell contacts and the nucleus: at adhesions it recruits VASP and α-actinin to regulate actin dynamics and focal adhesion turnover; in the nucleus it acts as a transcriptional coactivator for ETS factors (PEA3/ER81/ETV5), partly by directing MMP-15 transcription; its nuclear-cytoplasmic trafficking is controlled by a CRM1-dependent NES and by Rho-kinase activity; Src phosphorylates LPP at Y245/301/302 to drive invadopodia formation and metastasis; LPP also associates with the shelterin complex at telomeres; and its stability is regulated by UBE2S/TRIM21-mediated K11-linked polyubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LPP (Lipoma Preferred Partner) is a group-3 LIM-domain scaffold protein that couples actin-based adhesion structures to gene transcription, shuttling between focal adhesions and cell-cell contacts and the nucleus to control cell motility, adhesion turnover, and invasion [#0, #1]. It was first identified as the 3q27-28 translocation partner of HMGIC in lipomas, encoding a proline-rich N-terminus with a leucine-zipper and three C-terminal LIM domains [#0]. The LIM domains and the inter-LIM1/2 linker are the principal focal-adhesion targeting elements and also carry transactivation activity, while a separate N-terminal CRM1-dependent nuclear export signal restricts nuclear accumulation [#1, #2]. At adhesions and junctions, LPP binds VASP through its ActA-repeat region to promote junction assembly and recruits alpha-actinin into detergent-insoluble adhesion networks, an interaction required for adhesion turnover and migration [#1, #7, #10, #16]. In the nucleus LPP functions as a transcriptional coactivator for the ETS factors PEA3, ER81, and ETV5, occupying ETS-regulated promoters and, with ETV5, directly driving MMP-15 transcription to control N-cadherin cleavage and collective migration [#6, #14, #17]. Its trafficking and abundance are signal-responsive: Rho-kinase activity governs focal-adhesion association versus nuclear shuttling, TGFbeta redirects LPP to focal adhesions to license invasion, and Src phosphorylation at Y245/301/302 drives invadopodia formation and metastasis [#3, #16, #18]. LPP also associates with the shelterin complex (POT1, TRF2, TIN2) at a subset of telomeres and is required for telomere protection, distinguishing it from the closely related zyxin [#12, #13]. LPP stability is controlled by UBE2S/TRIM21-mediated K11-linked polyubiquitination, which promotes its degradation in bladder cancer [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the existence and domain architecture of LPP and linked it to lipoma genetics, defining the gene as an HMGIC translocation partner.\",\n      \"evidence\": \"cDNA cloning, sequencing, FISH and RT-PCR of lipoma fusion transcripts\",\n      \"pmids\": [\"8812423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign a cellular function to the protein\", \"Functional consequence of HMGIC/LPP fusion not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined LPP as a dually-localized protein, placing it at focal adhesions/cell contacts via VASP binding and in the nucleus via a CRM1-dependent NES, and showed it has intrinsic transactivation capacity.\",\n      \"evidence\": \"Immunofluorescence, Co-IP, leptomycin B treatment, GAL4 reporter assay\",\n      \"pmids\": [\"10637295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear transcriptional targets not identified\", \"Functional relevance of nuclear shuttling unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the molecular determinants of LPP targeting, showing LIM domains and the LIM1/2 linker drive focal-adhesion localization while being dispensable for nuclear targeting.\",\n      \"evidence\": \"Domain deletion/mutation constructs with immunofluorescence in cultured cells\",\n      \"pmids\": [\"12441356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence determinant of nuclear import not defined\", \"Endogenous depletion effects only shown by overexpression dominance\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended the LPP interactome and transactivation function, identifying Scrib as a C-terminal partner at cell-cell contacts and confirming LPP LIM domains transactivate within the HMGA2/LPP fusion.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, domain mapping (Scrib); GAL4 and element-specific reporter assays (fusion)\",\n      \"pmids\": [\"15649318\", \"15755872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of LPP-Scrib interaction not established at this stage\", \"Endogenous transcriptional targets still unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified LPP as a bona fide transcriptional coactivator of ETS factors and dissected its adhesion role, showing it coactivates PEA3/ER81, promotes cell-cell junction assembly via VASP, and is regulated by myocardin/RhoA-ROK in smooth muscle.\",\n      \"evidence\": \"Co-IP, ChIP on endogenous promoters, reporter assays with knockdown/overexpression; adhesion assays with domain mutants; myocardin overexpression and ROK inhibition with migration assays\",\n      \"pmids\": [\"16738319\", \"16613855\", \"16397143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ETS target genes not yet defined\", \"How nuclear vs adhesion pools are partitioned during signaling unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected LPP to noncanonical Wnt/PCP signaling and refined its adhesion mechanism, showing zebrafish Lpp is required for convergence-extension downstream of Wnt11/ROK2 and cooperates with Scrib, and that its alpha-actinin binding site governs cell-contact function.\",\n      \"evidence\": \"Morpholino knockdown, epistasis with Wnt11/ROK2, Co-IP (zebrafish); domain fragment targeting and fractionation (alpha-actinin)\",\n      \"pmids\": [\"18582857\", \"18413140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PCP role generalizes to mammals not tested\", \"Direct transcriptional vs cytoskeletal contribution to C&E not separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an unexpected nuclear genome-protective role, showing LPP associates with shelterin (POT1/TRF2/TIN2) at telomeres and is required to prevent telomere dysfunction, with specificity for LPP over zyxin.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP with shelterin components, ChIP, siRNA with TIF assay; immunofluorescence at telomeres\",\n      \"pmids\": [\"20634563\", \"21519191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of telomere protection by LPP unresolved\", \"How LPP is recruited to only a subset of telomeres unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked LPP-ETS cooperation to cancer invasion, identifying ETV5 as a regulatory partner promoting EMT and invasion and showing TGFbeta induces LPP through ROK in smooth muscle progenitors.\",\n      \"evidence\": \"Interaction/Co-IP studies and migration/invasion assays (ETV5); ROK inhibition, siRNA, migration assays (SMPC)\",\n      \"pmids\": [\"22266854\", \"22886954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ETV5/LPP target genes not identified at this stage\", \"TGFbeta-ROK-LPP link in SMPCs is a single low-confidence study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a mechanistic basis for LPP-driven invasion, showing TGFbeta relocalizes LPP to focal adhesions where its alpha-actinin interaction is required for adhesion turnover, migration, and invasion.\",\n      \"evidence\": \"siRNA, live-cell FRAP/TIRF imaging of focal adhesion turnover, Co-IP, alpha-actinin-disrupting domain mutants, invasion assays\",\n      \"pmids\": [\"23447672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream TGFbeta signal that triggers relocalization not fully defined\", \"Relationship between nuclear and adhesion pools during invasion unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a direct transcriptional output of LPP, showing LPP/ETV5 directly drive MMP-15 transcription, with MMP-15 cleaving N-cadherin to restrain collective migration and dissemination.\",\n      \"evidence\": \"siRNA, MMP-15 promoter reporter, 3D invasion assay, orthotopic mouse model, N-cadherin cleavage Western blot\",\n      \"pmids\": [\"26028032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependent suppressive vs promoting roles of LPP not reconciled\", \"Whether MMP-15 is the sole relevant target unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the post-translational and microenvironmental control of LPP-driven metastasis, showing Src phosphorylates LPP at Y245/301/302 to drive invadopodia and metastasis, and that CAF-derived signals upregulate endothelial LPP to control vascular permeability.\",\n      \"evidence\": \"Phospho-site Y->F mutants, LIM/alpha-actinin domain mutants, intravital chick CAM imaging, mouse metastasis model; CAF/MFAP5-FAK-ERK pathway inhibition, in vivo siRNA, permeability assays\",\n      \"pmids\": [\"28436416\", \"29251630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase-substrate stoichiometry and dynamics of Src phosphorylation not resolved\", \"How phosphorylation alters LPP partner binding mechanistically unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established how LPP abundance is controlled, identifying a UBE2S/TRIM21 complex that adds K11-linked polyubiquitin to drive LPP degradation and promote bladder cancer lymphatic metastasis.\",\n      \"evidence\": \"Co-IP, linkage-specific (K11/K48/K63) ubiquitination assays, siRNA rescue epistasis, in vivo metastasis model, patient organoids\",\n      \"pmids\": [\"37422473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site(s) on LPP not mapped\", \"Whether the same axis operates outside bladder cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LPP integrates its adhesion-scaffolding, ETS-coactivator, and telomere-protective activities into a single regulated program — and what governs partitioning between these pools — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LPP bound to its partners\", \"Mechanism coupling adhesion-localized to nuclear function not defined\", \"Telomere-protection mechanism uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 5, 6, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 10, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [1, 2, 3, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 18, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\"shelterin\"],\n    \"partners\": [\"VASP\", \"ACTN1\", \"SCRIB\", \"ETV5\", \"POT1\", \"TRF2\", \"TIN2\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}