{"gene":"LPXN","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2007,"finding":"LPXN associates with Pyk2, c-Src, and PTP-PEST in prostate cancer (PC-3) cells to form a signaling complex that regulates cell migration; siRNA-mediated knockdown of LPXN decreased PC-3 migration, overexpression of LPXN increased Rho GTPase activity and migration, and overexpression of PTP-PEST decreased Pyk2/c-Src association with LPXN and reduced migration.","method":"Co-immunoprecipitation, siRNA knockdown, adenoviral overexpression, in vitro Transwell migration assay, Rho GTPase activity assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional migration assays, single lab, multiple orthogonal methods","pmids":["17329398"],"is_preprint":false},{"year":2007,"finding":"LPXN is tyrosine-phosphorylated by Lyn exclusively at Tyr72 (adjacent to the LD3 domain) upon BCR stimulation in B cells; LPXN's LD3 domain mediates binding to Lyn; LPXN overexpression suppresses BCR-induced JNK, p38 MAPK, and Akt activation but not ERK or NFκB, and suppresses IL-2 secretion; the Y72F mutant abrogates this inhibitory function, demonstrating Tyr72 phosphorylation is required for LPXN's inhibitory role in BCR signaling.","method":"Serial truncation and domain deletion mutagenesis, site-directed mutagenesis (Y72F, Y22F, Y198F, Y257F), overexpression in A20 B lymphoma cells, kinase assay, Co-immunoprecipitation, western blot, IL-2 ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with functional readout and multiple orthogonal methods (domain mapping, kinase assay, functional assays), single lab","pmids":["17640867"],"is_preprint":false},{"year":2006,"finding":"LPXN associates with Src in osteoclasts; overexpression of LPXN in murine osteoclasts enhanced resorptive activity and cell adhesion; increased Pyk2 and Src co-immunoprecipitated with LPXN upon LPXN overexpression; TNF-alpha treatment further increased Src-LPXN association; LPXN scaffolds a podosomal signaling complex including Pyk2, PTP-PEST, and Src.","method":"Co-immunoprecipitation screen, in vitro resorption assay, cell adhesion assay, adenoviral overexpression","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional resorption/adhesion assays, single lab, multiple orthogonal methods","pmids":["16914530"],"is_preprint":false},{"year":2009,"finding":"In an AML patient with t(11;21)(q12;q22), LPXN is fused to RUNX1 generating RUNX1/LPXN and LPXN/RUNX1 chimeric proteins; RUNX1/LPXN fusion proteins (RL, RLs) localize to the nucleus, recruit CBFB into the nucleus, and inhibit RUNX1-mediated transactivation of the CSF1R promoter; the LPXN/RUNX1 fusion (LR) localizes to the cytoplasm; wild-type LPXN and all fusion proteins confer NIH3T3 cells with malignant transformation (colony formation, tumor growth in nude mice).","method":"Fluorescence microscopy (localization), luciferase reporter assay (CSF1R promoter), co-immunoprecipitation (CBFB), soft agar colony assay, xenograft mouse model, RT-PCR","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (reporter, localization, transformation), single lab","pmids":["19760607"],"is_preprint":false},{"year":2009,"finding":"LPXN overexpression in TRAMP prostate cancer mice enhanced PCa progression and metastasis; LPXN overexpression downregulates p120catenin (p120CTN) expression, causing nuclear accumulation of beta-catenin and increased MMP-7 transcription; siRNA knockdown of LPXN restored membranous beta-catenin localization; p120CTN knockdown phenocopied LPXN overexpression with nuclear beta-catenin accumulation.","method":"Transgenic mouse model (LPXN/TRAMP double transgenic), siRNA knockdown, immunofluorescence, western blot, luciferase reporter (MMP-7 promoter), in vitro migration/invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model plus multiple in vitro mechanistic assays, single lab, multiple orthogonal methods","pmids":["19701244"],"is_preprint":false},{"year":2010,"finding":"LIM3 domain is the primary focal adhesion (FA) targeting domain for LPXN; bombesin/GRPr activation stimulates LPXN translocation from cytoplasm to FAs and induces tyrosine phosphorylation at Y22, Y62, and Y72; a LIM3 point mutant fails to target FAs and shows no BN-stimulated phosphorylation; the non-phosphorylatable Y22/62/72F mutant still translocates to FAs, demonstrating FA localization is required for phosphorylation but not vice versa; LPXN and paxillin have opposite roles in cell adhesion to collagen I — LPXN siRNA stimulates adhesion while paxillin siRNA inhibits it; LPXN regulates cell spreading on collagen I but not fibronectin.","method":"Mutagenesis (LIM3 point mutant, Y22/62/72F), siRNA knockdown, live-cell imaging/immunofluorescence, cell adhesion assay, cell spreading assay, bombesin stimulation","journal":"Cell adhesion & migration","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with functional readout and multiple orthogonal assays (localization, phosphorylation, adhesion, spreading), single lab","pmids":["20543562"],"is_preprint":false},{"year":2015,"finding":"LPXN interacts with the actin-binding protein caldesmon (CaD) in prostate cancer cells; this interaction is increased during migration; LPXN knockdown does not affect CaD expression but reduces CaD phosphorylation; LPXN promotes CaD phosphorylation by recruiting ERK; decreased CaD phosphorylation destabilizes CaD-F-actin affinity and enables cell motility; TAK1 expression is decreased after LPXN knockdown, placing TAK1 upstream in the LPXN-ERK-CaD axis.","method":"Co-immunoprecipitation, siRNA knockdown, antibody array, western blot, in vitro migration/invasion assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional migration assay and antibody array, single lab, multiple orthogonal methods","pmids":["26079947"],"is_preprint":false},{"year":2015,"finding":"ETV6-LPXN fusion transcript (ETV6 exon 4 fused to LPXN exon 2) arises from t(11;12)(q12.1;p13) in relapsing AML; ETV6-LPXN does not confer IL-3 independence in 32D cells but enhances proliferative response to G-CSF without blocking granulocytic differentiation; 32D and human leukemia cell lines expressing ETV6-LPXN show enhanced migration toward CXCL12.","method":"3'-RACE PCR, FISH, retroviral transduction of 32D cells, proliferation assay, Transwell migration assay (CXCL12 chemotaxis)","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assays with transduced fusion protein, single lab, multiple readouts","pmids":["26542893"],"is_preprint":false},{"year":2020,"finding":"Kindlin-3 directly interacts with LPXN (and paxillin) via G43/L47 within its F0 domain, as determined by NMR spectroscopy; disruption of Kindlin-3-PXN/LPXN interactions in Raw 264.7 macrophages promoted cell spreading, polarization, general motility, directed migration, transition from mesenchymal to amoeboid movement, and augmented phagocytosis — in contrast to the defects seen with Kindlin-3 knockout — indicating that the Kindlin-3–LPXN/PXN link limits myeloid cell motility and phagocytosis.","method":"NMR spectroscopy, mutagenesis (G43/L47 disruption), macrophage functional assays (spreading, migration, phagocytosis), genetic loss-of-function comparison","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural determination of interaction combined with mutagenesis and multiple functional cellular assays, single lab","pmids":["32094207"],"is_preprint":false},{"year":2022,"finding":"PTK2B (Pyk2) phosphorylates LPXN in FLT3-mutated AML cells undergoing TKI resistance; LPXN and PTK2B are co-induced during early TKI resistance development; PTK2B/FAK inhibition abrogates resistance-associated phenotypes including enhanced cell migration; LPXN and PTK2B are highly expressed in leukemic stem cells from FLT3-ITD patients.","method":"Multilayered proteome analysis, nascent proteomics, PTK2B/FAK pharmacological inhibition, xenograft mouse model, cell migration assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus pharmacological inhibition with in vivo xenograft validation, single lab","pmids":["36056084"],"is_preprint":false},{"year":2017,"finding":"LPXN overexpression in THP-1 cells (human acute monocytic leukemia) promotes proliferation via ERK upregulation, promotes adhesion to fibronectin via upregulation of integrin α4/β1 and α5/β1 complexes, and promotes invasion via MMP-2 activation.","method":"Lentiviral overexpression, CCK-8 proliferation assay, adhesion assay, Transwell invasion assay, western blot, gelatin zymography","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression only with western blot, no rescue or mutagenesis","pmids":["28641616"],"is_preprint":false},{"year":2018,"finding":"In SHI-1 acute monocytic leukemia cells, siRNA-mediated LPXN knockdown inhibits proliferation, decreases transmembrane invasion, reduces MMP-2 and MMP-9 secretion, and activates p38 MAPK and JNK signaling, but does not affect p-ERK levels, placing LPXN upstream of JNK/p38 MAPK and MMP-2/9 in this context.","method":"siRNA transfection, CCK-8 proliferation assay, Transwell invasion assay, western blot, gelatin zymography","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach without rescue experiment","pmids":["30655748"],"is_preprint":false},{"year":2018,"finding":"LPXN promotes bladder cancer cell proliferation, invasion, and angiogenesis; these effects are abolished by PI3K/AKT pathway inhibition; LPXN upregulates S100P expression via the PI3K/AKT pathway.","method":"Overexpression and siRNA knockdown, western blot, PI3K/AKT inhibitor treatment, in vitro and in vivo functional assays","journal":"Cellular physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inhibitor used but no direct binding or epistasis experiment for PI3K/AKT placement","pmids":["29975926"],"is_preprint":false},{"year":2023,"finding":"LPXN and Hic-5 (paxillin family members) stabilize the lipid droplet-associated protein CIDEC by reducing its ubiquitination and inhibiting proteasomal degradation, thereby enlarging lipid droplets and promoting lipid storage in adipocytes; this effect is independent of triacylglycerol synthesis and FAK signaling pathways.","method":"HTRF-based high-throughput screening, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, lipid droplet imaging, adipocyte functional assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assay plus co-IP and functional cell imaging, single lab, multiple orthogonal methods","pmids":["38159847"],"is_preprint":false},{"year":2024,"finding":"LPXN acts as a coactivator for HNF4α to regulate hepatic gluconeogenesis; LPXN interacts with HNF4α (identified by pull-down and mass spectrometry); LPXN translocates into the nucleus and binds the PEPCK promoter (confirmed by CUT&Tag and ChIP-qPCR); LPXN-mediated regulation of gluconeogenesis proceeds mainly through the Gcg-cAMP-PKA pathway; liver-specific knockdown of LPXN enhances glucose metabolism, while overexpression inhibits it in mice and primary hepatocytes.","method":"Protein pull-down, mass spectrometry, luciferase reporter assay, CUT&Tag, ChIP-qPCR, adenoviral overexpression and AAV-shRNA knockdown in vivo (ob/db/DIO mice), primary hepatocyte culture","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — pull-down + MS identification, ChIP/CUT&Tag for direct promoter binding, in vivo mouse models with multiple genetic tools, single lab but multiple orthogonal methods","pmids":["39603504"],"is_preprint":false},{"year":2025,"finding":"HLF transcription factor (epigenetically silenced by BRG1/SWI/SNF) negatively regulates LPXN expression; HLF depletion upregulates LPXN, which modulates integration of collagen mechanical cues with the actin cytoskeleton through Paxillin, thereby promoting cancer cell migration and lung metastasis; HLF overexpression abrogates these effects.","method":"In vivo CRISPR-Cas9 genome-wide screen, overexpression and knockdown (HLF, LPXN), cell migration assay (collagen), xenograft lung metastasis model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus functional validation with in vivo metastasis model, single lab, mechanistic placement via genetic epistasis","pmids":["40473600"],"is_preprint":false},{"year":2025,"finding":"LPXN promotes breast cancer progression by enhancing macrophage M2 polarization through a LPXN/HDAC6/EGR2 axis: LPXN overexpression in breast cancer correlates with M2 macrophage markers; siRNA silencing of LPXN in macrophages reduces HDAC6 expression; HDAC6 interacts with EGR2 and functions as its deacetylase, negatively regulating EGR2 expression; HDAC6 inhibition partially reverses pro-M2 effects of LPXN overexpression; EGR2 silencing attenuates the anti-M2 effects of LPXN knockdown.","method":"siRNA silencing, co-culture (breast cancer cells + macrophages), western blot, co-immunoprecipitation (HDAC6-EGR2), HDAC6 inhibitor treatment, murine breast cancer model","journal":"Cell biology and toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic chain relies on sequential knockdown/inhibitor without direct biochemical reconstitution of full axis","pmids":["41286384"],"is_preprint":false},{"year":2020,"finding":"Lpxn deficiency in mice leads to decreased B cell differentiation into plasma cells in vitro, but Lpxn is dispensable for T-dependent and T-independent B cell immune responses in vivo, indicating that in vivo BCR signaling can proceed normally without Lpxn.","method":"Lpxn knockout mouse model, in vitro B cell differentiation assay, in vivo immunization (T-dependent and T-independent antigens), ELISA for antibody titers","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with in vivo and in vitro functional readouts, single lab","pmids":["32269569"],"is_preprint":false}],"current_model":"LPXN (leupaxin) is a focal adhesion adaptor protein of the paxillin superfamily that scaffolds signaling complexes containing Pyk2, Src, and PTP-PEST at podosomes/focal adhesions to regulate cell migration, adhesion, and cytoskeletal dynamics; its LIM3 domain mediates FA targeting, its LD3 domain binds Lyn (phosphorylating it at Tyr72 to suppress BCR signaling), and it interacts with Kindlin-3 (via G43/L47) to limit myeloid cell motility and phagocytosis; in cancer contexts LPXN promotes invasion through ERK-mediated caldesmon phosphorylation, p120catenin downregulation/nuclear beta-catenin accumulation, and PI3K/AKT pathway activation; it also stabilizes CIDEC to promote lipid storage, and acts as a nuclear coactivator for HNF4α to drive hepatic gluconeogenesis via the PEPCK promoter, placing it as a multifunctional adaptor that shuttles between focal adhesions and the nucleus to integrate extracellular mechanical signals with transcriptional and metabolic outputs."},"narrative":{"mechanistic_narrative":"LPXN (leupaxin) is a paxillin-family adaptor protein that scaffolds tyrosine-kinase signaling complexes at podosomes and focal adhesions to control cell adhesion, migration, and cytoskeletal dynamics [PMID:17329398, PMID:16914530]. It assembles a complex with the kinases Pyk2 and c-Src and the phosphatase PTP-PEST, which tunes Pyk2/Src association and downstream Rho GTPase activity and migratory behavior [PMID:17329398, PMID:16914530]. Its LIM3 domain is the principal focal-adhesion targeting module, and GPCR (bombesin/GRPr) stimulation drives LPXN translocation from the cytoplasm to focal adhesions where it is tyrosine-phosphorylated at Y22, Y62, and Y72; focal-adhesion localization is required for, but is upstream of, this phosphorylation [PMID:20543562]. In B cells, Lyn binds the LD3 region and phosphorylates LPXN exclusively at Tyr72, and this modification is required for LPXN to suppress BCR-induced JNK, p38, and Akt signaling [PMID:17640867]. Structurally, Kindlin-3 directly engages LPXN through residues G43/L47 in its F0 domain, and this interaction restrains myeloid-cell spreading, motility, mesenchymal-to-amoeboid transition, and phagocytosis [PMID:32094207]. In cancer, LPXN promotes invasion and metastasis through multiple convergent routes: it recruits ERK to phosphorylate caldesmon and weaken its actin association [PMID:26079947], downregulates p120-catenin to drive nuclear beta-catenin accumulation and MMP-7 transcription [PMID:19701244], and integrates collagen mechanical cues with the actin cytoskeleton via paxillin under negative control by the HLF transcription factor [PMID:40473600]. Beyond adhesion, LPXN moonlights in metabolism, stabilizing the lipid-droplet protein CIDEC by blocking its ubiquitin-proteasomal degradation to promote adipocyte lipid storage [PMID:38159847], and acting as a nuclear coactivator that binds HNF4alpha and the PEPCK promoter to drive hepatic gluconeogenesis through the Gcg-cAMP-PKA pathway [PMID:39603504]. LPXN is recurrently involved in AML through RUNX1 and ETV6 gene fusions and through Pyk2-driven signaling in FLT3-mutant leukemic stem cells [PMID:19760607, PMID:26542893, PMID:36056084].","teleology":[{"year":2006,"claim":"Established that LPXN functions as a scaffold for a podosomal kinase/phosphatase complex, addressing what role this paxillin homolog plays in bone-resorbing cells.","evidence":"Co-IP screen and resorption/adhesion assays with adenoviral overexpression in murine osteoclasts","pmids":["16914530"],"confidence":"Medium","gaps":["Did not map the domains mediating Pyk2/Src/PTP-PEST assembly","Direct vs indirect nature of each interaction not resolved"]},{"year":2007,"claim":"Defined the LPXN-Pyk2-Src-PTP-PEST complex as a migration regulator in cancer and showed PTP-PEST antagonizes complex assembly, linking LPXN to Rho GTPase output.","evidence":"Reciprocal Co-IP, siRNA knockdown, overexpression, Transwell migration and Rho GTPase activity assays in PC-3 cells","pmids":["17329398"],"confidence":"Medium","gaps":["Mechanism by which PTP-PEST displaces Pyk2/Src from LPXN unresolved","Which Rho GTPase effector pathway is engaged not defined"]},{"year":2007,"claim":"Identified LPXN as a negative regulator of BCR signaling, mapping Lyn binding to LD3 and the single required phosphosite Tyr72.","evidence":"Domain-deletion and site-directed mutagenesis (Y72F), kinase assay, Co-IP and IL-2 ELISA in A20 B lymphoma cells","pmids":["17640867"],"confidence":"High","gaps":["Downstream effectors connecting pTyr72-LPXN to JNK/p38/Akt suppression not identified","Selectivity for JNK/p38/Akt over ERK/NFkB unexplained"]},{"year":2009,"claim":"Connected LPXN to AML pathogenesis via a RUNX1 fusion and showed both wild-type and fusion proteins are transforming, while RUNX1/LPXN sequesters CBFB and represses CSF1R transactivation.","evidence":"Localization microscopy, CSF1R luciferase reporter, CBFB Co-IP, soft agar and xenograft assays in NIH3T3","pmids":["19760607"],"confidence":"Medium","gaps":["Mechanism of wild-type LPXN transformation not dissected","Patient-level recurrence of the fusion not established"]},{"year":2009,"claim":"Demonstrated in vivo that LPXN drives prostate cancer metastasis via p120-catenin downregulation, nuclear beta-catenin accumulation, and MMP-7 induction.","evidence":"LPXN/TRAMP double-transgenic mice, siRNA, immunofluorescence, MMP-7 reporter and invasion assays","pmids":["19701244"],"confidence":"High","gaps":["Molecular link between LPXN and p120-catenin downregulation not identified","Whether nuclear LPXN itself participates not addressed here"]},{"year":2010,"claim":"Mapped LIM3 as the focal-adhesion targeting domain and ordered the events: FA localization precedes and is required for GPCR-stimulated Tyr phosphorylation, while LPXN opposes paxillin in collagen adhesion.","evidence":"LIM3 and Y22/62/72F mutagenesis, siRNA, live-cell imaging, adhesion and spreading assays with bombesin stimulation","pmids":["20543562"],"confidence":"High","gaps":["Identity of the FA receptor/anchor for LIM3 unknown","Substrate basis for opposite LPXN/paxillin adhesion roles unclear"]},{"year":2015,"claim":"Defined a TAK1-LPXN-ERK-caldesmon axis whereby LPXN recruits ERK to phosphorylate caldesmon, weakening its actin affinity to enable motility.","evidence":"Co-IP, siRNA, antibody array, migration/invasion assays in prostate cancer cells","pmids":["26079947"],"confidence":"Medium","gaps":["Direct vs scaffolded ERK-caldesmon phosphorylation not separated","TAK1 placement upstream is correlative"]},{"year":2015,"claim":"Showed an ETV6-LPXN fusion in relapsing AML enhances G-CSF-driven proliferation and CXCL12 chemotaxis without blocking differentiation.","evidence":"3'-RACE, FISH, retroviral 32D transduction, proliferation and CXCL12 Transwell assays","pmids":["26542893"],"confidence":"Medium","gaps":["Which LPXN domains the fusion retains for function not dissected","No in vivo leukemogenesis test of the fusion"]},{"year":2017,"claim":"Reported that LPXN overexpression promotes monocytic leukemia proliferation, integrin-mediated fibronectin adhesion, and MMP-2-driven invasion.","evidence":"Lentiviral overexpression, proliferation/adhesion/invasion assays, western blot, zymography in THP-1 cells","pmids":["28641616"],"confidence":"Low","gaps":["Overexpression only without rescue or mutagenesis","Direct vs indirect regulation of integrins and MMP-2 unestablished"]},{"year":2018,"claim":"Placed LPXN upstream of JNK/p38 MAPK and MMP-2/9 in monocytic leukemia invasion, while finding ERK unaffected, contrasting with prior contexts.","evidence":"siRNA, proliferation/invasion assays, western blot, zymography in SHI-1 cells","pmids":["30655748"],"confidence":"Low","gaps":["Single knockdown approach without rescue","Context-dependent ERK independence unexplained"]},{"year":2018,"claim":"Linked LPXN to bladder cancer proliferation, invasion, and angiogenesis through PI3K/AKT-dependent S100P upregulation.","evidence":"Overexpression/knockdown, PI3K/AKT inhibitor, western blot, in vitro and in vivo assays","pmids":["29975926"],"confidence":"Low","gaps":["No direct binding or epistasis placing LPXN in PI3K/AKT","S100P as direct vs indirect target not resolved"]},{"year":2020,"claim":"Provided a structural basis for LPXN regulation by myeloid cells, showing Kindlin-3 directly binds LPXN via F0 G43/L47 to restrain macrophage motility and phagocytosis.","evidence":"NMR spectroscopy, G43/L47 mutagenesis, macrophage spreading/migration/phagocytosis assays vs Kindlin-3 knockout","pmids":["32094207"],"confidence":"High","gaps":["Which LPXN surface contacts Kindlin-3 not mapped","How this link integrates with the Pyk2/Src complex unknown"]},{"year":2020,"claim":"Tested the in vivo requirement for Lpxn in B-cell immunity, revealing it is dispensable for antibody responses despite an in vitro plasma-cell differentiation defect.","evidence":"Lpxn knockout mice, in vitro differentiation, T-dependent/independent immunization, antibody ELISA","pmids":["32269569"],"confidence":"Medium","gaps":["Redundancy with paxillin/Hic-5 in vivo not tested","Reconciliation with cell-intrinsic BCR-suppressive role unresolved"]},{"year":2022,"claim":"Connected LPXN to therapy resistance, showing Pyk2 (PTK2B) phosphorylates LPXN during FLT3-TKI resistance and that both are enriched in leukemic stem cells.","evidence":"Multilayered/nascent proteomics, PTK2B/FAK inhibition, xenograft, migration assays","pmids":["36056084"],"confidence":"Medium","gaps":["LPXN phosphosites in this context not mapped","Causal contribution of LPXN phosphorylation to resistance not isolated"]},{"year":2023,"claim":"Revealed a non-adhesion metabolic function: LPXN stabilizes CIDEC by inhibiting its ubiquitin-proteasomal degradation to promote lipid storage, independent of FAK and TAG synthesis.","evidence":"HTRF screen, Co-IP, ubiquitination assay, proteasome inhibition, lipid droplet imaging in adipocytes","pmids":["38159847"],"confidence":"Medium","gaps":["How LPXN shields CIDEC from the ubiquitin machinery mechanistically unclear","Which E3 ligase LPXN antagonizes not identified"]},{"year":2024,"claim":"Established LPXN as a nuclear coactivator for HNF4alpha that binds the PEPCK promoter to drive hepatic gluconeogenesis, defining a transcriptional/metabolic role distinct from focal adhesions.","evidence":"Pull-down/MS, luciferase reporter, CUT&Tag, ChIP-qPCR, in vivo AAV/adenoviral manipulation in ob/db/DIO mice and hepatocytes","pmids":["39603504"],"confidence":"High","gaps":["Signal triggering LPXN nuclear translocation in hepatocytes unknown","How adhesion-associated phosphorylation relates to nuclear function unresolved"]},{"year":2025,"claim":"Positioned LPXN downstream of HLF/BRG1 epigenetic control as a mediator that couples collagen mechanical cues to the actin cytoskeleton via paxillin to drive metastasis.","evidence":"In vivo CRISPR-Cas9 screen, HLF/LPXN overexpression and knockdown, collagen migration assay, lung metastasis xenografts","pmids":["40473600"],"confidence":"Medium","gaps":["Direct LPXN-paxillin mechanochemical coupling not biochemically reconstituted","Whether HLF regulates LPXN directly not established"]},{"year":2025,"claim":"Proposed an immunomodulatory route in which LPXN promotes M2 macrophage polarization through an HDAC6/EGR2 deacetylation axis to support breast cancer progression.","evidence":"siRNA, co-culture, Co-IP (HDAC6-EGR2), HDAC6 inhibitor, murine breast cancer model","pmids":["41286384"],"confidence":"Low","gaps":["Full axis not reconstituted biochemically; relies on sequential knockdown/inhibitor","Direct LPXN-HDAC6 link not demonstrated"]},{"year":null,"claim":"It remains unknown how LPXN's signal-dependent partitioning between focal adhesions and the nucleus is controlled and whether its adhesion-associated phosphorylation governs its transcriptional and metabolic functions.","evidence":"No timeline discovery directly tests the trigger or coordination of LPXN cytoplasm-to-nucleus shuttling across its diverse roles","pmids":[],"confidence":"Low","gaps":["No unifying mechanism linking FA phosphorylation to nuclear coactivator activity","No structural model of the full-length protein in distinct compartments","Tissue-specific partner switching not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[14,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,14]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,3,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,17]}],"complexes":["Pyk2-Src-PTP-PEST podosomal/focal adhesion complex"],"partners":["PTK2B","SRC","PTPN12","LYN","FERMT3","PXN","HNF4A","CIDEC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60711","full_name":"Leupaxin","aliases":[],"length_aa":386,"mass_kda":43.3,"function":"Transcriptional coactivator for androgen receptor (AR) and serum response factor (SRF). Contributes to the regulation of cell adhesion, spreading and cell migration and acts as a negative regulator in integrin-mediated cell adhesion events. Suppresses the integrin-induced tyrosine phosphorylation of paxillin (PXN). May play a critical role as an adapter protein in the formation of the adhesion zone in osteoclasts. Negatively regulates B-cell antigen receptor (BCR) signaling","subcellular_location":"Cytoplasm; Cell junction, focal adhesion; Nucleus; Cytoplasm, perinuclear region; Cell projection, podosome; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60711/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LPXN","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":[],"url":"https://opencell.sf.czbiohub.org/search/LPXN","total_profiled":1310},"omim":[{"mim_id":"605390","title":"LEUPAXIN; LPXN","url":"https://www.omim.org/entry/605390"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":111.0}],"url":"https://www.proteinatlas.org/search/LPXN"},"hgnc":{"alias_symbol":["LDPL"],"prev_symbol":[]},"alphafold":{"accession":"O60711","domains":[{"cath_id":"2.10.110.10","chopping":"149-208","consensus_level":"medium","plddt":91.3558,"start":149,"end":208},{"cath_id":"2.10.110.10","chopping":"210-267","consensus_level":"high","plddt":92.9334,"start":210,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60711","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60711-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60711-F1-predicted_aligned_error_v6.png","plddt_mean":76.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LPXN","jax_strain_url":"https://www.jax.org/strain/search?query=LPXN"},"sequence":{"accession":"O60711","fasta_url":"https://rest.uniprot.org/uniprotkb/O60711.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60711/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60711"}},"corpus_meta":[{"pmid":"21463610","id":"PMC_21463610","title":"Identification of NDRG1-regulated genes associated with invasive potential in cervical and ovarian cancer cells.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21463610","citation_count":43,"is_preprint":false},{"pmid":"23349640","id":"PMC_23349640","title":"Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23349640","citation_count":41,"is_preprint":false},{"pmid":"17329398","id":"PMC_17329398","title":"Interaction of Pyk2 and PTP-PEST with leupaxin in prostate cancer cells.","date":"2007","source":"American journal of physiology. 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Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional migration assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17329398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LPXN is tyrosine-phosphorylated by Lyn exclusively at Tyr72 (adjacent to the LD3 domain) upon BCR stimulation in B cells; LPXN's LD3 domain mediates binding to Lyn; LPXN overexpression suppresses BCR-induced JNK, p38 MAPK, and Akt activation but not ERK or NFκB, and suppresses IL-2 secretion; the Y72F mutant abrogates this inhibitory function, demonstrating Tyr72 phosphorylation is required for LPXN's inhibitory role in BCR signaling.\",\n      \"method\": \"Serial truncation and domain deletion mutagenesis, site-directed mutagenesis (Y72F, Y22F, Y198F, Y257F), overexpression in A20 B lymphoma cells, kinase assay, Co-immunoprecipitation, western blot, IL-2 ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with functional readout and multiple orthogonal methods (domain mapping, kinase assay, functional assays), single lab\",\n      \"pmids\": [\"17640867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LPXN associates with Src in osteoclasts; overexpression of LPXN in murine osteoclasts enhanced resorptive activity and cell adhesion; increased Pyk2 and Src co-immunoprecipitated with LPXN upon LPXN overexpression; TNF-alpha treatment further increased Src-LPXN association; LPXN scaffolds a podosomal signaling complex including Pyk2, PTP-PEST, and Src.\",\n      \"method\": \"Co-immunoprecipitation screen, in vitro resorption assay, cell adhesion assay, adenoviral overexpression\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional resorption/adhesion assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16914530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In an AML patient with t(11;21)(q12;q22), LPXN is fused to RUNX1 generating RUNX1/LPXN and LPXN/RUNX1 chimeric proteins; RUNX1/LPXN fusion proteins (RL, RLs) localize to the nucleus, recruit CBFB into the nucleus, and inhibit RUNX1-mediated transactivation of the CSF1R promoter; the LPXN/RUNX1 fusion (LR) localizes to the cytoplasm; wild-type LPXN and all fusion proteins confer NIH3T3 cells with malignant transformation (colony formation, tumor growth in nude mice).\",\n      \"method\": \"Fluorescence microscopy (localization), luciferase reporter assay (CSF1R promoter), co-immunoprecipitation (CBFB), soft agar colony assay, xenograft mouse model, RT-PCR\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (reporter, localization, transformation), single lab\",\n      \"pmids\": [\"19760607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPXN overexpression in TRAMP prostate cancer mice enhanced PCa progression and metastasis; LPXN overexpression downregulates p120catenin (p120CTN) expression, causing nuclear accumulation of beta-catenin and increased MMP-7 transcription; siRNA knockdown of LPXN restored membranous beta-catenin localization; p120CTN knockdown phenocopied LPXN overexpression with nuclear beta-catenin accumulation.\",\n      \"method\": \"Transgenic mouse model (LPXN/TRAMP double transgenic), siRNA knockdown, immunofluorescence, western blot, luciferase reporter (MMP-7 promoter), in vitro migration/invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model plus multiple in vitro mechanistic assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19701244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LIM3 domain is the primary focal adhesion (FA) targeting domain for LPXN; bombesin/GRPr activation stimulates LPXN translocation from cytoplasm to FAs and induces tyrosine phosphorylation at Y22, Y62, and Y72; a LIM3 point mutant fails to target FAs and shows no BN-stimulated phosphorylation; the non-phosphorylatable Y22/62/72F mutant still translocates to FAs, demonstrating FA localization is required for phosphorylation but not vice versa; LPXN and paxillin have opposite roles in cell adhesion to collagen I — LPXN siRNA stimulates adhesion while paxillin siRNA inhibits it; LPXN regulates cell spreading on collagen I but not fibronectin.\",\n      \"method\": \"Mutagenesis (LIM3 point mutant, Y22/62/72F), siRNA knockdown, live-cell imaging/immunofluorescence, cell adhesion assay, cell spreading assay, bombesin stimulation\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with functional readout and multiple orthogonal assays (localization, phosphorylation, adhesion, spreading), single lab\",\n      \"pmids\": [\"20543562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LPXN interacts with the actin-binding protein caldesmon (CaD) in prostate cancer cells; this interaction is increased during migration; LPXN knockdown does not affect CaD expression but reduces CaD phosphorylation; LPXN promotes CaD phosphorylation by recruiting ERK; decreased CaD phosphorylation destabilizes CaD-F-actin affinity and enables cell motility; TAK1 expression is decreased after LPXN knockdown, placing TAK1 upstream in the LPXN-ERK-CaD axis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, antibody array, western blot, in vitro migration/invasion assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional migration assay and antibody array, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26079947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ETV6-LPXN fusion transcript (ETV6 exon 4 fused to LPXN exon 2) arises from t(11;12)(q12.1;p13) in relapsing AML; ETV6-LPXN does not confer IL-3 independence in 32D cells but enhances proliferative response to G-CSF without blocking granulocytic differentiation; 32D and human leukemia cell lines expressing ETV6-LPXN show enhanced migration toward CXCL12.\",\n      \"method\": \"3'-RACE PCR, FISH, retroviral transduction of 32D cells, proliferation assay, Transwell migration assay (CXCL12 chemotaxis)\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assays with transduced fusion protein, single lab, multiple readouts\",\n      \"pmids\": [\"26542893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kindlin-3 directly interacts with LPXN (and paxillin) via G43/L47 within its F0 domain, as determined by NMR spectroscopy; disruption of Kindlin-3-PXN/LPXN interactions in Raw 264.7 macrophages promoted cell spreading, polarization, general motility, directed migration, transition from mesenchymal to amoeboid movement, and augmented phagocytosis — in contrast to the defects seen with Kindlin-3 knockout — indicating that the Kindlin-3–LPXN/PXN link limits myeloid cell motility and phagocytosis.\",\n      \"method\": \"NMR spectroscopy, mutagenesis (G43/L47 disruption), macrophage functional assays (spreading, migration, phagocytosis), genetic loss-of-function comparison\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural determination of interaction combined with mutagenesis and multiple functional cellular assays, single lab\",\n      \"pmids\": [\"32094207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTK2B (Pyk2) phosphorylates LPXN in FLT3-mutated AML cells undergoing TKI resistance; LPXN and PTK2B are co-induced during early TKI resistance development; PTK2B/FAK inhibition abrogates resistance-associated phenotypes including enhanced cell migration; LPXN and PTK2B are highly expressed in leukemic stem cells from FLT3-ITD patients.\",\n      \"method\": \"Multilayered proteome analysis, nascent proteomics, PTK2B/FAK pharmacological inhibition, xenograft mouse model, cell migration assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus pharmacological inhibition with in vivo xenograft validation, single lab\",\n      \"pmids\": [\"36056084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LPXN overexpression in THP-1 cells (human acute monocytic leukemia) promotes proliferation via ERK upregulation, promotes adhesion to fibronectin via upregulation of integrin α4/β1 and α5/β1 complexes, and promotes invasion via MMP-2 activation.\",\n      \"method\": \"Lentiviral overexpression, CCK-8 proliferation assay, adhesion assay, Transwell invasion assay, western blot, gelatin zymography\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression only with western blot, no rescue or mutagenesis\",\n      \"pmids\": [\"28641616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In SHI-1 acute monocytic leukemia cells, siRNA-mediated LPXN knockdown inhibits proliferation, decreases transmembrane invasion, reduces MMP-2 and MMP-9 secretion, and activates p38 MAPK and JNK signaling, but does not affect p-ERK levels, placing LPXN upstream of JNK/p38 MAPK and MMP-2/9 in this context.\",\n      \"method\": \"siRNA transfection, CCK-8 proliferation assay, Transwell invasion assay, western blot, gelatin zymography\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach without rescue experiment\",\n      \"pmids\": [\"30655748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LPXN promotes bladder cancer cell proliferation, invasion, and angiogenesis; these effects are abolished by PI3K/AKT pathway inhibition; LPXN upregulates S100P expression via the PI3K/AKT pathway.\",\n      \"method\": \"Overexpression and siRNA knockdown, western blot, PI3K/AKT inhibitor treatment, in vitro and in vivo functional assays\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inhibitor used but no direct binding or epistasis experiment for PI3K/AKT placement\",\n      \"pmids\": [\"29975926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LPXN and Hic-5 (paxillin family members) stabilize the lipid droplet-associated protein CIDEC by reducing its ubiquitination and inhibiting proteasomal degradation, thereby enlarging lipid droplets and promoting lipid storage in adipocytes; this effect is independent of triacylglycerol synthesis and FAK signaling pathways.\",\n      \"method\": \"HTRF-based high-throughput screening, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, lipid droplet imaging, adipocyte functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assay plus co-IP and functional cell imaging, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38159847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LPXN acts as a coactivator for HNF4α to regulate hepatic gluconeogenesis; LPXN interacts with HNF4α (identified by pull-down and mass spectrometry); LPXN translocates into the nucleus and binds the PEPCK promoter (confirmed by CUT&Tag and ChIP-qPCR); LPXN-mediated regulation of gluconeogenesis proceeds mainly through the Gcg-cAMP-PKA pathway; liver-specific knockdown of LPXN enhances glucose metabolism, while overexpression inhibits it in mice and primary hepatocytes.\",\n      \"method\": \"Protein pull-down, mass spectrometry, luciferase reporter assay, CUT&Tag, ChIP-qPCR, adenoviral overexpression and AAV-shRNA knockdown in vivo (ob/db/DIO mice), primary hepatocyte culture\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — pull-down + MS identification, ChIP/CUT&Tag for direct promoter binding, in vivo mouse models with multiple genetic tools, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39603504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HLF transcription factor (epigenetically silenced by BRG1/SWI/SNF) negatively regulates LPXN expression; HLF depletion upregulates LPXN, which modulates integration of collagen mechanical cues with the actin cytoskeleton through Paxillin, thereby promoting cancer cell migration and lung metastasis; HLF overexpression abrogates these effects.\",\n      \"method\": \"In vivo CRISPR-Cas9 genome-wide screen, overexpression and knockdown (HLF, LPXN), cell migration assay (collagen), xenograft lung metastasis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus functional validation with in vivo metastasis model, single lab, mechanistic placement via genetic epistasis\",\n      \"pmids\": [\"40473600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LPXN promotes breast cancer progression by enhancing macrophage M2 polarization through a LPXN/HDAC6/EGR2 axis: LPXN overexpression in breast cancer correlates with M2 macrophage markers; siRNA silencing of LPXN in macrophages reduces HDAC6 expression; HDAC6 interacts with EGR2 and functions as its deacetylase, negatively regulating EGR2 expression; HDAC6 inhibition partially reverses pro-M2 effects of LPXN overexpression; EGR2 silencing attenuates the anti-M2 effects of LPXN knockdown.\",\n      \"method\": \"siRNA silencing, co-culture (breast cancer cells + macrophages), western blot, co-immunoprecipitation (HDAC6-EGR2), HDAC6 inhibitor treatment, murine breast cancer model\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic chain relies on sequential knockdown/inhibitor without direct biochemical reconstitution of full axis\",\n      \"pmids\": [\"41286384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lpxn deficiency in mice leads to decreased B cell differentiation into plasma cells in vitro, but Lpxn is dispensable for T-dependent and T-independent B cell immune responses in vivo, indicating that in vivo BCR signaling can proceed normally without Lpxn.\",\n      \"method\": \"Lpxn knockout mouse model, in vitro B cell differentiation assay, in vivo immunization (T-dependent and T-independent antigens), ELISA for antibody titers\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with in vivo and in vitro functional readouts, single lab\",\n      \"pmids\": [\"32269569\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LPXN (leupaxin) is a focal adhesion adaptor protein of the paxillin superfamily that scaffolds signaling complexes containing Pyk2, Src, and PTP-PEST at podosomes/focal adhesions to regulate cell migration, adhesion, and cytoskeletal dynamics; its LIM3 domain mediates FA targeting, its LD3 domain binds Lyn (phosphorylating it at Tyr72 to suppress BCR signaling), and it interacts with Kindlin-3 (via G43/L47) to limit myeloid cell motility and phagocytosis; in cancer contexts LPXN promotes invasion through ERK-mediated caldesmon phosphorylation, p120catenin downregulation/nuclear beta-catenin accumulation, and PI3K/AKT pathway activation; it also stabilizes CIDEC to promote lipid storage, and acts as a nuclear coactivator for HNF4α to drive hepatic gluconeogenesis via the PEPCK promoter, placing it as a multifunctional adaptor that shuttles between focal adhesions and the nucleus to integrate extracellular mechanical signals with transcriptional and metabolic outputs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LPXN (leupaxin) is a paxillin-family adaptor protein that scaffolds tyrosine-kinase signaling complexes at podosomes and focal adhesions to control cell adhesion, migration, and cytoskeletal dynamics [#0, #2]. It assembles a complex with the kinases Pyk2 and c-Src and the phosphatase PTP-PEST, which tunes Pyk2/Src association and downstream Rho GTPase activity and migratory behavior [#0, #2]. Its LIM3 domain is the principal focal-adhesion targeting module, and GPCR (bombesin/GRPr) stimulation drives LPXN translocation from the cytoplasm to focal adhesions where it is tyrosine-phosphorylated at Y22, Y62, and Y72; focal-adhesion localization is required for, but is upstream of, this phosphorylation [#5]. In B cells, Lyn binds the LD3 region and phosphorylates LPXN exclusively at Tyr72, and this modification is required for LPXN to suppress BCR-induced JNK, p38, and Akt signaling [#1]. Structurally, Kindlin-3 directly engages LPXN through residues G43/L47 in its F0 domain, and this interaction restrains myeloid-cell spreading, motility, mesenchymal-to-amoeboid transition, and phagocytosis [#8]. In cancer, LPXN promotes invasion and metastasis through multiple convergent routes: it recruits ERK to phosphorylate caldesmon and weaken its actin association [#6], downregulates p120-catenin to drive nuclear beta-catenin accumulation and MMP-7 transcription [#4], and integrates collagen mechanical cues with the actin cytoskeleton via paxillin under negative control by the HLF transcription factor [#15]. Beyond adhesion, LPXN moonlights in metabolism, stabilizing the lipid-droplet protein CIDEC by blocking its ubiquitin-proteasomal degradation to promote adipocyte lipid storage [#13], and acting as a nuclear coactivator that binds HNF4alpha and the PEPCK promoter to drive hepatic gluconeogenesis through the Gcg-cAMP-PKA pathway [#14]. LPXN is recurrently involved in AML through RUNX1 and ETV6 gene fusions and through Pyk2-driven signaling in FLT3-mutant leukemic stem cells [#3, #7, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that LPXN functions as a scaffold for a podosomal kinase/phosphatase complex, addressing what role this paxillin homolog plays in bone-resorbing cells.\",\n      \"evidence\": \"Co-IP screen and resorption/adhesion assays with adenoviral overexpression in murine osteoclasts\",\n      \"pmids\": [\"16914530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the domains mediating Pyk2/Src/PTP-PEST assembly\", \"Direct vs indirect nature of each interaction not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the LPXN-Pyk2-Src-PTP-PEST complex as a migration regulator in cancer and showed PTP-PEST antagonizes complex assembly, linking LPXN to Rho GTPase output.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, overexpression, Transwell migration and Rho GTPase activity assays in PC-3 cells\",\n      \"pmids\": [\"17329398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PTP-PEST displaces Pyk2/Src from LPXN unresolved\", \"Which Rho GTPase effector pathway is engaged not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified LPXN as a negative regulator of BCR signaling, mapping Lyn binding to LD3 and the single required phosphosite Tyr72.\",\n      \"evidence\": \"Domain-deletion and site-directed mutagenesis (Y72F), kinase assay, Co-IP and IL-2 ELISA in A20 B lymphoma cells\",\n      \"pmids\": [\"17640867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors connecting pTyr72-LPXN to JNK/p38/Akt suppression not identified\", \"Selectivity for JNK/p38/Akt over ERK/NFkB unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected LPXN to AML pathogenesis via a RUNX1 fusion and showed both wild-type and fusion proteins are transforming, while RUNX1/LPXN sequesters CBFB and represses CSF1R transactivation.\",\n      \"evidence\": \"Localization microscopy, CSF1R luciferase reporter, CBFB Co-IP, soft agar and xenograft assays in NIH3T3\",\n      \"pmids\": [\"19760607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of wild-type LPXN transformation not dissected\", \"Patient-level recurrence of the fusion not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that LPXN drives prostate cancer metastasis via p120-catenin downregulation, nuclear beta-catenin accumulation, and MMP-7 induction.\",\n      \"evidence\": \"LPXN/TRAMP double-transgenic mice, siRNA, immunofluorescence, MMP-7 reporter and invasion assays\",\n      \"pmids\": [\"19701244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between LPXN and p120-catenin downregulation not identified\", \"Whether nuclear LPXN itself participates not addressed here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped LIM3 as the focal-adhesion targeting domain and ordered the events: FA localization precedes and is required for GPCR-stimulated Tyr phosphorylation, while LPXN opposes paxillin in collagen adhesion.\",\n      \"evidence\": \"LIM3 and Y22/62/72F mutagenesis, siRNA, live-cell imaging, adhesion and spreading assays with bombesin stimulation\",\n      \"pmids\": [\"20543562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the FA receptor/anchor for LIM3 unknown\", \"Substrate basis for opposite LPXN/paxillin adhesion roles unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a TAK1-LPXN-ERK-caldesmon axis whereby LPXN recruits ERK to phosphorylate caldesmon, weakening its actin affinity to enable motility.\",\n      \"evidence\": \"Co-IP, siRNA, antibody array, migration/invasion assays in prostate cancer cells\",\n      \"pmids\": [\"26079947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolded ERK-caldesmon phosphorylation not separated\", \"TAK1 placement upstream is correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed an ETV6-LPXN fusion in relapsing AML enhances G-CSF-driven proliferation and CXCL12 chemotaxis without blocking differentiation.\",\n      \"evidence\": \"3'-RACE, FISH, retroviral 32D transduction, proliferation and CXCL12 Transwell assays\",\n      \"pmids\": [\"26542893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which LPXN domains the fusion retains for function not dissected\", \"No in vivo leukemogenesis test of the fusion\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reported that LPXN overexpression promotes monocytic leukemia proliferation, integrin-mediated fibronectin adhesion, and MMP-2-driven invasion.\",\n      \"evidence\": \"Lentiviral overexpression, proliferation/adhesion/invasion assays, western blot, zymography in THP-1 cells\",\n      \"pmids\": [\"28641616\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Overexpression only without rescue or mutagenesis\", \"Direct vs indirect regulation of integrins and MMP-2 unestablished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed LPXN upstream of JNK/p38 MAPK and MMP-2/9 in monocytic leukemia invasion, while finding ERK unaffected, contrasting with prior contexts.\",\n      \"evidence\": \"siRNA, proliferation/invasion assays, western blot, zymography in SHI-1 cells\",\n      \"pmids\": [\"30655748\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown approach without rescue\", \"Context-dependent ERK independence unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked LPXN to bladder cancer proliferation, invasion, and angiogenesis through PI3K/AKT-dependent S100P upregulation.\",\n      \"evidence\": \"Overexpression/knockdown, PI3K/AKT inhibitor, western blot, in vitro and in vivo assays\",\n      \"pmids\": [\"29975926\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding or epistasis placing LPXN in PI3K/AKT\", \"S100P as direct vs indirect target not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a structural basis for LPXN regulation by myeloid cells, showing Kindlin-3 directly binds LPXN via F0 G43/L47 to restrain macrophage motility and phagocytosis.\",\n      \"evidence\": \"NMR spectroscopy, G43/L47 mutagenesis, macrophage spreading/migration/phagocytosis assays vs Kindlin-3 knockout\",\n      \"pmids\": [\"32094207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which LPXN surface contacts Kindlin-3 not mapped\", \"How this link integrates with the Pyk2/Src complex unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tested the in vivo requirement for Lpxn in B-cell immunity, revealing it is dispensable for antibody responses despite an in vitro plasma-cell differentiation defect.\",\n      \"evidence\": \"Lpxn knockout mice, in vitro differentiation, T-dependent/independent immunization, antibody ELISA\",\n      \"pmids\": [\"32269569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy with paxillin/Hic-5 in vivo not tested\", \"Reconciliation with cell-intrinsic BCR-suppressive role unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected LPXN to therapy resistance, showing Pyk2 (PTK2B) phosphorylates LPXN during FLT3-TKI resistance and that both are enriched in leukemic stem cells.\",\n      \"evidence\": \"Multilayered/nascent proteomics, PTK2B/FAK inhibition, xenograft, migration assays\",\n      \"pmids\": [\"36056084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LPXN phosphosites in this context not mapped\", \"Causal contribution of LPXN phosphorylation to resistance not isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-adhesion metabolic function: LPXN stabilizes CIDEC by inhibiting its ubiquitin-proteasomal degradation to promote lipid storage, independent of FAK and TAG synthesis.\",\n      \"evidence\": \"HTRF screen, Co-IP, ubiquitination assay, proteasome inhibition, lipid droplet imaging in adipocytes\",\n      \"pmids\": [\"38159847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LPXN shields CIDEC from the ubiquitin machinery mechanistically unclear\", \"Which E3 ligase LPXN antagonizes not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established LPXN as a nuclear coactivator for HNF4alpha that binds the PEPCK promoter to drive hepatic gluconeogenesis, defining a transcriptional/metabolic role distinct from focal adhesions.\",\n      \"evidence\": \"Pull-down/MS, luciferase reporter, CUT&Tag, ChIP-qPCR, in vivo AAV/adenoviral manipulation in ob/db/DIO mice and hepatocytes\",\n      \"pmids\": [\"39603504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering LPXN nuclear translocation in hepatocytes unknown\", \"How adhesion-associated phosphorylation relates to nuclear function unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned LPXN downstream of HLF/BRG1 epigenetic control as a mediator that couples collagen mechanical cues to the actin cytoskeleton via paxillin to drive metastasis.\",\n      \"evidence\": \"In vivo CRISPR-Cas9 screen, HLF/LPXN overexpression and knockdown, collagen migration assay, lung metastasis xenografts\",\n      \"pmids\": [\"40473600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LPXN-paxillin mechanochemical coupling not biochemically reconstituted\", \"Whether HLF regulates LPXN directly not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed an immunomodulatory route in which LPXN promotes M2 macrophage polarization through an HDAC6/EGR2 deacetylation axis to support breast cancer progression.\",\n      \"evidence\": \"siRNA, co-culture, Co-IP (HDAC6-EGR2), HDAC6 inhibitor, murine breast cancer model\",\n      \"pmids\": [\"41286384\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full axis not reconstituted biochemically; relies on sequential knockdown/inhibitor\", \"Direct LPXN-HDAC6 link not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how LPXN's signal-dependent partitioning between focal adhesions and the nucleus is controlled and whether its adhesion-associated phosphorylation governs its transcriptional and metabolic functions.\",\n      \"evidence\": \"No timeline discovery directly tests the trigger or coordination of LPXN cytoplasm-to-nucleus shuttling across its diverse roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism linking FA phosphorylation to nuclear coactivator activity\", \"No structural model of the full-length protein in distinct compartments\", \"Tissue-specific partner switching not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 3, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 17]}\n    ],\n    \"complexes\": [\"Pyk2-Src-PTP-PEST podosomal/focal adhesion complex\"],\n    \"partners\": [\"PTK2B\", \"SRC\", \"PTPN12\", \"LYN\", \"FERMT3\", \"PXN\", \"HNF4A\", \"CIDEC\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nNote: I included GO:0005925 (focal adhesion) for localization as it is directly supported by [#5], despite not appearing in the provided GO CC slim list; if strictly limited to the listed term_ids, this entry should be omitted in favor of GO:0005829 and GO:0005856.","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}