{"gene":"ILK","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"ILK gene was mapped to human chromosome 11p15.5-p15.4 by fluorescence in situ hybridization, establishing its genomic locus.","method":"Fluorescence in situ hybridization (FISH) on metaphase and decondensed chromatin fibers","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytogenetic mapping with FISH and confirmatory relational mapping, single lab","pmids":["9177792"],"is_preprint":false},{"year":2001,"finding":"ILK binds directly to the paxillin LD1 motif via a paxillin-binding subdomain (PBS) in its C-terminus; PBS mutations abolish paxillin binding in vitro and prevent ILK localization to focal adhesions in fibroblasts, demonstrating that paxillin binding is required for focal adhesion targeting of ILK.","method":"Microsequencing of paxillin-binding proteins, in vitro binding assay, co-immunoprecipitation from fibroblasts, GFP-ILK immunofluorescence, PBS point mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro direct binding, and loss-of-function mutations with defined localization phenotype, multiple orthogonal methods in one study","pmids":["11304546"],"is_preprint":false},{"year":2002,"finding":"C. elegans PAT-4/ILK (the sole ILK ortholog) functions as an adaptor protein within integrin adhesion complexes; kinase-dead ILK fully rescues pat-4 null mutants; UNC-112 was identified as a new ILK binding partner. In pat-4 null embryos, vinculin, UNC-89, actin and myosin fail to be recruited to integrin foci, while PAT-4/ILK itself requires UNC-52, integrin, and UNC-112 for proper recruitment.","method":"C. elegans genetic screen, null mutant analysis, transgenic kinase-dead rescue, yeast two-hybrid/binding assay for UNC-112 interaction","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic null with complete kinase-dead rescue (epistasis), new binding partner identified, replicated across multiple genetic backgrounds","pmids":["12015115"],"is_preprint":false},{"year":2002,"finding":"PINCH-2 forms a complex with ILK via its LIM1 domain; PINCH-2–ILK and PINCH-1–ILK interactions are mutually exclusive; deletion of LIM1 prevents ILK binding and focal adhesion localization of PINCH-2; overexpression of PINCH-2 inhibits PINCH-1–ILK interaction and reduces cell spreading and migration.","method":"Co-immunoprecipitation, deletion mutant analysis, immunofluorescence, cell spreading/migration assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion mutants and functional cell-based assays, single lab","pmids":["12167643"],"is_preprint":false},{"year":2003,"finding":"ILK-deficient mouse embryos die at peri-implantation due to failure to polarize epiblast and cavitate; ILK-null fibroblasts show abnormal F-actin aggregates, impaired spreading, delayed focal adhesion formation. Expression of kinase-inactive or paxillin-binding-defective ILK rescues actin organization, cell spreading, FA formation and proliferation, demonstrating that ILK modulates actin rearrangements at integrin-adhesion sites primarily through its adaptor function rather than kinase activity.","method":"Conditional mouse knockout (Cre/lox), fibroblast culture analysis, rescue with kinase-dead and paxillin-binding mutants, F-actin staining","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo knockout with defined phenotype, multiple mutant rescue experiments confirming adaptor (not kinase) function","pmids":["12670870"],"is_preprint":false},{"year":2003,"finding":"PINCH-1 and ILK are mutually required for cell spreading, motility, and survival in human cells; depletion of ILK by RNAi reduces Ser473 but not Thr308 phosphorylation of PKB/Akt. PINCH-1, ILK and alpha-parvin are mutually dependent for maintenance of their protein levels, coordinated by proteasomal degradation.","method":"RNA interference (siRNA) knockdown of PINCH-1, ILK, alpha-parvin; cell spreading/motility/survival assays; Western blot for PKB/Akt phosphorylation; proteasome inhibitor experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic RNAi knockdown with multiple orthogonal functional readouts, single lab but comprehensive","pmids":["14551191"],"is_preprint":false},{"year":2004,"finding":"ILKAP (protein phosphatase 2C) selectively associates with ILK, suppresses ILK immune complex kinase activity, and specifically inhibits GSK-3beta phosphorylation at S9 without affecting PKB Ser473 phosphorylation; overexpression of ILK but not dominant-negative ILK rescues ILKAP-mediated inhibition of GSK-3beta phosphorylation.","method":"siRNA silencing of ILKAP, ILK immune complex kinase assay, co-immunoprecipitation, overexpression rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay from immunoprecipitate, siRNA and overexpression with specific substrate readout, single lab","pmids":["14990992"],"is_preprint":false},{"year":2004,"finding":"ILK is required for assembly of fibrillar (matrix-forming) adhesions rich in alpha5beta1 integrin in endothelial cells; ILK depletion by RNAi eliminates fibrillar adhesions, impairs cell spreading/migration, and prevents capillary morphogenesis on Matrigel.","method":"RNA interference in bovine aortic endothelial cells, immunofluorescence for adhesion markers, migration assay, capillary morphogenesis assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with multiple cell-biological readouts, single lab","pmids":["15316070"],"is_preprint":false},{"year":2004,"finding":"ILK stimulates HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner, leading to upregulation of VEGF in prostate cancer cells; in endothelial cells, VEGF stimulates ILK activity, and ILK inhibition blocks VEGF-mediated migration, capillary formation, and angiogenesis in vitro and in vivo.","method":"siRNA knockdown of ILK, ILK kinase inhibitor treatment, in vitro capillary formation assay, in vivo angiogenesis assay, Western blot for HIF-1alpha/VEGF","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological inhibition with multiple functional assays, single lab","pmids":["14749128"],"is_preprint":false},{"year":2005,"finding":"Overexpression of ILK induces actin filament rearrangements, lamellipodia formation, and increased cell migration/invasion via PI3K-dependent activation of Akt and Rac1; dominant-negative ILK abolishes fibronectin peptide (PHSRN)-induced actin rearrangements and migration.","method":"ILK overexpression and dominant-negative mutant expression, Rac1 activity assay, PI3K inhibitor treatment, migration/invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple dominant-negative and inhibitor experiments with functional readouts, single lab","pmids":["15735674"],"is_preprint":false},{"year":2006,"finding":"Gi-coupled receptor agonists preferentially activate PI3K and ILK, leading to ILK-dependent phosphorylation of CPI-17 at Thr38 and MLC20 at Ser19, causing smooth muscle contraction; a kinase-inactive ILK mutant (R211A) abolishes these phosphorylations; ILK and the PAK1/p38 MAPK pathway reciprocally inhibit each other downstream of PI3K.","method":"Expression of ILK(R211A) dominant-negative mutant, siRNA for ILK, kinase activity assay, smooth muscle contraction measurement, phosphorylation assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant plus siRNA with specific substrate phosphorylation readout, single lab","pmids":["16472257"],"is_preprint":false},{"year":2007,"finding":"ILK is enriched in axonal tips of polarized neurons; inhibition of ILK (by inhibitors, kinase-inactive mutant, or siRNA) blocks axon formation, while kinase-hyperactive ILK induces multiple axons. Epistasis experiments place ILK downstream of PI3K and upstream of Akt and GSK-3beta in neuronal polarity.","method":"Chemical inhibitors of ILK, dominant-negative and hyperactive ILK mutants, siRNA knockdown, epistasis with PI3K/Akt/GSK-3beta pathway components, immunofluorescence","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic/pharmacological perturbations, epistasis placement, defined phenotypic readout, single lab","pmids":["17490631"],"is_preprint":false},{"year":2008,"finding":"Rsu-1 co-localizes with ILK at focal contacts and co-immunoprecipitates with the ILK-PINCH1 complex in non-transformed cells; following Ras transformation, Rsu-1 association with the PINCH1-ILK complex is greatly reduced via a Mek-ERK-dependent mechanism involving Rsu-1 alternative splicing.","method":"Co-immunoprecipitation, immunofluorescence co-localization, MEK inhibitor treatment, siRNA knockdown, migration assay","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and co-localization with inhibitor experiments in multiple cell lines, single lab","pmids":["18436335"],"is_preprint":false},{"year":2009,"finding":"ELMO2 simultaneously binds ILK and RhoG forming tripartite ERI complexes; Tbeta4 binds ILK in lamellipodia upon profilin-dependent release from G-actin, and Tbeta4-ILK complexes recruit and activate Akt2, resulting in matrix metalloproteinase-2 production; this couples actin polymerization at the leading edge to matrix degradation.","method":"FRET analysis of Tbeta4-G-actin interaction, Co-immunoprecipitation, spatial localization studies, Akt2 activation assay, MMP-2 production measurement","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus Co-IP with functional assays, single lab, multiple orthogonal methods","pmids":["19460343"],"is_preprint":false},{"year":2011,"finding":"Recombinant ILK from bacteria or mammalian cells shows no kinase activity toward GSK-3beta with either Mn2+ or Mg2+; whole-cell kinase assay using mammalian lysates identified no specific ILK substrates; high-resolution crystal structure shows Mn-bound ILK adopts the same pseudo-active site conformation as Mg-bound ILK; the K220M 'kinase-dead' mutation impairs structural integrity rather than ATP binding, providing mechanistic basis for renal agenesis phenotype. ILK is a bona fide pseudokinase.","method":"In vitro kinase assay (recombinant protein), proteomics-based whole-cell kinase substrate screen, X-ray crystallography, thermodynamic stability analysis, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution + crystal structure + thermodynamic analysis + mutagenesis + proteomics, multiple orthogonal methods rigorously addressing kinase activity","pmids":["21524996"],"is_preprint":false},{"year":2012,"finding":"ILK interacts with Rictor (mTORC2 component); TGF-β1 treatment induces ILK-Rictor complex formation and ILK-dependent phosphorylation of Rictor on Thr1135; disruption of the ILK/Rictor complex by siRNA suppresses TGF-β1-induced EMT and Snail/Slug nuclear translocation in mammary epithelial cells.","method":"Co-immunoprecipitation, siRNA knockdown, ILK inhibitor treatment, immunofluorescence for Snail/Slug localization, Western blot for Rictor phosphorylation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA and inhibitor with defined phosphorylation site, single lab","pmids":["22310280"],"is_preprint":false},{"year":2012,"finding":"ADAM12L co-immunoprecipitates with ILK in cells via its cytoplasmic tail; ADAM12L redistributes to focal adhesions with ILK upon beta1 integrin activation; depletion of ILK inhibits ADAM12L-induced Akt Ser473 phosphorylation and survival; overexpression of ADAM12L promotes kinase activity from ILK immunoprecipitates.","method":"Co-immunoprecipitation, immunofluorescence, ILK knockdown, ILK immune complex kinase assay, Akt phosphorylation Western blot","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined cytoplasmic tail requirement, kinase assay from immunoprecipitate, single lab","pmids":["22767580"],"is_preprint":false},{"year":2013,"finding":"β1 integrins, via ILK, orient microtubule plus ends at the basolateral membrane; ILK depletion (Cre-lox deletion) prevents lumen formation in mammary gland organoids by blocking endocytic removal of apical proteins from the basement-membrane-cell interface and internal Golgi positioning; Rac1 is not involved in this axis.","method":"Cre-lox conditional deletion in mammary gland, 3D primary culture model, live microtubule dynamics imaging, endocytosis assays, Golgi positioning analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic deletion, multiple mechanistic readouts (microtubule polarity, endocytosis, Golgi), in vivo and in vitro validation","pmids":["23263281"],"is_preprint":false},{"year":2015,"finding":"ELMO2-RhoG-ILK (ERI) tripartite complexes regulate microtubule dynamics in an integrin-independent manner in differentiated keratinocytes; depletion of ILK reduces microtubule growth and increases catastrophe frequency; ERI-mediated microtubule stabilization requires ILK for ELMO2 or RhoG to have effect, and is mediated downstream through Rac1 activation of stathmin phosphorylation and CRMP2 activation via GSK-3beta.","method":"ILK conditional gene inactivation (Cre/lox), live microtubule dynamics analysis, ELMO2/RhoG overexpression rescue assays, Rac1/stathmin/GSK-3beta inhibitor experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic deletion plus rescue experiments with defined molecular pathway through multiple downstream effectors","pmids":["25995380"],"is_preprint":false},{"year":2018,"finding":"Pseudokinase ILK recruits PINCH and Parvin into a heterotrimeric IPP complex that triggers F-actin filament bundling via two WASP-Homology-2 actin-binding motifs (one from PINCH, one from Parvin); Mg-ATP bound to the pseudoactive site of ILK sensitizes this process; mutations impairing ATP binding severely impair stress fiber formation, cell spreading and migration.","method":"Structural analysis, biochemical F-actin bundling assay, mutagenesis of WH2 motifs and ATP-binding site, cell spreading/migration assays, co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural, biochemical reconstitution, mutagenesis, and cell functional assays in one study with multiple orthogonal methods","pmids":["30367047"],"is_preprint":false},{"year":2018,"finding":"Kindlin-2 binds directly to a conserved surface on the C-lobe of the ILK pseudokinase domain (pKD); ILK mutations at this site inhibit kindlin-2 binding while maintaining pKD structural integrity; kindlin-binding-defective ILK mutants show impaired focal adhesion localization and fail to rescue spreading defects in ILK knockdown cells; kindlin-2 mutants with impaired ILK binding also fail to support cell spreading.","method":"Conservation-guided mutagenesis, binding assays, ILK knockdown rescue experiments, focal adhesion localization by immunofluorescence, cell spreading assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis mapping with structural integrity controls, reciprocal mutation analyses on both binding partners, defined functional readout","pmids":["30254023"],"is_preprint":false},{"year":2018,"finding":"Endothelial cell-specific ILK depletion hyper-activates VEGFR3 signaling and causes lymphatic vascular overgrowth; ILK impedes interactions between VEGFR3 and β1 integrin; deletion of one Itgb1 allele rescues lymphatic overgrowth caused by ILK loss; mechanical stimulation disrupts ILK-β1 integrin assembly, enabling β1 integrin to interact with VEGFR3.","method":"Endothelial cell-specific Cre deletion of ILK and Itgb1, VEGFR3 phosphorylation assays, Co-immunoprecipitation of VEGFR3 and β1 integrin, lymphatic vessel growth quantification in cornea/skin/myocardium","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic deletion, epistasis rescue by Itgb1 haploinsufficiency, Co-IP mechanistic data, multiple organ phenotype assessment","pmids":["30518533"],"is_preprint":false},{"year":2019,"finding":"Two arrhythmogenic cardiomyopathy-associated missense variants (p.H33N and p.H77Y) in the ILK ankyrin repeat domain disrupt the ILK-PINCH complex (predicted by in silico binding studies); mutant ILK expressed in H9c2 cells shows aberrant prominent cytoplasmic localization; expression of p.H77Y and p.P70L ILK under a cardiac-specific promoter in zebrafish causes cardiac dysfunction and death by 2–3 weeks.","method":"Exome sequencing, in silico binding modeling, transfection in H9c2 cells with immunofluorescence, zebrafish cardiac-specific overexpression with functional cardiac assessment","journal":"Translational research : the journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional zebrafish model with defined cardiac phenotype plus cell localization data, but in silico binding model rather than direct structural data","pmids":["30802431"],"is_preprint":false},{"year":2021,"finding":"Endothelin A receptor (ETAR) signaling drives invadopodia in ovarian cancer cells via β-arrestin1 linking ILK to the βPIX complex, which activates Rac3 GTPase; downstream, Rac3 phosphorylates PAK1 and cofilin to promote invadopodium-dependent ECM proteolysis and invasion; ILK/Rac3 signaling also supports cancer-mesothelial cell communication and transmigration.","method":"Co-immunoprecipitation of ILK/βPIX/β-arrestin1, Rac3 activity assay, invadopodium formation and ECM degradation assays, in vivo ETAR antagonist treatment","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined signaling axis, functional invadopodia assays, in vivo validation, single lab","pmids":["33657382"],"is_preprint":false},{"year":2023,"finding":"Injured mesothelial cells produce extracellular vesicles containing high levels of ILK; ILK packaged in EVs is delivered to fibroblasts and activates them via the p38 MAPK signaling pathway, driving peritoneal fibrogenesis.","method":"EV proteomics, single-cell RNA sequencing, EV isolation and transfer experiments, Rab27a knockdown to block EV secretion, Western blot for p38 MAPK activation in recipient fibroblasts, GW4869 (EV inhibitor) treatment","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EV transfer experiment with defined signaling readout (p38 MAPK), genetic blockade of EV secretion, single lab","pmids":["37357686"],"is_preprint":false}],"current_model":"ILK is a bona fide pseudokinase (lacking intrinsic kinase activity, with a degraded active site confirmed by crystallography and in vitro assays) that functions as the central scaffold of the heterotrimeric IPP (ILK–PINCH–Parvin) complex at integrin-containing focal adhesions; it links β1/β3 integrin cytoplasmic tails to the actin cytoskeleton by recruiting PINCH (via its ankyrin repeat domain) and Parvin (via its pseudokinase domain), with the Mg-ATP-occupied pseudoactive site allosterically enabling F-actin bundling through WH2 motifs on PINCH and Parvin; ILK also interacts with paxillin (LD1 motif), kindlin-2 (C-lobe of pseudokinase domain), ELMO2/RhoG, Rictor (mTORC2), and thymosin-β4, thereby coordinating integrin-to-actin linkage, microtubule plus-end polarization, mechanotransduction, VEGFR3 regulation, and downstream signaling through Akt/PKB and GSK-3β."},"narrative":{"mechanistic_narrative":"ILK is the central scaffold of integrin-based focal adhesions, linking the cytoplasmic tails of integrins to the actin cytoskeleton and coordinating adhesion-dependent signaling, cell spreading, migration, and tissue morphogenesis [PMID:12670870, PMID:30367047]. Despite its kinase-like domain, ILK is a bona fide pseudokinase: recombinant ILK has no detectable activity toward GSK-3beta, no specific substrate emerged from whole-cell screens, and its crystal structure shows a degraded pseudo-active site, with the 'kinase-dead' K220M mutation impairing structural integrity rather than catalysis [PMID:21524996]. Consistent with this, in vivo knockout and rescue experiments establish that ILK functions through its adaptor role rather than catalytic activity — kinase-inactive ILK fully rescues C. elegans pat-4 nulls and restores actin organization, spreading, and focal adhesion formation in ILK-null fibroblasts [PMID:12015115, PMID:12670870]. ILK assembles the heterotrimeric IPP complex by recruiting PINCH through its ankyrin repeat domain and Parvin, and triggers F-actin bundling via WH2 motifs contributed by PINCH and Parvin, a process sensitized by Mg-ATP bound in the pseudoactive site [PMID:12167643, PMID:30367047]. ILK additionally engages paxillin through a C-terminal paxillin-binding subdomain required for focal adhesion targeting [PMID:11304546] and binds kindlin-2 on the C-lobe of its pseudokinase domain to support adhesion localization and spreading [PMID:30254023]. Through ELMO2–RhoG complexes ILK orients microtubule plus-ends and regulates microtubule dynamics, contributing to epithelial lumen formation and keratinocyte polarity [PMID:19460343, PMID:23263281, PMID:25995380]. ILK loss/perturbation is propagated into downstream signaling including PKB/Akt Ser473 and GSK-3beta phosphorylation, HIF-1alpha/VEGF-driven angiogenesis, mTORC2 (Rictor) coupling to TGF-beta-induced EMT, and regulation of VEGFR3–beta1 integrin interaction in lymphatic vessel growth [PMID:14551191, PMID:14749128, PMID:22310280, PMID:30518533]. ILK missense variants in the ankyrin repeat domain are associated with arrhythmogenic cardiomyopathy and disrupt the ILK–PINCH complex [PMID:30802431].","teleology":[{"year":1997,"claim":"Establishing the human genomic locus of ILK provided the foundation for subsequent functional and disease-association studies.","evidence":"FISH mapping on metaphase chromosomes and chromatin fibers","pmids":["9177792"],"confidence":"Medium","gaps":["No functional or mechanistic information from mapping alone","Does not address protein activity or partners"]},{"year":2001,"claim":"The question of how ILK is targeted to focal adhesions was answered by mapping a direct paxillin-binding subdomain required for localization.","evidence":"In vitro binding, reciprocal Co-IP, and PBS point mutants with GFP-ILK localization in fibroblasts","pmids":["11304546"],"confidence":"High","gaps":["Does not establish whether paxillin binding is sufficient or only necessary","Functional consequences downstream of localization not resolved here"]},{"year":2002,"claim":"Genetic and biochemical work resolved whether ILK acts as a catalytic enzyme or a structural adaptor by showing kinase-dead ILK fully rescues null worms and by identifying core complex partners.","evidence":"C. elegans pat-4 null genetics with kinase-dead rescue, recruitment epistasis, and PINCH-2 LIM1 Co-IP/deletion mapping in mammalian cells","pmids":["12015115","12167643"],"confidence":"High","gaps":["Mutually exclusive PINCH-1/PINCH-2 binding consequence in vivo unclear","Did not directly test catalytic activity biochemically"]},{"year":2003,"claim":"In vivo knockout established that ILK's essential adaptor function in actin organization and embryonic polarity is kinase-independent, and that IPP components are mutually stabilized.","evidence":"Conditional mouse knockout with kinase-dead and paxillin-binding-defective rescue; RNAi of PINCH-1/ILK/alpha-parvin with proteasome inhibition and Akt phospho-readouts","pmids":["12670870","14551191"],"confidence":"High","gaps":["Mechanism linking ILK to selective Ser473 (not Thr308) Akt phosphorylation not defined","Direct molecular basis of mutual protein stabilization unresolved"]},{"year":2004,"claim":"Multiple studies connected ILK to adhesion-type-specific assembly and to angiogenic and substrate-specific signaling outputs, though catalytic claims relied on immune-complex assays.","evidence":"RNAi in endothelial cells (fibrillar adhesions, capillary morphogenesis); ILKAP/PP2C Co-IP and immune-complex kinase assay; siRNA/inhibitor analysis of HIF-1alpha/VEGF angiogenesis","pmids":["15316070","14990992","14749128"],"confidence":"Medium","gaps":["Immune-complex kinase activity later shown not to reflect intrinsic ILK catalysis","GSK-3beta and HIF-1alpha effects could be indirect/scaffold-mediated"]},{"year":2005,"claim":"Overexpression and dominant-negative studies linked ILK to PI3K-dependent Akt/Rac1 activation driving actin remodeling, migration, and invasion.","evidence":"ILK overexpression and dominant-negative mutants, Rac1 activity assay, PI3K inhibition, migration/invasion assays","pmids":["15735674"],"confidence":"Medium","gaps":["Overexpression may not reflect physiological stoichiometry","Direct versus indirect contribution to Rac1 activation unresolved"]},{"year":2006,"claim":"Smooth muscle studies attributed contractile signaling (CPI-17/MLC20 phosphorylation) to ILK using kinase-dead R211A, framing ILK as catalytically active.","evidence":"ILK(R211A) dominant-negative and siRNA, kinase assays, contraction and phosphorylation measurements","pmids":["16472257"],"confidence":"Medium","gaps":["Catalytic interpretation conflicts with later pseudokinase evidence","R211A effects may reflect scaffold disruption rather than lost catalysis"]},{"year":2007,"claim":"Epistasis in polarizing neurons placed ILK between PI3K and Akt/GSK-3beta in axon specification, extending its role to neuronal polarity.","evidence":"ILK inhibitors, kinase-inactive and hyperactive mutants, siRNA, epistasis with PI3K/Akt/GSK-3beta, immunofluorescence","pmids":["17490631"],"confidence":"Medium","gaps":["Hyperactive-mutant phenotype hard to reconcile with pseudokinase model","Molecular mechanism of axon-tip enrichment not defined"]},{"year":2008,"claim":"Identification of Rsu-1 within the PINCH1-ILK complex and its loss upon Ras transformation linked the IPP scaffold to oncogenic signaling.","evidence":"Co-IP, co-localization, MEK inhibition, siRNA, migration assays in transformed and non-transformed cells","pmids":["18436335"],"confidence":"Medium","gaps":["Direct versus indirect Rsu-1 binding to ILK not resolved","Functional consequence of Rsu-1 loss for adhesion incompletely defined"]},{"year":2009,"claim":"ELMO2/RhoG and thymosin-beta4 were defined as ILK partners coupling leading-edge actin polymerization to Akt2 activation and MMP-2-mediated matrix degradation.","evidence":"FRET, Co-IP, spatial localization, Akt2 activation and MMP-2 assays","pmids":["19460343"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the tripartite ERI complex not structurally defined","Whether Tbeta4-ILK signaling requires the IPP complex unclear"]},{"year":2011,"claim":"Rigorous reconstitution, proteomics, and crystallography resolved the long-standing catalytic controversy by establishing ILK as a bona fide pseudokinase and reinterpreting kinase-dead mutations as structural.","evidence":"Recombinant in vitro kinase assays, whole-cell substrate proteomics, X-ray crystallography, thermodynamic stability, mutagenesis","pmids":["21524996"],"confidence":"High","gaps":["Reframes but does not re-test every prior immune-complex-based catalytic claim","Role of ATP occupancy in the pseudo-active site functionally defined only later"]},{"year":2012,"claim":"ILK was linked to mTORC2 and ADAM12L, connecting the scaffold to TGF-beta-driven EMT and integrin-coupled survival signaling.","evidence":"Co-IP, siRNA, ILK inhibitor, Rictor Thr1135 phospho and Akt Ser473 readouts, Snail/Slug localization","pmids":["22310280","22767580"],"confidence":"Medium","gaps":["Whether ILK directly phosphorylates Rictor conflicts with pseudokinase status","Immune-complex kinase activity attributed to ADAM12L not mechanistically defined"]},{"year":2013,"claim":"Conditional deletion established that beta1-integrin/ILK orients microtubule plus-ends and Golgi to drive apical clearance and epithelial lumen formation, independent of Rac1.","evidence":"Cre-lox deletion in mammary organoids, live microtubule imaging, endocytosis and Golgi-positioning assays","pmids":["23263281"],"confidence":"High","gaps":["Molecular bridge from ILK to microtubule plus-ends in this context not identified","Effector linking ILK to endocytic apical clearance unresolved"]},{"year":2015,"claim":"The ELMO2-RhoG-ILK complex was shown to regulate microtubule dynamics integrin-independently in keratinocytes, defining a downstream Rac1/stathmin/GSK-3beta/CRMP2 pathway.","evidence":"Conditional ILK inactivation, live microtubule dynamics, ELMO2/RhoG rescue, Rac1/stathmin/GSK-3beta inhibitor experiments","pmids":["25995380"],"confidence":"High","gaps":["How ILK acts on microtubules independent of integrin engagement not structurally defined","Direct versus indirect link to stathmin/CRMP2 unresolved"]},{"year":2018,"claim":"Structural and biochemical work defined the architecture of IPP-mediated F-actin bundling, mapped the kindlin-2 binding surface, and revealed ILK control of VEGFR3-beta1 integrin crosstalk in lymphatics.","evidence":"Structural analysis with F-actin bundling and WH2/ATP-site mutagenesis; conservation-guided kindlin-2 binding mutants; endothelial ILK/Itgb1 conditional deletion with VEGFR3 Co-IP and rescue","pmids":["30367047","30254023","30518533"],"confidence":"High","gaps":["How Mg-ATP allosterically sensitizes bundling at the molecular level only partly defined","Mechanical regulation of ILK-beta1 assembly not structurally characterized"]},{"year":2019,"claim":"Arrhythmogenic cardiomyopathy variants in the ILK ankyrin repeat domain were linked to disease via IPP-complex disruption and cardiac dysfunction in vivo.","evidence":"Exome sequencing, in silico binding modeling, H9c2 localization, zebrafish cardiac-specific overexpression","pmids":["30802431"],"confidence":"Medium","gaps":["ILK-PINCH disruption inferred from in silico modeling, not direct structural data","Zebrafish overexpression may not fully model human loss-of-function pathology"]},{"year":2021,"claim":"ILK was placed within a beta-arrestin1/betaPIX/Rac3 axis driving invadopodia and ECM proteolysis downstream of endothelin A receptor in ovarian cancer.","evidence":"Co-IP of ILK/betaPIX/beta-arrestin1, Rac3 activity, invadopodia and ECM degradation assays, in vivo ETAR antagonist","pmids":["33657382"],"confidence":"Medium","gaps":["Direct ILK interaction surfaces in this complex not mapped","Requirement for the canonical IPP complex in this signaling not tested"]},{"year":2023,"claim":"ILK was shown to act non-cell-autonomously, exported in extracellular vesicles to activate fibroblasts via p38 MAPK and drive peritoneal fibrosis.","evidence":"EV proteomics, scRNA-seq, EV transfer, Rab27a knockdown and GW4869 inhibition, p38 MAPK readout","pmids":["37357686"],"confidence":"Medium","gaps":["Molecular mechanism by which EV-delivered ILK activates p38 unclear","Whether ILK acts as scaffold or via partners in recipient cells not defined"]},{"year":null,"claim":"How the Mg-ATP-occupied pseudo-active site allosterically couples to F-actin bundling and partner engagement, and how mechanical force reconfigures ILK-integrin assemblies, remain mechanistically incomplete.","evidence":"","pmids":[],"confidence":"High","gaps":["No full structural model of the force-dependent ILK-integrin-VEGFR3 switch","Allosteric transmission from ATP site to WH2-driven bundling not resolved at atomic resolution"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,19,20]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,19]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[19,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,7,20]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,22]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,4,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,15,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,17,21]}],"complexes":["IPP (ILK-PINCH-Parvin) complex","focal adhesion","ELMO2-RhoG-ILK (ERI) complex","ILK-Rictor (mTORC2)"],"partners":["PINCH","PARVIN","PXN","FERMT2","ELMO2","RICTOR","RHOG","ILKAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13418","full_name":"Scaffold protein ILK","aliases":["ILK-1","ILK-2","Inactive integrin-linked kinase","p59ILK"],"length_aa":452,"mass_kda":51.4,"function":"Scaffold protein which mediates protein-protein interactions during a range of cellular events including focal adhesion assembly, cell adhesion and cell migration (PubMed:17420447, PubMed:20005845, PubMed:30367047, PubMed:32528174). 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Mediates trafficking of caveolae to the cell surface in an ITGB1-dependent manner by promoting the recruitment of IQGAP1 to the cell cortex which cooperates with its effector DIAPH1 to locally stabilize microtubules and allow stable insertion of caveolae into the plasma membrane (By similarity). Required for the maintenance of mitotic spindle integrity by promoting phosphorylation of TACC3 by AURKA (PubMed:18283114). 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34690754","citation_count":24,"is_preprint":false},{"pmid":"22666394","id":"PMC_22666394","title":"ILK induces cardiomyogenesis in the human heart.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22666394","citation_count":24,"is_preprint":false},{"pmid":"33657382","id":"PMC_33657382","title":"Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33657382","citation_count":23,"is_preprint":false},{"pmid":"24371086","id":"PMC_24371086","title":"ILK modulates epithelial polarity and matrix formation in hair follicles.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24371086","citation_count":23,"is_preprint":false},{"pmid":"28457660","id":"PMC_28457660","title":"ILK regulates MSCs survival and angiogenesis partially through AKT and mTOR signaling pathways.","date":"2017","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/28457660","citation_count":22,"is_preprint":false},{"pmid":"17498677","id":"PMC_17498677","title":"Role of ERK1/2 and PI3-K in the regulation of CTGF-induced ILK expression in HK-2 cells.","date":"2007","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17498677","citation_count":22,"is_preprint":false},{"pmid":"22767580","id":"PMC_22767580","title":"Identification of ILK as a new partner of the ADAM12 disintegrin and metalloprotease in cell adhesion and survival.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22767580","citation_count":22,"is_preprint":false},{"pmid":"35379775","id":"PMC_35379775","title":"Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial-mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35379775","citation_count":21,"is_preprint":false},{"pmid":"36768775","id":"PMC_36768775","title":"The Expression of TGF-β1, SMAD3, ILK and miRNA-21 in the Ectopic and Eutopic Endometrium of Women with Endometriosis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768775","citation_count":20,"is_preprint":false},{"pmid":"24472646","id":"PMC_24472646","title":"Integrin linked kinase (ILK) is required for lens epithelial cell survival, proliferation and differentiation.","date":"2014","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/24472646","citation_count":19,"is_preprint":false},{"pmid":"29409901","id":"PMC_29409901","title":"ILK-induced epithelial-mesenchymal transition promotes the invasive phenotype in adenomyosis.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29409901","citation_count":19,"is_preprint":false},{"pmid":"25098374","id":"PMC_25098374","title":"Gender-based differences in cardiac remodeling and ILK expression after myocardial infarction.","date":"2014","source":"Arquivos brasileiros de cardiologia","url":"https://pubmed.ncbi.nlm.nih.gov/25098374","citation_count":19,"is_preprint":false},{"pmid":"30814673","id":"PMC_30814673","title":"ILK promotes survival and self-renewal of hypoxic MSCs via the activation of lncTCF7-Wnt pathway induced by IL-6/STAT3 signaling.","date":"2019","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30814673","citation_count":19,"is_preprint":false},{"pmid":"34118875","id":"PMC_34118875","title":"β-elemene alleviates airway stenosis via the ILK/Akt pathway modulated by MIR143HG sponging miR-1275.","date":"2021","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34118875","citation_count":19,"is_preprint":false},{"pmid":"32260415","id":"PMC_32260415","title":"Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32260415","citation_count":18,"is_preprint":false},{"pmid":"30182767","id":"PMC_30182767","title":"ILK enhances migration and invasion abilities of human endometrial stromal cells by facilitating the epithelial-mesenchymal transition.","date":"2018","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30182767","citation_count":18,"is_preprint":false},{"pmid":"19923885","id":"PMC_19923885","title":"Oncogenic ILK, tumor suppression and all that JNK.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19923885","citation_count":17,"is_preprint":false},{"pmid":"20857141","id":"PMC_20857141","title":"Integrin-linked kinase (ILK) in pulmonary fibrosis.","date":"2010","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20857141","citation_count":17,"is_preprint":false},{"pmid":"30636169","id":"PMC_30636169","title":"MicroR-542-3p can mediate ILK and further inhibit cell proliferation, migration and invasion in osteosarcoma cells.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/30636169","citation_count":17,"is_preprint":false},{"pmid":"22814720","id":"PMC_22814720","title":"Integrin-linked kinase (ILK) expression correlates with tumor severity in clear cell renal carcinoma.","date":"2012","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/22814720","citation_count":17,"is_preprint":false},{"pmid":"29152644","id":"PMC_29152644","title":"HMGA1 participates in MHCC97H cell proliferation and invasion through the ILK/Akt/GSK3β signaling pathway.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29152644","citation_count":16,"is_preprint":false},{"pmid":"33879841","id":"PMC_33879841","title":"Targeting the ILK/YAP axis by LFG-500 blocks epithelial-mesenchymal transition and metastasis.","date":"2021","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/33879841","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48793,"output_tokens":6665,"usd":0.123177,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15628,"output_tokens":5947,"usd":0.113407,"stage2_stop_reason":"end_turn"},"total_usd":0.236584,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"ILK gene was mapped to human chromosome 11p15.5-p15.4 by fluorescence in situ hybridization, establishing its genomic locus.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) on metaphase and decondensed chromatin fibers\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytogenetic mapping with FISH and confirmatory relational mapping, single lab\",\n      \"pmids\": [\"9177792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ILK binds directly to the paxillin LD1 motif via a paxillin-binding subdomain (PBS) in its C-terminus; PBS mutations abolish paxillin binding in vitro and prevent ILK localization to focal adhesions in fibroblasts, demonstrating that paxillin binding is required for focal adhesion targeting of ILK.\",\n      \"method\": \"Microsequencing of paxillin-binding proteins, in vitro binding assay, co-immunoprecipitation from fibroblasts, GFP-ILK immunofluorescence, PBS point mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro direct binding, and loss-of-function mutations with defined localization phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11304546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C. elegans PAT-4/ILK (the sole ILK ortholog) functions as an adaptor protein within integrin adhesion complexes; kinase-dead ILK fully rescues pat-4 null mutants; UNC-112 was identified as a new ILK binding partner. In pat-4 null embryos, vinculin, UNC-89, actin and myosin fail to be recruited to integrin foci, while PAT-4/ILK itself requires UNC-52, integrin, and UNC-112 for proper recruitment.\",\n      \"method\": \"C. elegans genetic screen, null mutant analysis, transgenic kinase-dead rescue, yeast two-hybrid/binding assay for UNC-112 interaction\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic null with complete kinase-dead rescue (epistasis), new binding partner identified, replicated across multiple genetic backgrounds\",\n      \"pmids\": [\"12015115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PINCH-2 forms a complex with ILK via its LIM1 domain; PINCH-2–ILK and PINCH-1–ILK interactions are mutually exclusive; deletion of LIM1 prevents ILK binding and focal adhesion localization of PINCH-2; overexpression of PINCH-2 inhibits PINCH-1–ILK interaction and reduces cell spreading and migration.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant analysis, immunofluorescence, cell spreading/migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion mutants and functional cell-based assays, single lab\",\n      \"pmids\": [\"12167643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ILK-deficient mouse embryos die at peri-implantation due to failure to polarize epiblast and cavitate; ILK-null fibroblasts show abnormal F-actin aggregates, impaired spreading, delayed focal adhesion formation. Expression of kinase-inactive or paxillin-binding-defective ILK rescues actin organization, cell spreading, FA formation and proliferation, demonstrating that ILK modulates actin rearrangements at integrin-adhesion sites primarily through its adaptor function rather than kinase activity.\",\n      \"method\": \"Conditional mouse knockout (Cre/lox), fibroblast culture analysis, rescue with kinase-dead and paxillin-binding mutants, F-actin staining\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo knockout with defined phenotype, multiple mutant rescue experiments confirming adaptor (not kinase) function\",\n      \"pmids\": [\"12670870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PINCH-1 and ILK are mutually required for cell spreading, motility, and survival in human cells; depletion of ILK by RNAi reduces Ser473 but not Thr308 phosphorylation of PKB/Akt. PINCH-1, ILK and alpha-parvin are mutually dependent for maintenance of their protein levels, coordinated by proteasomal degradation.\",\n      \"method\": \"RNA interference (siRNA) knockdown of PINCH-1, ILK, alpha-parvin; cell spreading/motility/survival assays; Western blot for PKB/Akt phosphorylation; proteasome inhibitor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic RNAi knockdown with multiple orthogonal functional readouts, single lab but comprehensive\",\n      \"pmids\": [\"14551191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ILKAP (protein phosphatase 2C) selectively associates with ILK, suppresses ILK immune complex kinase activity, and specifically inhibits GSK-3beta phosphorylation at S9 without affecting PKB Ser473 phosphorylation; overexpression of ILK but not dominant-negative ILK rescues ILKAP-mediated inhibition of GSK-3beta phosphorylation.\",\n      \"method\": \"siRNA silencing of ILKAP, ILK immune complex kinase assay, co-immunoprecipitation, overexpression rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay from immunoprecipitate, siRNA and overexpression with specific substrate readout, single lab\",\n      \"pmids\": [\"14990992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ILK is required for assembly of fibrillar (matrix-forming) adhesions rich in alpha5beta1 integrin in endothelial cells; ILK depletion by RNAi eliminates fibrillar adhesions, impairs cell spreading/migration, and prevents capillary morphogenesis on Matrigel.\",\n      \"method\": \"RNA interference in bovine aortic endothelial cells, immunofluorescence for adhesion markers, migration assay, capillary morphogenesis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with multiple cell-biological readouts, single lab\",\n      \"pmids\": [\"15316070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ILK stimulates HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner, leading to upregulation of VEGF in prostate cancer cells; in endothelial cells, VEGF stimulates ILK activity, and ILK inhibition blocks VEGF-mediated migration, capillary formation, and angiogenesis in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown of ILK, ILK kinase inhibitor treatment, in vitro capillary formation assay, in vivo angiogenesis assay, Western blot for HIF-1alpha/VEGF\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological inhibition with multiple functional assays, single lab\",\n      \"pmids\": [\"14749128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Overexpression of ILK induces actin filament rearrangements, lamellipodia formation, and increased cell migration/invasion via PI3K-dependent activation of Akt and Rac1; dominant-negative ILK abolishes fibronectin peptide (PHSRN)-induced actin rearrangements and migration.\",\n      \"method\": \"ILK overexpression and dominant-negative mutant expression, Rac1 activity assay, PI3K inhibitor treatment, migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple dominant-negative and inhibitor experiments with functional readouts, single lab\",\n      \"pmids\": [\"15735674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Gi-coupled receptor agonists preferentially activate PI3K and ILK, leading to ILK-dependent phosphorylation of CPI-17 at Thr38 and MLC20 at Ser19, causing smooth muscle contraction; a kinase-inactive ILK mutant (R211A) abolishes these phosphorylations; ILK and the PAK1/p38 MAPK pathway reciprocally inhibit each other downstream of PI3K.\",\n      \"method\": \"Expression of ILK(R211A) dominant-negative mutant, siRNA for ILK, kinase activity assay, smooth muscle contraction measurement, phosphorylation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant plus siRNA with specific substrate phosphorylation readout, single lab\",\n      \"pmids\": [\"16472257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ILK is enriched in axonal tips of polarized neurons; inhibition of ILK (by inhibitors, kinase-inactive mutant, or siRNA) blocks axon formation, while kinase-hyperactive ILK induces multiple axons. Epistasis experiments place ILK downstream of PI3K and upstream of Akt and GSK-3beta in neuronal polarity.\",\n      \"method\": \"Chemical inhibitors of ILK, dominant-negative and hyperactive ILK mutants, siRNA knockdown, epistasis with PI3K/Akt/GSK-3beta pathway components, immunofluorescence\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic/pharmacological perturbations, epistasis placement, defined phenotypic readout, single lab\",\n      \"pmids\": [\"17490631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rsu-1 co-localizes with ILK at focal contacts and co-immunoprecipitates with the ILK-PINCH1 complex in non-transformed cells; following Ras transformation, Rsu-1 association with the PINCH1-ILK complex is greatly reduced via a Mek-ERK-dependent mechanism involving Rsu-1 alternative splicing.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, MEK inhibitor treatment, siRNA knockdown, migration assay\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and co-localization with inhibitor experiments in multiple cell lines, single lab\",\n      \"pmids\": [\"18436335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ELMO2 simultaneously binds ILK and RhoG forming tripartite ERI complexes; Tbeta4 binds ILK in lamellipodia upon profilin-dependent release from G-actin, and Tbeta4-ILK complexes recruit and activate Akt2, resulting in matrix metalloproteinase-2 production; this couples actin polymerization at the leading edge to matrix degradation.\",\n      \"method\": \"FRET analysis of Tbeta4-G-actin interaction, Co-immunoprecipitation, spatial localization studies, Akt2 activation assay, MMP-2 production measurement\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus Co-IP with functional assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19460343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Recombinant ILK from bacteria or mammalian cells shows no kinase activity toward GSK-3beta with either Mn2+ or Mg2+; whole-cell kinase assay using mammalian lysates identified no specific ILK substrates; high-resolution crystal structure shows Mn-bound ILK adopts the same pseudo-active site conformation as Mg-bound ILK; the K220M 'kinase-dead' mutation impairs structural integrity rather than ATP binding, providing mechanistic basis for renal agenesis phenotype. ILK is a bona fide pseudokinase.\",\n      \"method\": \"In vitro kinase assay (recombinant protein), proteomics-based whole-cell kinase substrate screen, X-ray crystallography, thermodynamic stability analysis, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution + crystal structure + thermodynamic analysis + mutagenesis + proteomics, multiple orthogonal methods rigorously addressing kinase activity\",\n      \"pmids\": [\"21524996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ILK interacts with Rictor (mTORC2 component); TGF-β1 treatment induces ILK-Rictor complex formation and ILK-dependent phosphorylation of Rictor on Thr1135; disruption of the ILK/Rictor complex by siRNA suppresses TGF-β1-induced EMT and Snail/Slug nuclear translocation in mammary epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ILK inhibitor treatment, immunofluorescence for Snail/Slug localization, Western blot for Rictor phosphorylation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA and inhibitor with defined phosphorylation site, single lab\",\n      \"pmids\": [\"22310280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM12L co-immunoprecipitates with ILK in cells via its cytoplasmic tail; ADAM12L redistributes to focal adhesions with ILK upon beta1 integrin activation; depletion of ILK inhibits ADAM12L-induced Akt Ser473 phosphorylation and survival; overexpression of ADAM12L promotes kinase activity from ILK immunoprecipitates.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ILK knockdown, ILK immune complex kinase assay, Akt phosphorylation Western blot\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined cytoplasmic tail requirement, kinase assay from immunoprecipitate, single lab\",\n      \"pmids\": [\"22767580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"β1 integrins, via ILK, orient microtubule plus ends at the basolateral membrane; ILK depletion (Cre-lox deletion) prevents lumen formation in mammary gland organoids by blocking endocytic removal of apical proteins from the basement-membrane-cell interface and internal Golgi positioning; Rac1 is not involved in this axis.\",\n      \"method\": \"Cre-lox conditional deletion in mammary gland, 3D primary culture model, live microtubule dynamics imaging, endocytosis assays, Golgi positioning analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic deletion, multiple mechanistic readouts (microtubule polarity, endocytosis, Golgi), in vivo and in vitro validation\",\n      \"pmids\": [\"23263281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ELMO2-RhoG-ILK (ERI) tripartite complexes regulate microtubule dynamics in an integrin-independent manner in differentiated keratinocytes; depletion of ILK reduces microtubule growth and increases catastrophe frequency; ERI-mediated microtubule stabilization requires ILK for ELMO2 or RhoG to have effect, and is mediated downstream through Rac1 activation of stathmin phosphorylation and CRMP2 activation via GSK-3beta.\",\n      \"method\": \"ILK conditional gene inactivation (Cre/lox), live microtubule dynamics analysis, ELMO2/RhoG overexpression rescue assays, Rac1/stathmin/GSK-3beta inhibitor experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic deletion plus rescue experiments with defined molecular pathway through multiple downstream effectors\",\n      \"pmids\": [\"25995380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pseudokinase ILK recruits PINCH and Parvin into a heterotrimeric IPP complex that triggers F-actin filament bundling via two WASP-Homology-2 actin-binding motifs (one from PINCH, one from Parvin); Mg-ATP bound to the pseudoactive site of ILK sensitizes this process; mutations impairing ATP binding severely impair stress fiber formation, cell spreading and migration.\",\n      \"method\": \"Structural analysis, biochemical F-actin bundling assay, mutagenesis of WH2 motifs and ATP-binding site, cell spreading/migration assays, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural, biochemical reconstitution, mutagenesis, and cell functional assays in one study with multiple orthogonal methods\",\n      \"pmids\": [\"30367047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kindlin-2 binds directly to a conserved surface on the C-lobe of the ILK pseudokinase domain (pKD); ILK mutations at this site inhibit kindlin-2 binding while maintaining pKD structural integrity; kindlin-binding-defective ILK mutants show impaired focal adhesion localization and fail to rescue spreading defects in ILK knockdown cells; kindlin-2 mutants with impaired ILK binding also fail to support cell spreading.\",\n      \"method\": \"Conservation-guided mutagenesis, binding assays, ILK knockdown rescue experiments, focal adhesion localization by immunofluorescence, cell spreading assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis mapping with structural integrity controls, reciprocal mutation analyses on both binding partners, defined functional readout\",\n      \"pmids\": [\"30254023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endothelial cell-specific ILK depletion hyper-activates VEGFR3 signaling and causes lymphatic vascular overgrowth; ILK impedes interactions between VEGFR3 and β1 integrin; deletion of one Itgb1 allele rescues lymphatic overgrowth caused by ILK loss; mechanical stimulation disrupts ILK-β1 integrin assembly, enabling β1 integrin to interact with VEGFR3.\",\n      \"method\": \"Endothelial cell-specific Cre deletion of ILK and Itgb1, VEGFR3 phosphorylation assays, Co-immunoprecipitation of VEGFR3 and β1 integrin, lymphatic vessel growth quantification in cornea/skin/myocardium\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic deletion, epistasis rescue by Itgb1 haploinsufficiency, Co-IP mechanistic data, multiple organ phenotype assessment\",\n      \"pmids\": [\"30518533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Two arrhythmogenic cardiomyopathy-associated missense variants (p.H33N and p.H77Y) in the ILK ankyrin repeat domain disrupt the ILK-PINCH complex (predicted by in silico binding studies); mutant ILK expressed in H9c2 cells shows aberrant prominent cytoplasmic localization; expression of p.H77Y and p.P70L ILK under a cardiac-specific promoter in zebrafish causes cardiac dysfunction and death by 2–3 weeks.\",\n      \"method\": \"Exome sequencing, in silico binding modeling, transfection in H9c2 cells with immunofluorescence, zebrafish cardiac-specific overexpression with functional cardiac assessment\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional zebrafish model with defined cardiac phenotype plus cell localization data, but in silico binding model rather than direct structural data\",\n      \"pmids\": [\"30802431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelin A receptor (ETAR) signaling drives invadopodia in ovarian cancer cells via β-arrestin1 linking ILK to the βPIX complex, which activates Rac3 GTPase; downstream, Rac3 phosphorylates PAK1 and cofilin to promote invadopodium-dependent ECM proteolysis and invasion; ILK/Rac3 signaling also supports cancer-mesothelial cell communication and transmigration.\",\n      \"method\": \"Co-immunoprecipitation of ILK/βPIX/β-arrestin1, Rac3 activity assay, invadopodium formation and ECM degradation assays, in vivo ETAR antagonist treatment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined signaling axis, functional invadopodia assays, in vivo validation, single lab\",\n      \"pmids\": [\"33657382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Injured mesothelial cells produce extracellular vesicles containing high levels of ILK; ILK packaged in EVs is delivered to fibroblasts and activates them via the p38 MAPK signaling pathway, driving peritoneal fibrogenesis.\",\n      \"method\": \"EV proteomics, single-cell RNA sequencing, EV isolation and transfer experiments, Rab27a knockdown to block EV secretion, Western blot for p38 MAPK activation in recipient fibroblasts, GW4869 (EV inhibitor) treatment\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EV transfer experiment with defined signaling readout (p38 MAPK), genetic blockade of EV secretion, single lab\",\n      \"pmids\": [\"37357686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ILK is a bona fide pseudokinase (lacking intrinsic kinase activity, with a degraded active site confirmed by crystallography and in vitro assays) that functions as the central scaffold of the heterotrimeric IPP (ILK–PINCH–Parvin) complex at integrin-containing focal adhesions; it links β1/β3 integrin cytoplasmic tails to the actin cytoskeleton by recruiting PINCH (via its ankyrin repeat domain) and Parvin (via its pseudokinase domain), with the Mg-ATP-occupied pseudoactive site allosterically enabling F-actin bundling through WH2 motifs on PINCH and Parvin; ILK also interacts with paxillin (LD1 motif), kindlin-2 (C-lobe of pseudokinase domain), ELMO2/RhoG, Rictor (mTORC2), and thymosin-β4, thereby coordinating integrin-to-actin linkage, microtubule plus-end polarization, mechanotransduction, VEGFR3 regulation, and downstream signaling through Akt/PKB and GSK-3β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ILK is the central scaffold of integrin-based focal adhesions, linking the cytoplasmic tails of integrins to the actin cytoskeleton and coordinating adhesion-dependent signaling, cell spreading, migration, and tissue morphogenesis [#4, #19]. Despite its kinase-like domain, ILK is a bona fide pseudokinase: recombinant ILK has no detectable activity toward GSK-3beta, no specific substrate emerged from whole-cell screens, and its crystal structure shows a degraded pseudo-active site, with the 'kinase-dead' K220M mutation impairing structural integrity rather than catalysis [#14]. Consistent with this, in vivo knockout and rescue experiments establish that ILK functions through its adaptor role rather than catalytic activity — kinase-inactive ILK fully rescues C. elegans pat-4 nulls and restores actin organization, spreading, and focal adhesion formation in ILK-null fibroblasts [#2, #4]. ILK assembles the heterotrimeric IPP complex by recruiting PINCH through its ankyrin repeat domain and Parvin, and triggers F-actin bundling via WH2 motifs contributed by PINCH and Parvin, a process sensitized by Mg-ATP bound in the pseudoactive site [#3, #19]. ILK additionally engages paxillin through a C-terminal paxillin-binding subdomain required for focal adhesion targeting [#1] and binds kindlin-2 on the C-lobe of its pseudokinase domain to support adhesion localization and spreading [#20]. Through ELMO2–RhoG complexes ILK orients microtubule plus-ends and regulates microtubule dynamics, contributing to epithelial lumen formation and keratinocyte polarity [#13, #17, #18]. ILK loss/perturbation is propagated into downstream signaling including PKB/Akt Ser473 and GSK-3beta phosphorylation, HIF-1alpha/VEGF-driven angiogenesis, mTORC2 (Rictor) coupling to TGF-beta-induced EMT, and regulation of VEGFR3–beta1 integrin interaction in lymphatic vessel growth [#5, #8, #15, #21]. ILK missense variants in the ankyrin repeat domain are associated with arrhythmogenic cardiomyopathy and disrupt the ILK–PINCH complex [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the human genomic locus of ILK provided the foundation for subsequent functional and disease-association studies.\",\n      \"evidence\": \"FISH mapping on metaphase chromosomes and chromatin fibers\",\n      \"pmids\": [\"9177792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or mechanistic information from mapping alone\", \"Does not address protein activity or partners\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The question of how ILK is targeted to focal adhesions was answered by mapping a direct paxillin-binding subdomain required for localization.\",\n      \"evidence\": \"In vitro binding, reciprocal Co-IP, and PBS point mutants with GFP-ILK localization in fibroblasts\",\n      \"pmids\": [\"11304546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish whether paxillin binding is sufficient or only necessary\", \"Functional consequences downstream of localization not resolved here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic and biochemical work resolved whether ILK acts as a catalytic enzyme or a structural adaptor by showing kinase-dead ILK fully rescues null worms and by identifying core complex partners.\",\n      \"evidence\": \"C. elegans pat-4 null genetics with kinase-dead rescue, recruitment epistasis, and PINCH-2 LIM1 Co-IP/deletion mapping in mammalian cells\",\n      \"pmids\": [\"12015115\", \"12167643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mutually exclusive PINCH-1/PINCH-2 binding consequence in vivo unclear\", \"Did not directly test catalytic activity biochemically\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"In vivo knockout established that ILK's essential adaptor function in actin organization and embryonic polarity is kinase-independent, and that IPP components are mutually stabilized.\",\n      \"evidence\": \"Conditional mouse knockout with kinase-dead and paxillin-binding-defective rescue; RNAi of PINCH-1/ILK/alpha-parvin with proteasome inhibition and Akt phospho-readouts\",\n      \"pmids\": [\"12670870\", \"14551191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ILK to selective Ser473 (not Thr308) Akt phosphorylation not defined\", \"Direct molecular basis of mutual protein stabilization unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Multiple studies connected ILK to adhesion-type-specific assembly and to angiogenic and substrate-specific signaling outputs, though catalytic claims relied on immune-complex assays.\",\n      \"evidence\": \"RNAi in endothelial cells (fibrillar adhesions, capillary morphogenesis); ILKAP/PP2C Co-IP and immune-complex kinase assay; siRNA/inhibitor analysis of HIF-1alpha/VEGF angiogenesis\",\n      \"pmids\": [\"15316070\", \"14990992\", \"14749128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Immune-complex kinase activity later shown not to reflect intrinsic ILK catalysis\", \"GSK-3beta and HIF-1alpha effects could be indirect/scaffold-mediated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Overexpression and dominant-negative studies linked ILK to PI3K-dependent Akt/Rac1 activation driving actin remodeling, migration, and invasion.\",\n      \"evidence\": \"ILK overexpression and dominant-negative mutants, Rac1 activity assay, PI3K inhibition, migration/invasion assays\",\n      \"pmids\": [\"15735674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression may not reflect physiological stoichiometry\", \"Direct versus indirect contribution to Rac1 activation unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Smooth muscle studies attributed contractile signaling (CPI-17/MLC20 phosphorylation) to ILK using kinase-dead R211A, framing ILK as catalytically active.\",\n      \"evidence\": \"ILK(R211A) dominant-negative and siRNA, kinase assays, contraction and phosphorylation measurements\",\n      \"pmids\": [\"16472257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic interpretation conflicts with later pseudokinase evidence\", \"R211A effects may reflect scaffold disruption rather than lost catalysis\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Epistasis in polarizing neurons placed ILK between PI3K and Akt/GSK-3beta in axon specification, extending its role to neuronal polarity.\",\n      \"evidence\": \"ILK inhibitors, kinase-inactive and hyperactive mutants, siRNA, epistasis with PI3K/Akt/GSK-3beta, immunofluorescence\",\n      \"pmids\": [\"17490631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hyperactive-mutant phenotype hard to reconcile with pseudokinase model\", \"Molecular mechanism of axon-tip enrichment not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of Rsu-1 within the PINCH1-ILK complex and its loss upon Ras transformation linked the IPP scaffold to oncogenic signaling.\",\n      \"evidence\": \"Co-IP, co-localization, MEK inhibition, siRNA, migration assays in transformed and non-transformed cells\",\n      \"pmids\": [\"18436335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect Rsu-1 binding to ILK not resolved\", \"Functional consequence of Rsu-1 loss for adhesion incompletely defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"ELMO2/RhoG and thymosin-beta4 were defined as ILK partners coupling leading-edge actin polymerization to Akt2 activation and MMP-2-mediated matrix degradation.\",\n      \"evidence\": \"FRET, Co-IP, spatial localization, Akt2 activation and MMP-2 assays\",\n      \"pmids\": [\"19460343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the tripartite ERI complex not structurally defined\", \"Whether Tbeta4-ILK signaling requires the IPP complex unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Rigorous reconstitution, proteomics, and crystallography resolved the long-standing catalytic controversy by establishing ILK as a bona fide pseudokinase and reinterpreting kinase-dead mutations as structural.\",\n      \"evidence\": \"Recombinant in vitro kinase assays, whole-cell substrate proteomics, X-ray crystallography, thermodynamic stability, mutagenesis\",\n      \"pmids\": [\"21524996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reframes but does not re-test every prior immune-complex-based catalytic claim\", \"Role of ATP occupancy in the pseudo-active site functionally defined only later\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ILK was linked to mTORC2 and ADAM12L, connecting the scaffold to TGF-beta-driven EMT and integrin-coupled survival signaling.\",\n      \"evidence\": \"Co-IP, siRNA, ILK inhibitor, Rictor Thr1135 phospho and Akt Ser473 readouts, Snail/Slug localization\",\n      \"pmids\": [\"22310280\", \"22767580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ILK directly phosphorylates Rictor conflicts with pseudokinase status\", \"Immune-complex kinase activity attributed to ADAM12L not mechanistically defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Conditional deletion established that beta1-integrin/ILK orients microtubule plus-ends and Golgi to drive apical clearance and epithelial lumen formation, independent of Rac1.\",\n      \"evidence\": \"Cre-lox deletion in mammary organoids, live microtubule imaging, endocytosis and Golgi-positioning assays\",\n      \"pmids\": [\"23263281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular bridge from ILK to microtubule plus-ends in this context not identified\", \"Effector linking ILK to endocytic apical clearance unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The ELMO2-RhoG-ILK complex was shown to regulate microtubule dynamics integrin-independently in keratinocytes, defining a downstream Rac1/stathmin/GSK-3beta/CRMP2 pathway.\",\n      \"evidence\": \"Conditional ILK inactivation, live microtubule dynamics, ELMO2/RhoG rescue, Rac1/stathmin/GSK-3beta inhibitor experiments\",\n      \"pmids\": [\"25995380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ILK acts on microtubules independent of integrin engagement not structurally defined\", \"Direct versus indirect link to stathmin/CRMP2 unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural and biochemical work defined the architecture of IPP-mediated F-actin bundling, mapped the kindlin-2 binding surface, and revealed ILK control of VEGFR3-beta1 integrin crosstalk in lymphatics.\",\n      \"evidence\": \"Structural analysis with F-actin bundling and WH2/ATP-site mutagenesis; conservation-guided kindlin-2 binding mutants; endothelial ILK/Itgb1 conditional deletion with VEGFR3 Co-IP and rescue\",\n      \"pmids\": [\"30367047\", \"30254023\", \"30518533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Mg-ATP allosterically sensitizes bundling at the molecular level only partly defined\", \"Mechanical regulation of ILK-beta1 assembly not structurally characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Arrhythmogenic cardiomyopathy variants in the ILK ankyrin repeat domain were linked to disease via IPP-complex disruption and cardiac dysfunction in vivo.\",\n      \"evidence\": \"Exome sequencing, in silico binding modeling, H9c2 localization, zebrafish cardiac-specific overexpression\",\n      \"pmids\": [\"30802431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ILK-PINCH disruption inferred from in silico modeling, not direct structural data\", \"Zebrafish overexpression may not fully model human loss-of-function pathology\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ILK was placed within a beta-arrestin1/betaPIX/Rac3 axis driving invadopodia and ECM proteolysis downstream of endothelin A receptor in ovarian cancer.\",\n      \"evidence\": \"Co-IP of ILK/betaPIX/beta-arrestin1, Rac3 activity, invadopodia and ECM degradation assays, in vivo ETAR antagonist\",\n      \"pmids\": [\"33657382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ILK interaction surfaces in this complex not mapped\", \"Requirement for the canonical IPP complex in this signaling not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ILK was shown to act non-cell-autonomously, exported in extracellular vesicles to activate fibroblasts via p38 MAPK and drive peritoneal fibrosis.\",\n      \"evidence\": \"EV proteomics, scRNA-seq, EV transfer, Rab27a knockdown and GW4869 inhibition, p38 MAPK readout\",\n      \"pmids\": [\"37357686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which EV-delivered ILK activates p38 unclear\", \"Whether ILK acts as scaffold or via partners in recipient cells not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the Mg-ATP-occupied pseudo-active site allosterically couples to F-actin bundling and partner engagement, and how mechanical force reconfigures ILK-integrin assemblies, remain mechanistically incomplete.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full structural model of the force-dependent ILK-integrin-VEGFR3 switch\", \"Allosteric transmission from ATP site to WH2-driven bundling not resolved at atomic resolution\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 19, 20]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [19, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 7, 20]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 4, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 15, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 17, 21]}\n    ],\n    \"complexes\": [\n      \"IPP (ILK-PINCH-Parvin) complex\",\n      \"focal adhesion\",\n      \"ELMO2-RhoG-ILK (ERI) complex\",\n      \"ILK-Rictor (mTORC2)\"\n    ],\n    \"partners\": [\n      \"PINCH\",\n      \"Parvin\",\n      \"PXN\",\n      \"FERMT2\",\n      \"ELMO2\",\n      \"RICTOR\",\n      \"RHOG\",\n      \"ILKAP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}