{"gene":"PHLDB2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2002,"finding":"LL5beta (PHLDB2) selectively binds phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) via its PH domain in vitro; its subcellular localization is dynamically regulated by PI3K activity, moving from vesicular compartments at low PIP3 to cytoplasmic/plasma membrane localization at high PIP3; PH domain mutants unable to bind PIP3 are constitutively vesicular. LL5beta also binds the cytoskeletal adaptor gamma-filamin tightly and in a PI3K-independent manner both in vitro and in vivo.","method":"In vitro PIP3-binding assay, PI3K inhibitor treatments (wortmannin/LY294002), PDGFR mutant expression, GFP-fusion live imaging, co-immunoprecipitation, PH domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay with mutagenesis, in vivo co-IP, and multiple pharmacological/genetic perturbations in one study","pmids":["12376540"],"is_preprint":false},{"year":2005,"finding":"LL5beta is concentrated at the cytoplasmic face of the postsynaptic membrane at the neuromuscular junction, its highest levels border regions of highest AChR density, and it binds filamin (a synaptic cytoskeletal protein). Perturbing LL5beta expression in myotubes inhibits AChR aggregation, establishing a role in postsynaptic apparatus assembly.","method":"Microarray-based synaptic transcript enrichment screen, immunolocalization, filamin binding assay, siRNA/dominant-negative perturbation in myotubes with AChR aggregation readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization, binding assay, and loss-of-function with defined cellular phenotype in one focused study","pmids":["15851520"],"is_preprint":false},{"year":2006,"finding":"LL5beta forms a complex with ELKS and CLASPs at the cell cortex; LL5beta is required for cortical CLASP accumulation and microtubule stabilization. LL5beta recruitment to the cortex is PI3K/PIP3-dependent but does not require intact microtubules. Cortical LL5beta/ELKS clusters form near but distinct from focal adhesions and can influence focal adhesion size.","method":"Mass spectrometry-based identification of CLASP partners, co-immunoprecipitation, RNAi knockdown, live-cell imaging, PI3K inhibitor treatments, microtubule depolymerization assays in HeLa cells and fibroblasts","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based complex identification, reciprocal Co-IP, RNAi with defined phenotype, multiple orthogonal methods, replicated across cell types","pmids":["16824950"],"is_preprint":false},{"year":2006,"finding":"An N-terminal region of LL5beta is responsible for binding to the C-terminus of filamins (including filamin C); a separate additional domain cooperates to localize the complex to punctate vesicular structures under low PI3K activity. PtdIns(3,4,5)P3 binding to the C-terminal PH domain prevents this vesicular localization under high PI3K activity.","method":"Domain deletion/mutagenesis of LL5beta, co-localization with filamin C and L-FILIP, overexpression under varying PI3K conditions","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with mutagenesis and localization, single lab, no in vitro reconstitution","pmids":["17174070"],"is_preprint":false},{"year":2010,"finding":"LL5beta, directed to the plasma membrane by PtdIns(3,4,5)P3, recruits filamin A and the PIP3-phosphatase SHIP2 to sites of PIP3 accumulation. This recruits filamin A to cross-link newly polymerized F-actin and enhances lamellipodium formation. Co-recruited SHIP2 then dephosphorylates PIP3 at the same location, providing reciprocal feedback regulation. Depletion of either filamin A or LL5beta, or expression of an actin-cross-linking mutant of filamin A or a LL5beta PIP3-binding mutant, inhibits lamellipodium formation.","method":"Co-immunoprecipitation, siRNA knockdown, mutant overexpression, EGF stimulation assay, live-cell imaging in COS-7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple domain mutants, knockdown and overexpression with defined phenotype, multiple orthogonal methods in one study","pmids":["20236936"],"is_preprint":false},{"year":2013,"finding":"LL5beta interacts with three actin cytoskeleton regulators — Amotl2, Asef2, and Flii — as identified by purification of LL5beta-associated proteins from myotubes. LL5beta and its interacting partners are components of synaptic podosomes; LL5beta plays a key role in postsynaptic maturation at the NMJ.","method":"Affinity purification/mass spectrometry of LL5beta-associated proteins from myotubes, co-immunoprecipitation, RNAi knockdown with podosome and NMJ morphology readouts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome, Co-IP validation, RNAi with defined phenotype, multiple orthogonal methods","pmids":["23525008"],"is_preprint":false},{"year":2014,"finding":"BMP2 stimulation triggers PI3K p55γ/p110α-dependent PIP3 production at the leading edge, which recruits LL5beta to the cytocortex; knockdown of LL5beta impairs BMP2-induced actin reorganization and chemotaxis of mesenchymal progenitor cells, placing LL5beta as a downstream effector in the BMP2-PI3K-PIP3 signaling axis.","method":"Protein interaction studies (Co-IP), mass spectrometry identification of LL5beta, live-cell imaging, siRNA knockdown of p55γ or LL5beta, PI3K inhibitor treatment, migration/chemotaxis assays","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS identification, knockdown with functional readout, single lab","pmids":["24885555"],"is_preprint":false},{"year":2015,"finding":"LL5beta is required for CLASP2-dependent microtubule capture at the neuromuscular junction membrane; knockdown of LL5beta or forced expression of a CLASP2 fragment blocking CLASP2/LL5beta interaction inhibits microtubule capture and impairs focal AChR vesicle delivery to postsynaptic clusters. In vivo knockdown of LL5beta at the NMJ reduces AChR density and insertion into the postsynaptic membrane.","method":"RNAi knockdown in cultured myotubes, dominant-negative CLASP2 fragment expression, live-cell vesicle tracking, in vivo RNAi at NMJ with AChR density quantification","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple loss-of-function strategies (RNAi, dominant-negative), in vitro and in vivo validation, defined molecular and cellular phenotypes","pmids":["25589673"],"is_preprint":false},{"year":2016,"finding":"Prickle1 associates with CLASPs and LL5beta (PHLDB2) and is required for LL5beta-dependent accumulation of CLASPs at the cell edge, thereby promoting focal adhesion disassembly during cell polarization and migration. Prickle1 membrane localization via its farnesyl moiety is necessary for binding CLASPs and LL5beta and for promoting microtubule targeting of focal adhesions.","method":"Co-immunoprecipitation, RNAi knockdown of CLASPs/LL5beta, live-cell imaging of focal adhesion dynamics, farnesylation mutant analysis in MKN1 gastric cancer cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi with defined phenotype, mutant analysis, single lab","pmids":["27378169"],"is_preprint":false},{"year":2019,"finding":"Phldb2 binds the postsynaptic scaffolding molecule PSD-95 and is required for PSD-95 localization and turnover in dendritic spines; Phldb2 also binds GluA1 and GluA2 (AMPA receptor subunits) and is indispensable for the interaction between NMDA receptors and CaMKII, and for synaptic AMPA receptor density. BDNF application recruits Phldb2 toward postsynaptic membrane in spines in a PI3K-dependent manner. Phldb2 knockout mice show impaired LTP and memory formation.","method":"Co-immunoprecipitation, BDNF stimulation with live imaging, PI3K inhibitor treatment, Phldb2 knockout mouse with LTP electrophysiology and memory behavioral assay, synaptic fractionation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for multiple partners, genetic KO mouse with electrophysiological and behavioral phenotypes, PI3K perturbation, multiple orthogonal methods","pmids":["30867511"],"is_preprint":false},{"year":2019,"finding":"PHLDB2 binds MDM2 and facilitates MDM2-mediated E-cadherin degradation. PHLDB2 knockdown attenuates colon cancer cell migration, invasion, and TGF-β/EGF-induced E-cadherin reduction.","method":"Co-immunoprecipitation, siRNA knockdown, TGF-β/EGF treatment, wound healing and transwell invasion assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for MDM2 interaction, siRNA knockdown with migration/invasion phenotype, single lab","pmids":["31346319"],"is_preprint":false},{"year":2021,"finding":"NOTCH3 transcriptionally upregulates PHLDB2 expression, and PHLDB2 acts as a downstream functional modulator activating the Akt-mTOR signaling pathway in gastric cancer cells. siRNA-mediated knockdown of PHLDB2 suppresses proliferation, invasion, and sensitizes cells to chemotherapy.","method":"RNA-seq profiling after NOTCH3 knockdown, siRNA knockdown of PHLDB2, functional cell assays, pathway analysis","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA-seq based identification, siRNA knockdown with functional readout, no direct biochemical demonstration of NOTCH3-PHLDB2 transcriptional mechanism beyond correlation","pmids":["33452458"],"is_preprint":false},{"year":2021,"finding":"Oxidative stress promotes METTL14-mediated N6-methyladenosine (m6A) modification of PHLDB2 mRNA, facilitating its protein expression. Upregulated PHLDB2 stabilizes EGFR and promotes its nuclear translocation, activating EGFR signaling and causing cetuximab resistance. The Arg1163 residue of PHLDB2 is critical for interaction with EGFR; R1163A mutation abrogates EGFR regulatory function.","method":"RNA immunoprecipitation, mass spectrometry, Duolink proximity ligation assay, site-directed mutagenesis (R1163A), CRC cell lines and mouse models","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation assay and mass spectrometry for EGFR interaction, site-directed mutagenesis, multiple functional assays, single lab","pmids":["34952201"],"is_preprint":false},{"year":2022,"finding":"The Legionella pneumophila effector Lem8 is a Cys-His-Asp protease activated by host 14-3-3ζ; activated Lem8 cleaves PHLDB2 (Phldb2), thereby inhibiting host cell migration and cytoskeletal organization. Lem8 undergoes 14-3-3ζ-dependent self-cleavage.","method":"In vitro protease activity assay with Cys-His-Asp catalytic motif mutagenesis, co-immunoprecipitation of Lem8 with 14-3-3ζ, identification of Phldb2 as substrate, cell migration assay after Lem8 expression","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic residue mutagenesis, in vitro protease assay, substrate identification, 14-3-3ζ interaction Co-IP, functional migration readout in single rigorous study","pmids":["35175192"],"is_preprint":false},{"year":2022,"finding":"Phldb2 binds specifically to drebrin A (adult-type isoform) but not drebrin E (embryonic isoform) in hippocampal neurons. In Phldb2 knockout mice, drebrin A localization in hippocampal spines is altered; immature filopodium-type spines increase and mushroom spines decrease in CA1, and Phldb2 suppresses abnormal filopodium formation induced by drebrin A overexpression.","method":"Co-immunoprecipitation (isoform-selective), Phldb2 knockout mouse, immunofluorescence of spine morphology, drebrin A overexpression rescue experiments","journal":"Neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-selective Co-IP, genetic KO with morphological phenotype, overexpression rescue, single lab","pmids":["36162735"],"is_preprint":false},{"year":2023,"finding":"LL5beta directly interacts with ERC1 (ELKS/CAST family scaffold) through minimal fragments LL5β(381-510) and ERC1(270-370), involving intrinsically disordered regions in a reversible, high-affinity heterotypic interaction. Expression of LL5β(381-510) fragment hampers endogenous ERC1/LL5beta complex formation, delocalizes ERC1 from the leading edge, reduces invadopodia density, and inhibits tumor cell invasion.","method":"NMR spectroscopy, co-immunoprecipitation, fragment competition assay, transwell invasion assay, live-cell imaging of invadopodia in MDA-MB-231 cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization plus Co-IP plus functional competition fragment assay with invasion phenotype, single lab but multiple orthogonal methods","pmids":["37437062"],"is_preprint":false},{"year":2025,"finding":"PHLDB2 contains intrinsically disordered regions (IDRs) and forms dynamic, reversible liquid-liquid phase separation condensates in cells, as confirmed by FRAP. PHLDB2 knockdown suppresses EMT markers, inhibits tumor growth and pulmonary metastasis in TNBC xenograft models.","method":"PONDR IDR prediction, immunofluorescence, FRAP assay, siRNA knockdown in MDA-MB-231/HCC38 cells, in vivo xenograft and metastasis models","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP confirms LLPS, in vivo model, siRNA knockdown with phenotype, but single lab and no mechanistic reconstitution of phase separation function","pmids":["41319208"],"is_preprint":false},{"year":2025,"finding":"ELKS/LL5beta cortical patches define insulin secretion sites in pancreatic beta cells; however, secretion occurs at only ~5% of the patch area, predominantly at margins of ELKS patches devoid of microtubules, indicating that LL5beta-containing platforms are necessary but not sufficient to specify secretion hot spots and that local MT disassembly within these platforms gates secretory activity.","method":"TIRF microscopy of intact mouse islets, live imaging of secretion event localization relative to ELKS/LL5beta patches and MT distribution","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct TIRF imaging of secretion events vs. LL5beta patch structure in intact tissue, single lab, no genetic perturbation of LL5beta in this study","pmids":["40366873"],"is_preprint":false}],"current_model":"PHLDB2 (LL5beta) is a PIP3-sensing PH-domain scaffold protein that is recruited to the plasma membrane/cell cortex by PI3K-generated PtdIns(3,4,5)P3, where it nucleates a multi-protein platform — including CLASPs, ELKS/ERC1, filamin A, and SHIP2 — to anchor microtubule plus ends to the cortex, drive focal adhesion disassembly, promote lamellipodium formation, and mediate directed vesicle delivery (e.g., AChR vesicles at the NMJ and insulin granules in beta cells); in neurons it additionally binds PSD-95, AMPA receptor subunits, and drebrin A to regulate dendritic spine morphology and LTP, while in cancer contexts it stabilizes EGFR, interacts with MDM2 to degrade E-cadherin, undergoes liquid-liquid phase separation, and can be proteolytically inactivated by the bacterial effector Lem8 to suppress host cell motility."},"narrative":{"mechanistic_narrative":"PHLDB2 (LL5beta) is a PI3K-responsive PH-domain scaffold that builds cortical platforms linking phosphoinositide signaling to the microtubule and actin cytoskeleton [PMID:12376540, PMID:16824950]. Its PH domain selectively binds PtdIns(3,4,5)P3, so that PI3K activity dynamically controls its movement between vesicular compartments and the plasma membrane/cell cortex, while a separate N-terminal region binds filamin independently of PI3K [PMID:12376540, PMID:17174070]. At the cortex, PHLDB2 assembles a multiprotein platform with ELKS/ERC1 and CLASPs that captures and stabilizes microtubule plus ends, and it directly engages ERC1 through intrinsically disordered regions [PMID:16824950, PMID:37437062]. Through this platform PHLDB2 organizes actin-based protrusion and adhesion remodeling: PIP3-directed PHLDB2 recruits filamin A to cross-link F-actin and co-recruits the PIP3 phosphatase SHIP2 to drive lamellipodium formation [PMID:20236936], and acts downstream of BMP2-PI3K signaling to support actin reorganization and chemotaxis [PMID:24885555]. At the neuromuscular junction, PHLDB2 nucleates postsynaptic assembly and CLASP2-dependent microtubule capture that delivers AChR vesicles to postsynaptic clusters, and loss of PHLDB2 reduces AChR aggregation and density [PMID:15851520, PMID:23525008, PMID:25589673]. In neurons, PHLDB2 binds PSD-95, AMPA receptor subunits GluA1/GluA2, and the adult-type isoform drebrin A to control dendritic spine maturation, synaptic receptor density, and LTP, with knockout mice showing impaired memory [PMID:30867511, PMID:36162735]. In cancer it stabilizes EGFR through an interaction requiring Arg1163 and promotes EGFR signaling and cetuximab resistance, binds MDM2 to facilitate E-cadherin degradation, and forms reversible liquid-liquid phase-separation condensates that support EMT, invasion, and metastasis [PMID:31346319, PMID:34952201, PMID:37437062, PMID:41319208]. PHLDB2 is also a direct substrate of the Legionella pneumophila protease effector Lem8, whose cleavage of PHLDB2 suppresses host cell migration and cytoskeletal organization [PMID:35175192].","teleology":[{"year":2002,"claim":"Established the molecular logic by which PHLDB2 is positioned in cells: it is a PIP3 sensor whose localization is set by PI3K activity, while also constitutively binding filamin.","evidence":"In vitro PIP3-binding assay, PH domain mutagenesis, PI3K inhibition, and co-IP in cultured cells","pmids":["12376540"],"confidence":"High","gaps":["Does not define the downstream cortical machinery recruited by membrane-localized PHLDB2","Functional consequence of filamin binding not yet established"]},{"year":2005,"claim":"Showed PHLDB2 has a physiological role at the postsynaptic membrane of the NMJ, linking it to AChR clustering and synaptic apparatus assembly.","evidence":"Synaptic transcript screen, immunolocalization, filamin binding, and loss-of-function in myotubes scoring AChR aggregation","pmids":["15851520"],"confidence":"High","gaps":["Mechanism connecting PHLDB2 to AChR aggregation not resolved","Cytoskeletal effectors at the postsynaptic platform unidentified"]},{"year":2006,"claim":"Defined the core cortical microtubule-capture platform: PHLDB2 recruits CLASPs via ELKS in a PIP3-dependent manner to stabilize microtubules near focal adhesions.","evidence":"Mass spectrometry of CLASP partners, reciprocal Co-IP, RNAi with microtubule/focal-adhesion phenotypes across HeLa and fibroblasts; plus domain mapping of filamin binding","pmids":["16824950","17174070"],"confidence":"High","gaps":["Stoichiometry and structural basis of the ELKS/CLASP/PHLDB2 complex not defined","How cortical clusters communicate with focal adhesions unresolved"]},{"year":2010,"claim":"Extended PHLDB2 function to actin-based protrusion, showing it couples PIP3 sensing to filamin A-mediated actin cross-linking and SHIP2-mediated feedback at lamellipodia.","evidence":"Reciprocal Co-IP, domain mutants, knockdown/overexpression with lamellipodium readout after EGF in COS-7 cells","pmids":["20236936"],"confidence":"High","gaps":["Quantitative kinetics of the PIP3 feedback loop not measured","Interplay between actin protrusion and microtubule capture roles unresolved"]},{"year":2013,"claim":"Expanded the PHLDB2 actin interactome (Amotl2, Asef2, Flii) and tied it to synaptic podosomes and postsynaptic maturation at the NMJ.","evidence":"Affinity purification/MS from myotubes, Co-IP, RNAi with podosome and NMJ morphology readouts","pmids":["23525008"],"confidence":"High","gaps":["Individual contributions of Amotl2/Asef2/Flii to PHLDB2 function not dissected","Direct vs. indirect nature of these associations not all established"]},{"year":2014,"claim":"Placed PHLDB2 downstream of a defined receptor signal (BMP2-PI3K-PIP3) for directional cell migration.","evidence":"Co-IP, MS identification, siRNA of p55γ or PHLDB2, PI3K inhibition, chemotaxis assays in mesenchymal progenitors","pmids":["24885555"],"confidence":"Medium","gaps":["Single lab","Does not establish whether BMP2 effect is direct on PHLDB2 recruitment versus broad PIP3 elevation"]},{"year":2015,"claim":"Demonstrated the functional output of the cortical platform at the NMJ: PHLDB2 is required for CLASP2-dependent microtubule capture that delivers AChR vesicles, validated in vivo.","evidence":"RNAi, dominant-negative CLASP2 fragment, live vesicle tracking in myotubes, and in vivo NMJ RNAi with AChR density","pmids":["25589673"],"confidence":"High","gaps":["Vesicle tethering/fusion machinery linked to PHLDB2 platforms not identified","Generality to other secretory systems not addressed here"]},{"year":2016,"claim":"Identified Prickle1 as an upstream organizer that, via membrane farnesylation, drives PHLDB2/CLASP cortical accumulation to promote focal adhesion disassembly during migration.","evidence":"Co-IP, RNAi, farnesylation mutant, and focal adhesion live imaging in gastric cancer cells","pmids":["27378169"],"confidence":"Medium","gaps":["Single lab","Direct vs. bridged interaction between Prickle1 and PHLDB2 not resolved"]},{"year":2019,"claim":"Established a neuronal synaptic role distinct from the NMJ: PHLDB2 organizes PSD-95 and AMPA receptors and is required for normal synaptic plasticity and memory.","evidence":"Reciprocal Co-IP for PSD-95/GluA1/GluA2, BDNF/PI3K imaging, and knockout mouse with LTP and behavioral phenotypes","pmids":["30867511"],"confidence":"High","gaps":["Structural basis of receptor scaffolding not defined","Whether spine role uses the same ELKS/CLASP platform unresolved"]},{"year":2019,"claim":"Opened a cancer mechanism: PHLDB2 binds MDM2 to promote E-cadherin degradation and tumor cell migration/invasion.","evidence":"Co-IP, siRNA, TGF-β/EGF treatment, and migration/invasion assays in colon cancer cells","pmids":["31346319"],"confidence":"Medium","gaps":["Single lab","Whether PHLDB2 directly promotes MDM2 ubiquitination of E-cadherin not shown"]},{"year":2021,"claim":"Linked PHLDB2 to oncogenic signaling networks, as a NOTCH3-regulated activator of Akt-mTOR in gastric cancer.","evidence":"RNA-seq after NOTCH3 knockdown, siRNA of PHLDB2, functional assays and pathway analysis","pmids":["33452458"],"confidence":"Low","gaps":["Correlative transcriptional link only; direct NOTCH3-PHLDB2 regulatory mechanism not demonstrated","How PHLDB2 activates Akt-mTOR not defined"]},{"year":2021,"claim":"Defined an m6A-regulated EGFR-stabilizing function: oxidative stress and METTL14-driven m6A boost PHLDB2, which stabilizes EGFR and drives nuclear translocation and cetuximab resistance via an Arg1163-dependent interaction.","evidence":"RNA-IP, MS, proximity ligation assay, R1163A mutagenesis, CRC cell lines and mouse models","pmids":["34952201"],"confidence":"Medium","gaps":["Single lab","Direct vs. complex-mediated PHLDB2-EGFR contact not structurally resolved"]},{"year":2022,"claim":"Revealed PHLDB2 as a target of host-pathogen warfare: the Legionella effector protease Lem8, activated by 14-3-3ζ, cleaves PHLDB2 to suppress host migration and cytoskeletal organization.","evidence":"In vitro protease assay with catalytic mutants, Lem8/14-3-3ζ Co-IP, substrate identification, and migration assay","pmids":["35175192"],"confidence":"High","gaps":["Cleavage site on PHLDB2 and fate of fragments not detailed","Which PHLDB2-dependent cytoskeletal output is most affected not isolated"]},{"year":2022,"claim":"Refined the synaptic mechanism by showing PHLDB2 binds adult-type drebrin A and suppresses immature filopodial spine formation, controlling spine maturation.","evidence":"Isoform-selective Co-IP, knockout mouse spine morphology, and drebrin A overexpression rescue in hippocampal neurons","pmids":["36162735"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between drebrin A binding and spine shape change not fully resolved"]},{"year":2023,"claim":"Provided structural and functional dissection of the PHLDB2-ERC1 interaction, mapping a reversible high-affinity contact via intrinsically disordered regions that supports invadopodia and tumor invasion.","evidence":"NMR of minimal fragments, Co-IP, competition fragment expression, invasion and invadopodia imaging in breast cancer cells","pmids":["37437062"],"confidence":"High","gaps":["Single lab","Affinity values and full-length complex architecture not reported here"]},{"year":2025,"claim":"Identified intrinsically disordered region-driven liquid-liquid phase separation as a property of PHLDB2 linked to EMT, tumor growth, and metastasis.","evidence":"IDR prediction, FRAP, siRNA in breast cancer cells, and xenograft/metastasis models","pmids":["41319208"],"confidence":"Medium","gaps":["Single lab","Whether condensate formation is mechanistically required for the cytoskeletal/scaffolding functions not reconstituted"]},{"year":2025,"claim":"Showed in intact tissue that PHLDB2/ELKS cortical patches mark but do not fully specify insulin secretion sites, with local microtubule disassembly gating where secretion occurs.","evidence":"TIRF imaging of secretion events relative to ELKS/LL5beta patches and microtubules in intact mouse islets","pmids":["40366873"],"confidence":"Medium","gaps":["No genetic perturbation of PHLDB2 in this study","Molecular trigger for local MT disassembly within patches unknown"]},{"year":null,"claim":"How PHLDB2's distinct activities — cortical microtubule capture, actin protrusion, synaptic scaffolding, EGFR stabilization, and phase separation — are mechanistically integrated and selectively deployed in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the full cortical platform","Whether LLPS underlies the canonical CLASP/ELKS platform function untested","Tissue-specific partner selection logic undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,9,15]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,5,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,4,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12,16]}],"complexes":["ELKS/LL5beta-CLASP cortical platform","synaptic podosome"],"partners":["ERC1","CLASP2","FLNA","FLNC","SHIP2/INPPL1","PSD-95/DLG4","MDM2","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86SQ0","full_name":"Pleckstrin homology-like domain family B member 2","aliases":["Protein LL5-beta"],"length_aa":1253,"mass_kda":142.2,"function":"Seems to be involved in the assembly of the postsynaptic apparatus. May play a role in acetyl-choline receptor (AChR) aggregation in the postsynaptic membrane (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cell cortex; Membrane; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q86SQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHLDB2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHLDB2","total_profiled":1310},"omim":[{"mim_id":"610298","title":"PLECKSTRIN HOMOLOGY-LIKE DOMAIN, FAMILY B, MEMBER 2; PHLDB2","url":"https://www.omim.org/entry/610298"},{"mim_id":"607127","title":"ELKS/RAB6-INTERACTING/CAST FAMILY, MEMBER 1; ERC1","url":"https://www.omim.org/entry/607127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHLDB2"},"hgnc":{"alias_symbol":["LL5beta","FLJ21791","LL5b"],"prev_symbol":[]},"alphafold":{"accession":"Q86SQ0","domains":[{"cath_id":"1.10.287,1.10.287","chopping":"586-816","consensus_level":"high","plddt":93.6861,"start":586,"end":816},{"cath_id":"2.30.29.30","chopping":"1121-1252","consensus_level":"high","plddt":88.1395,"start":1121,"end":1252},{"cath_id":"1.20.5","chopping":"1045-1107","consensus_level":"medium","plddt":83.5268,"start":1045,"end":1107}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SQ0-F1-predicted_aligned_error_v6.png","plddt_mean":58.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHLDB2","jax_strain_url":"https://www.jax.org/strain/search?query=PHLDB2"},"sequence":{"accession":"Q86SQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86SQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86SQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SQ0"}},"corpus_meta":[{"pmid":"16824950","id":"PMC_16824950","title":"CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta.","date":"2006","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16824950","citation_count":256,"is_preprint":false},{"pmid":"15851520","id":"PMC_15851520","title":"LL5beta: a regulator of postsynaptic differentiation identified in a screen for synaptically enriched transcripts at the neuromuscular junction.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15851520","citation_count":73,"is_preprint":false},{"pmid":"28392396","id":"PMC_28392396","title":"p53 target miR-29c-3p suppresses colon cancer cell invasion and migration through inhibition of PHLDB2.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28392396","citation_count":50,"is_preprint":false},{"pmid":"12376540","id":"PMC_12376540","title":"LL5beta is a phosphatidylinositol (3,4,5)-trisphosphate sensor that can bind the cytoskeletal adaptor, gamma-filamin.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12376540","citation_count":45,"is_preprint":false},{"pmid":"23525008","id":"PMC_23525008","title":"Amotl2 interacts with LL5β, localizes to podosomes and regulates postsynaptic differentiation in muscle.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23525008","citation_count":44,"is_preprint":false},{"pmid":"27378169","id":"PMC_27378169","title":"Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27378169","citation_count":35,"is_preprint":false},{"pmid":"24885555","id":"PMC_24885555","title":"BMP2-induced chemotaxis requires PI3K p55γ/p110α-dependent phosphatidylinositol (3,4,5)-triphosphate production and LL5β recruitment at the cytocortex.","date":"2014","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/24885555","citation_count":34,"is_preprint":false},{"pmid":"33452458","id":"PMC_33452458","title":"NOTCH3, a crucial target of miR-491-5p/miR-875-5p, promotes gastric carcinogenesis by upregulating PHLDB2 expression and activating Akt pathway.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33452458","citation_count":33,"is_preprint":false},{"pmid":"20236936","id":"PMC_20236936","title":"LL5beta directs the translocation of filamin A and SHIP2 to sites of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulation, and PtdIns(3,4,5)P3 localization is mutually modified by co-recruited SHIP2.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20236936","citation_count":32,"is_preprint":false},{"pmid":"25589673","id":"PMC_25589673","title":"CLASP2-dependent microtubule capture at the neuromuscular junction membrane requires LL5β and actin for focal delivery of acetylcholine receptor vesicles.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25589673","citation_count":30,"is_preprint":false},{"pmid":"35175192","id":"PMC_35175192","title":"Legionella pneumophila regulates host cell motility by targeting Phldb2 with a 14-3-3ζ-dependent protease effector.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35175192","citation_count":28,"is_preprint":false},{"pmid":"34952201","id":"PMC_34952201","title":"PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal Cancer.","date":"2021","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34952201","citation_count":26,"is_preprint":false},{"pmid":"34746118","id":"PMC_34746118","title":"NR2F1-AS1/miR-190a/PHLDB2 Induces the Epithelial-Mesenchymal Transformation Process in Gastric Cancer by Promoting Phosphorylation of AKT3.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34746118","citation_count":22,"is_preprint":false},{"pmid":"30867511","id":"PMC_30867511","title":"PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30867511","citation_count":19,"is_preprint":false},{"pmid":"33320958","id":"PMC_33320958","title":"Oncometabolite L-2-hydroxyglurate directly induces vasculogenic mimicry through PHLDB2 in renal cell carcinoma.","date":"2021","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33320958","citation_count":19,"is_preprint":false},{"pmid":"31346319","id":"PMC_31346319","title":"Oncogenic effect of PHLDB2 is associated with epithelial-mesenchymal transition and E-cadherin regulation in colorectal cancer.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31346319","citation_count":18,"is_preprint":false},{"pmid":"17174070","id":"PMC_17174070","title":"Structural determinants of LL5beta subcellular localisation and association with filamin C.","date":"2006","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/17174070","citation_count":10,"is_preprint":false},{"pmid":"22111664","id":"PMC_22111664","title":"Functions of intronic nucleotide variants in the gene encoding pleckstrin homology like domain beta 2 (PHLDB2) on susceptibility to vascular dementia.","date":"2011","source":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/22111664","citation_count":8,"is_preprint":false},{"pmid":"40366873","id":"PMC_40366873","title":"Directed insulin secretion from beta cells occurs at cortical sites devoid of microtubules at the edges of ELKS/LL5β patches.","date":"2025","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/40366873","citation_count":4,"is_preprint":false},{"pmid":"38397469","id":"PMC_38397469","title":"Depletion of PHLDB2 Suppresses Epithelial-Mesenchymal Transition and Enhances Anti-Tumor Immunity in Head and Neck Squamous Cell Carcinoma.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38397469","citation_count":3,"is_preprint":false},{"pmid":"37437062","id":"PMC_37437062","title":"Interfering with the ERC1-LL5β interaction disrupts plasma membrane-Associated platforms and affects tumor cell motility.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37437062","citation_count":2,"is_preprint":false},{"pmid":"34337001","id":"PMC_34337001","title":"RNA-seq-Based Screening in Coal Dust-Treated Cells Identified PHLDB2 as a Novel Lung Cancer-Related Molecular Marker.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/34337001","citation_count":2,"is_preprint":false},{"pmid":"36162735","id":"PMC_36162735","title":"Phldb2 is essential for regulating hippocampal dendritic spine morphology through drebrin in an adult-type isoform-specific manner.","date":"2022","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/36162735","citation_count":2,"is_preprint":false},{"pmid":"39553950","id":"PMC_39553950","title":"Directed insulin secretion from beta cells occurs at cortical sites devoid of microtubules at the edges of ELKS/LL5β patches.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39553950","citation_count":1,"is_preprint":false},{"pmid":"41319208","id":"PMC_41319208","title":"Phase Separation of PHLDB2 Drives EMT and Tumor Progression in Triple-Negative Breast Cancer.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41319208","citation_count":0,"is_preprint":false},{"pmid":"41133469","id":"PMC_41133469","title":"Liquid‑liquid phase separation of PHLDB2 promotes oral squamous cell carcinoma metastasis through regulating epithelial mesenchymal transition and PIK3CA expression.","date":"2025","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/41133469","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.31.630861","title":"Single-cell RNA sequencing analysis reveals new insights for intersex gonad initiation and early sex differentiation of goats","date":"2024-12-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.31.630861","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.19.624272","title":"Sensitivity to Vγ9Vδ2TCR T cells is imprinted after single mutations during early oncogenesis","date":"2024-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.19.624272","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16646,"output_tokens":5138,"usd":0.063504,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13386,"output_tokens":5391,"usd":0.100852,"stage2_stop_reason":"end_turn"},"total_usd":0.164356,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"LL5beta (PHLDB2) selectively binds phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) via its PH domain in vitro; its subcellular localization is dynamically regulated by PI3K activity, moving from vesicular compartments at low PIP3 to cytoplasmic/plasma membrane localization at high PIP3; PH domain mutants unable to bind PIP3 are constitutively vesicular. LL5beta also binds the cytoskeletal adaptor gamma-filamin tightly and in a PI3K-independent manner both in vitro and in vivo.\",\n      \"method\": \"In vitro PIP3-binding assay, PI3K inhibitor treatments (wortmannin/LY294002), PDGFR mutant expression, GFP-fusion live imaging, co-immunoprecipitation, PH domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay with mutagenesis, in vivo co-IP, and multiple pharmacological/genetic perturbations in one study\",\n      \"pmids\": [\"12376540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LL5beta is concentrated at the cytoplasmic face of the postsynaptic membrane at the neuromuscular junction, its highest levels border regions of highest AChR density, and it binds filamin (a synaptic cytoskeletal protein). Perturbing LL5beta expression in myotubes inhibits AChR aggregation, establishing a role in postsynaptic apparatus assembly.\",\n      \"method\": \"Microarray-based synaptic transcript enrichment screen, immunolocalization, filamin binding assay, siRNA/dominant-negative perturbation in myotubes with AChR aggregation readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization, binding assay, and loss-of-function with defined cellular phenotype in one focused study\",\n      \"pmids\": [\"15851520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LL5beta forms a complex with ELKS and CLASPs at the cell cortex; LL5beta is required for cortical CLASP accumulation and microtubule stabilization. LL5beta recruitment to the cortex is PI3K/PIP3-dependent but does not require intact microtubules. Cortical LL5beta/ELKS clusters form near but distinct from focal adhesions and can influence focal adhesion size.\",\n      \"method\": \"Mass spectrometry-based identification of CLASP partners, co-immunoprecipitation, RNAi knockdown, live-cell imaging, PI3K inhibitor treatments, microtubule depolymerization assays in HeLa cells and fibroblasts\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based complex identification, reciprocal Co-IP, RNAi with defined phenotype, multiple orthogonal methods, replicated across cell types\",\n      \"pmids\": [\"16824950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"An N-terminal region of LL5beta is responsible for binding to the C-terminus of filamins (including filamin C); a separate additional domain cooperates to localize the complex to punctate vesicular structures under low PI3K activity. PtdIns(3,4,5)P3 binding to the C-terminal PH domain prevents this vesicular localization under high PI3K activity.\",\n      \"method\": \"Domain deletion/mutagenesis of LL5beta, co-localization with filamin C and L-FILIP, overexpression under varying PI3K conditions\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with mutagenesis and localization, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"17174070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LL5beta, directed to the plasma membrane by PtdIns(3,4,5)P3, recruits filamin A and the PIP3-phosphatase SHIP2 to sites of PIP3 accumulation. This recruits filamin A to cross-link newly polymerized F-actin and enhances lamellipodium formation. Co-recruited SHIP2 then dephosphorylates PIP3 at the same location, providing reciprocal feedback regulation. Depletion of either filamin A or LL5beta, or expression of an actin-cross-linking mutant of filamin A or a LL5beta PIP3-binding mutant, inhibits lamellipodium formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, mutant overexpression, EGF stimulation assay, live-cell imaging in COS-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple domain mutants, knockdown and overexpression with defined phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20236936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LL5beta interacts with three actin cytoskeleton regulators — Amotl2, Asef2, and Flii — as identified by purification of LL5beta-associated proteins from myotubes. LL5beta and its interacting partners are components of synaptic podosomes; LL5beta plays a key role in postsynaptic maturation at the NMJ.\",\n      \"method\": \"Affinity purification/mass spectrometry of LL5beta-associated proteins from myotubes, co-immunoprecipitation, RNAi knockdown with podosome and NMJ morphology readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome, Co-IP validation, RNAi with defined phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"23525008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BMP2 stimulation triggers PI3K p55γ/p110α-dependent PIP3 production at the leading edge, which recruits LL5beta to the cytocortex; knockdown of LL5beta impairs BMP2-induced actin reorganization and chemotaxis of mesenchymal progenitor cells, placing LL5beta as a downstream effector in the BMP2-PI3K-PIP3 signaling axis.\",\n      \"method\": \"Protein interaction studies (Co-IP), mass spectrometry identification of LL5beta, live-cell imaging, siRNA knockdown of p55γ or LL5beta, PI3K inhibitor treatment, migration/chemotaxis assays\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS identification, knockdown with functional readout, single lab\",\n      \"pmids\": [\"24885555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LL5beta is required for CLASP2-dependent microtubule capture at the neuromuscular junction membrane; knockdown of LL5beta or forced expression of a CLASP2 fragment blocking CLASP2/LL5beta interaction inhibits microtubule capture and impairs focal AChR vesicle delivery to postsynaptic clusters. In vivo knockdown of LL5beta at the NMJ reduces AChR density and insertion into the postsynaptic membrane.\",\n      \"method\": \"RNAi knockdown in cultured myotubes, dominant-negative CLASP2 fragment expression, live-cell vesicle tracking, in vivo RNAi at NMJ with AChR density quantification\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple loss-of-function strategies (RNAi, dominant-negative), in vitro and in vivo validation, defined molecular and cellular phenotypes\",\n      \"pmids\": [\"25589673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Prickle1 associates with CLASPs and LL5beta (PHLDB2) and is required for LL5beta-dependent accumulation of CLASPs at the cell edge, thereby promoting focal adhesion disassembly during cell polarization and migration. Prickle1 membrane localization via its farnesyl moiety is necessary for binding CLASPs and LL5beta and for promoting microtubule targeting of focal adhesions.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of CLASPs/LL5beta, live-cell imaging of focal adhesion dynamics, farnesylation mutant analysis in MKN1 gastric cancer cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi with defined phenotype, mutant analysis, single lab\",\n      \"pmids\": [\"27378169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phldb2 binds the postsynaptic scaffolding molecule PSD-95 and is required for PSD-95 localization and turnover in dendritic spines; Phldb2 also binds GluA1 and GluA2 (AMPA receptor subunits) and is indispensable for the interaction between NMDA receptors and CaMKII, and for synaptic AMPA receptor density. BDNF application recruits Phldb2 toward postsynaptic membrane in spines in a PI3K-dependent manner. Phldb2 knockout mice show impaired LTP and memory formation.\",\n      \"method\": \"Co-immunoprecipitation, BDNF stimulation with live imaging, PI3K inhibitor treatment, Phldb2 knockout mouse with LTP electrophysiology and memory behavioral assay, synaptic fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for multiple partners, genetic KO mouse with electrophysiological and behavioral phenotypes, PI3K perturbation, multiple orthogonal methods\",\n      \"pmids\": [\"30867511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHLDB2 binds MDM2 and facilitates MDM2-mediated E-cadherin degradation. PHLDB2 knockdown attenuates colon cancer cell migration, invasion, and TGF-β/EGF-induced E-cadherin reduction.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, TGF-β/EGF treatment, wound healing and transwell invasion assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for MDM2 interaction, siRNA knockdown with migration/invasion phenotype, single lab\",\n      \"pmids\": [\"31346319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NOTCH3 transcriptionally upregulates PHLDB2 expression, and PHLDB2 acts as a downstream functional modulator activating the Akt-mTOR signaling pathway in gastric cancer cells. siRNA-mediated knockdown of PHLDB2 suppresses proliferation, invasion, and sensitizes cells to chemotherapy.\",\n      \"method\": \"RNA-seq profiling after NOTCH3 knockdown, siRNA knockdown of PHLDB2, functional cell assays, pathway analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA-seq based identification, siRNA knockdown with functional readout, no direct biochemical demonstration of NOTCH3-PHLDB2 transcriptional mechanism beyond correlation\",\n      \"pmids\": [\"33452458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oxidative stress promotes METTL14-mediated N6-methyladenosine (m6A) modification of PHLDB2 mRNA, facilitating its protein expression. Upregulated PHLDB2 stabilizes EGFR and promotes its nuclear translocation, activating EGFR signaling and causing cetuximab resistance. The Arg1163 residue of PHLDB2 is critical for interaction with EGFR; R1163A mutation abrogates EGFR regulatory function.\",\n      \"method\": \"RNA immunoprecipitation, mass spectrometry, Duolink proximity ligation assay, site-directed mutagenesis (R1163A), CRC cell lines and mouse models\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation assay and mass spectrometry for EGFR interaction, site-directed mutagenesis, multiple functional assays, single lab\",\n      \"pmids\": [\"34952201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The Legionella pneumophila effector Lem8 is a Cys-His-Asp protease activated by host 14-3-3ζ; activated Lem8 cleaves PHLDB2 (Phldb2), thereby inhibiting host cell migration and cytoskeletal organization. Lem8 undergoes 14-3-3ζ-dependent self-cleavage.\",\n      \"method\": \"In vitro protease activity assay with Cys-His-Asp catalytic motif mutagenesis, co-immunoprecipitation of Lem8 with 14-3-3ζ, identification of Phldb2 as substrate, cell migration assay after Lem8 expression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic residue mutagenesis, in vitro protease assay, substrate identification, 14-3-3ζ interaction Co-IP, functional migration readout in single rigorous study\",\n      \"pmids\": [\"35175192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Phldb2 binds specifically to drebrin A (adult-type isoform) but not drebrin E (embryonic isoform) in hippocampal neurons. In Phldb2 knockout mice, drebrin A localization in hippocampal spines is altered; immature filopodium-type spines increase and mushroom spines decrease in CA1, and Phldb2 suppresses abnormal filopodium formation induced by drebrin A overexpression.\",\n      \"method\": \"Co-immunoprecipitation (isoform-selective), Phldb2 knockout mouse, immunofluorescence of spine morphology, drebrin A overexpression rescue experiments\",\n      \"journal\": \"Neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-selective Co-IP, genetic KO with morphological phenotype, overexpression rescue, single lab\",\n      \"pmids\": [\"36162735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LL5beta directly interacts with ERC1 (ELKS/CAST family scaffold) through minimal fragments LL5β(381-510) and ERC1(270-370), involving intrinsically disordered regions in a reversible, high-affinity heterotypic interaction. Expression of LL5β(381-510) fragment hampers endogenous ERC1/LL5beta complex formation, delocalizes ERC1 from the leading edge, reduces invadopodia density, and inhibits tumor cell invasion.\",\n      \"method\": \"NMR spectroscopy, co-immunoprecipitation, fragment competition assay, transwell invasion assay, live-cell imaging of invadopodia in MDA-MB-231 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization plus Co-IP plus functional competition fragment assay with invasion phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37437062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHLDB2 contains intrinsically disordered regions (IDRs) and forms dynamic, reversible liquid-liquid phase separation condensates in cells, as confirmed by FRAP. PHLDB2 knockdown suppresses EMT markers, inhibits tumor growth and pulmonary metastasis in TNBC xenograft models.\",\n      \"method\": \"PONDR IDR prediction, immunofluorescence, FRAP assay, siRNA knockdown in MDA-MB-231/HCC38 cells, in vivo xenograft and metastasis models\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP confirms LLPS, in vivo model, siRNA knockdown with phenotype, but single lab and no mechanistic reconstitution of phase separation function\",\n      \"pmids\": [\"41319208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELKS/LL5beta cortical patches define insulin secretion sites in pancreatic beta cells; however, secretion occurs at only ~5% of the patch area, predominantly at margins of ELKS patches devoid of microtubules, indicating that LL5beta-containing platforms are necessary but not sufficient to specify secretion hot spots and that local MT disassembly within these platforms gates secretory activity.\",\n      \"method\": \"TIRF microscopy of intact mouse islets, live imaging of secretion event localization relative to ELKS/LL5beta patches and MT distribution\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct TIRF imaging of secretion events vs. LL5beta patch structure in intact tissue, single lab, no genetic perturbation of LL5beta in this study\",\n      \"pmids\": [\"40366873\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHLDB2 (LL5beta) is a PIP3-sensing PH-domain scaffold protein that is recruited to the plasma membrane/cell cortex by PI3K-generated PtdIns(3,4,5)P3, where it nucleates a multi-protein platform — including CLASPs, ELKS/ERC1, filamin A, and SHIP2 — to anchor microtubule plus ends to the cortex, drive focal adhesion disassembly, promote lamellipodium formation, and mediate directed vesicle delivery (e.g., AChR vesicles at the NMJ and insulin granules in beta cells); in neurons it additionally binds PSD-95, AMPA receptor subunits, and drebrin A to regulate dendritic spine morphology and LTP, while in cancer contexts it stabilizes EGFR, interacts with MDM2 to degrade E-cadherin, undergoes liquid-liquid phase separation, and can be proteolytically inactivated by the bacterial effector Lem8 to suppress host cell motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHLDB2 (LL5beta) is a PI3K-responsive PH-domain scaffold that builds cortical platforms linking phosphoinositide signaling to the microtubule and actin cytoskeleton [#0, #2]. Its PH domain selectively binds PtdIns(3,4,5)P3, so that PI3K activity dynamically controls its movement between vesicular compartments and the plasma membrane/cell cortex, while a separate N-terminal region binds filamin independently of PI3K [#0, #3]. At the cortex, PHLDB2 assembles a multiprotein platform with ELKS/ERC1 and CLASPs that captures and stabilizes microtubule plus ends, and it directly engages ERC1 through intrinsically disordered regions [#2, #15]. Through this platform PHLDB2 organizes actin-based protrusion and adhesion remodeling: PIP3-directed PHLDB2 recruits filamin A to cross-link F-actin and co-recruits the PIP3 phosphatase SHIP2 to drive lamellipodium formation [#4], and acts downstream of BMP2-PI3K signaling to support actin reorganization and chemotaxis [#6]. At the neuromuscular junction, PHLDB2 nucleates postsynaptic assembly and CLASP2-dependent microtubule capture that delivers AChR vesicles to postsynaptic clusters, and loss of PHLDB2 reduces AChR aggregation and density [#1, #5, #7]. In neurons, PHLDB2 binds PSD-95, AMPA receptor subunits GluA1/GluA2, and the adult-type isoform drebrin A to control dendritic spine maturation, synaptic receptor density, and LTP, with knockout mice showing impaired memory [#9, #14]. In cancer it stabilizes EGFR through an interaction requiring Arg1163 and promotes EGFR signaling and cetuximab resistance, binds MDM2 to facilitate E-cadherin degradation, and forms reversible liquid-liquid phase-separation condensates that support EMT, invasion, and metastasis [#10, #12, #15, #16]. PHLDB2 is also a direct substrate of the Legionella pneumophila protease effector Lem8, whose cleavage of PHLDB2 suppresses host cell migration and cytoskeletal organization [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the molecular logic by which PHLDB2 is positioned in cells: it is a PIP3 sensor whose localization is set by PI3K activity, while also constitutively binding filamin.\",\n      \"evidence\": \"In vitro PIP3-binding assay, PH domain mutagenesis, PI3K inhibition, and co-IP in cultured cells\",\n      \"pmids\": [\"12376540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the downstream cortical machinery recruited by membrane-localized PHLDB2\", \"Functional consequence of filamin binding not yet established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed PHLDB2 has a physiological role at the postsynaptic membrane of the NMJ, linking it to AChR clustering and synaptic apparatus assembly.\",\n      \"evidence\": \"Synaptic transcript screen, immunolocalization, filamin binding, and loss-of-function in myotubes scoring AChR aggregation\",\n      \"pmids\": [\"15851520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting PHLDB2 to AChR aggregation not resolved\", \"Cytoskeletal effectors at the postsynaptic platform unidentified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the core cortical microtubule-capture platform: PHLDB2 recruits CLASPs via ELKS in a PIP3-dependent manner to stabilize microtubules near focal adhesions.\",\n      \"evidence\": \"Mass spectrometry of CLASP partners, reciprocal Co-IP, RNAi with microtubule/focal-adhesion phenotypes across HeLa and fibroblasts; plus domain mapping of filamin binding\",\n      \"pmids\": [\"16824950\", \"17174070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the ELKS/CLASP/PHLDB2 complex not defined\", \"How cortical clusters communicate with focal adhesions unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended PHLDB2 function to actin-based protrusion, showing it couples PIP3 sensing to filamin A-mediated actin cross-linking and SHIP2-mediated feedback at lamellipodia.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mutants, knockdown/overexpression with lamellipodium readout after EGF in COS-7 cells\",\n      \"pmids\": [\"20236936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative kinetics of the PIP3 feedback loop not measured\", \"Interplay between actin protrusion and microtubule capture roles unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded the PHLDB2 actin interactome (Amotl2, Asef2, Flii) and tied it to synaptic podosomes and postsynaptic maturation at the NMJ.\",\n      \"evidence\": \"Affinity purification/MS from myotubes, Co-IP, RNAi with podosome and NMJ morphology readouts\",\n      \"pmids\": [\"23525008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of Amotl2/Asef2/Flii to PHLDB2 function not dissected\", \"Direct vs. indirect nature of these associations not all established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed PHLDB2 downstream of a defined receptor signal (BMP2-PI3K-PIP3) for directional cell migration.\",\n      \"evidence\": \"Co-IP, MS identification, siRNA of p55γ or PHLDB2, PI3K inhibition, chemotaxis assays in mesenchymal progenitors\",\n      \"pmids\": [\"24885555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not establish whether BMP2 effect is direct on PHLDB2 recruitment versus broad PIP3 elevation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated the functional output of the cortical platform at the NMJ: PHLDB2 is required for CLASP2-dependent microtubule capture that delivers AChR vesicles, validated in vivo.\",\n      \"evidence\": \"RNAi, dominant-negative CLASP2 fragment, live vesicle tracking in myotubes, and in vivo NMJ RNAi with AChR density\",\n      \"pmids\": [\"25589673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Vesicle tethering/fusion machinery linked to PHLDB2 platforms not identified\", \"Generality to other secretory systems not addressed here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Prickle1 as an upstream organizer that, via membrane farnesylation, drives PHLDB2/CLASP cortical accumulation to promote focal adhesion disassembly during migration.\",\n      \"evidence\": \"Co-IP, RNAi, farnesylation mutant, and focal adhesion live imaging in gastric cancer cells\",\n      \"pmids\": [\"27378169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs. bridged interaction between Prickle1 and PHLDB2 not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a neuronal synaptic role distinct from the NMJ: PHLDB2 organizes PSD-95 and AMPA receptors and is required for normal synaptic plasticity and memory.\",\n      \"evidence\": \"Reciprocal Co-IP for PSD-95/GluA1/GluA2, BDNF/PI3K imaging, and knockout mouse with LTP and behavioral phenotypes\",\n      \"pmids\": [\"30867511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of receptor scaffolding not defined\", \"Whether spine role uses the same ELKS/CLASP platform unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Opened a cancer mechanism: PHLDB2 binds MDM2 to promote E-cadherin degradation and tumor cell migration/invasion.\",\n      \"evidence\": \"Co-IP, siRNA, TGF-β/EGF treatment, and migration/invasion assays in colon cancer cells\",\n      \"pmids\": [\"31346319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether PHLDB2 directly promotes MDM2 ubiquitination of E-cadherin not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PHLDB2 to oncogenic signaling networks, as a NOTCH3-regulated activator of Akt-mTOR in gastric cancer.\",\n      \"evidence\": \"RNA-seq after NOTCH3 knockdown, siRNA of PHLDB2, functional assays and pathway analysis\",\n      \"pmids\": [\"33452458\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative transcriptional link only; direct NOTCH3-PHLDB2 regulatory mechanism not demonstrated\", \"How PHLDB2 activates Akt-mTOR not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an m6A-regulated EGFR-stabilizing function: oxidative stress and METTL14-driven m6A boost PHLDB2, which stabilizes EGFR and drives nuclear translocation and cetuximab resistance via an Arg1163-dependent interaction.\",\n      \"evidence\": \"RNA-IP, MS, proximity ligation assay, R1163A mutagenesis, CRC cell lines and mouse models\",\n      \"pmids\": [\"34952201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs. complex-mediated PHLDB2-EGFR contact not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed PHLDB2 as a target of host-pathogen warfare: the Legionella effector protease Lem8, activated by 14-3-3ζ, cleaves PHLDB2 to suppress host migration and cytoskeletal organization.\",\n      \"evidence\": \"In vitro protease assay with catalytic mutants, Lem8/14-3-3ζ Co-IP, substrate identification, and migration assay\",\n      \"pmids\": [\"35175192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site on PHLDB2 and fate of fragments not detailed\", \"Which PHLDB2-dependent cytoskeletal output is most affected not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the synaptic mechanism by showing PHLDB2 binds adult-type drebrin A and suppresses immature filopodial spine formation, controlling spine maturation.\",\n      \"evidence\": \"Isoform-selective Co-IP, knockout mouse spine morphology, and drebrin A overexpression rescue in hippocampal neurons\",\n      \"pmids\": [\"36162735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between drebrin A binding and spine shape change not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided structural and functional dissection of the PHLDB2-ERC1 interaction, mapping a reversible high-affinity contact via intrinsically disordered regions that supports invadopodia and tumor invasion.\",\n      \"evidence\": \"NMR of minimal fragments, Co-IP, competition fragment expression, invasion and invadopodia imaging in breast cancer cells\",\n      \"pmids\": [\"37437062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Affinity values and full-length complex architecture not reported here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified intrinsically disordered region-driven liquid-liquid phase separation as a property of PHLDB2 linked to EMT, tumor growth, and metastasis.\",\n      \"evidence\": \"IDR prediction, FRAP, siRNA in breast cancer cells, and xenograft/metastasis models\",\n      \"pmids\": [\"41319208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether condensate formation is mechanistically required for the cytoskeletal/scaffolding functions not reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed in intact tissue that PHLDB2/ELKS cortical patches mark but do not fully specify insulin secretion sites, with local microtubule disassembly gating where secretion occurs.\",\n      \"evidence\": \"TIRF imaging of secretion events relative to ELKS/LL5beta patches and microtubules in intact mouse islets\",\n      \"pmids\": [\"40366873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic perturbation of PHLDB2 in this study\", \"Molecular trigger for local MT disassembly within patches unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHLDB2's distinct activities — cortical microtubule capture, actin protrusion, synaptic scaffolding, EGFR stabilization, and phase separation — are mechanistically integrated and selectively deployed in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the full cortical platform\", \"Whether LLPS underlies the canonical CLASP/ELKS platform function untested\", \"Tissue-specific partner selection logic undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 9, 15]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 5, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 16]}\n    ],\n    \"complexes\": [\"ELKS/LL5beta-CLASP cortical platform\", \"synaptic podosome\"],\n    \"partners\": [\"ERC1\", \"CLASP2\", \"FLNA\", \"FLNC\", \"SHIP2/INPPL1\", \"PSD-95/DLG4\", \"MDM2\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}