{"gene":"SCRIB","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2000,"finding":"Human Scrib (hScrib) is targeted for ubiquitin-mediated degradation by high-risk HPV E6 proteins in complex with the E6AP ubiquitin-protein ligase; hScrib binds directly to E6 via its PDZ domains interacting with a conserved C-terminal PDZ-binding motif on E6. E6 expression induces degradation of hScrib in vivo and loss of tight junction integrity (ZO-1 mislocalization), dependent on the PDZ-binding epitope of E6.","method":"In vitro ubiquitination assay, co-immunoprecipitation, GFP-hScrib localization in MDCK cells, E6 expression with ZO-1 immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution plus in vivo degradation assay with domain-mapping; foundational mechanistic paper replicated by subsequent work","pmids":["11027293"],"is_preprint":false},{"year":2003,"finding":"Mutation in mouse Scrb1 causes defects in polarization of stereociliary bundles in cochlear hair cells, and Scrb1 genetically interacts with Vangl2 (Loop-tail) in regulating planar cell polarity (PCP) in mammals; double heterozygotes show phenotypes comparable to Vangl2 homozygotes, establishing Scrb1 as a PCP gene.","method":"Mouse genetics, genetic epistasis (Scrb1 × Vangl2 double heterozygotes), cochlear hair cell morphology analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with quantitative phenotypic readout, replicated by independent labs","pmids":["12724779"],"is_preprint":false},{"year":2003,"finding":"Disruption of Scrb1 in the circletail mouse (single-base insertion causing frameshift and premature stop) causes craniorachischisis; Scrb1 expression overlaps with Vangl2 expression and circletail genetically interacts with loop-tail (Vangl2), placing Scrb1 in the same pathway as Vangl2 for neural tube closure initiation.","method":"Positional cloning, sequencing, expression analysis, genetic interaction (Crc × loop-tail cross)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning plus genetic epistasis, independently confirmed by subsequent studies","pmids":["12499390"],"is_preprint":false},{"year":2003,"finding":"Drosophila Scrib (with Dlg and Lgl) regulates neuroblast asymmetric cell division: Scrib shows apical cortical enrichment at prophase/metaphase, and scrib mutants display defects in basal protein targeting, reduced apical cortical domain size, and asymmetric mitotic spindle defects leading to symmetric or inverted cell divisions.","method":"Drosophila genetics, immunofluorescence, loss-of-function mutant analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with multiple quantitative phenotypic readouts, ortholog of mammalian SCRIB","pmids":["12545176"],"is_preprint":false},{"year":2005,"finding":"Scrib directly interacts with the zyxin family member LPP via its PDZ domains binding to the C-terminus of LPP; both proteins colocalize at cell-cell contacts. The interaction links Scrib to a signaling pathway between cell-cell contacts and the nucleus.","method":"Co-immunoprecipitation, GST pulldown, immunofluorescence colocalization in MDCKII and CV-1 cells","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal binding assays (Co-IP and GST pulldown) in a single lab with colocalization","pmids":["15649318"],"is_preprint":false},{"year":2005,"finding":"Scrib also interacts with TRIP6 (another zyxin family member) via its third PDZ domain binding to the TRIP6 C-terminus, but does not interact with zyxin, ajuba, or LIMD1, demonstrating selectivity in Scrib PDZ-domain interactions.","method":"Co-immunoprecipitation, GST pulldown with deletion constructs, immunofluorescence","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding with domain mapping, single lab, two orthogonal methods","pmids":["16137684"],"is_preprint":false},{"year":2006,"finding":"Mammalian Scrib controls Cdc42 localization and activation during astrocyte polarized migration by interacting and colocalizing with βPIX (a GEF for Rac/Cdc42) at the leading edge; perturbation of Scrib localization or Scrib-βPIX interaction inhibits βPIX polarized recruitment and Cdc42 activation, which in turn impairs APC and Dlg1 recruitment to the leading edge.","method":"siRNA knockdown, dominant-negative constructs, immunofluorescence, scratch-wound migration assay, Cdc42 activity assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, DN, interaction mapping, GTPase activity) with clear epistatic pathway placement","pmids":["17081755"],"is_preprint":false},{"year":2008,"finding":"Scrib associates with PAK (a serine-threonine kinase) through the βPIX/GIT1 scaffold complex at the leading edge; Scrib-deficient cells show decreased cortical PAK, impaired PAK activation by Rac, and loss of polarized active Rac at the leading edge, demonstrating that Scrib is required for PAK and Rac function during cell migration.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown in T47D cells and primary MEFs, chemotaxis assay, active Rac immunofluorescence","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, reciprocal Co-IP, functional assays with clear mechanistic readout","pmids":["18716323"],"is_preprint":false},{"year":2009,"finding":"Scrib interacts with MCC (a binding partner for β-catenin) in a PDZ-dependent manner; MCC and Scrib colocalize at the cell membrane, and reduced MCC expression impairs directed cell migration independently of Rac1, Cdc42, and PAK activation.","method":"Yeast two-hybrid (isolation), co-immunoprecipitation, immunofluorescence, siRNA knockdown, migration assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain validation, single lab, functional knockdown with mechanistic nuance","pmids":["19555689"],"is_preprint":false},{"year":2011,"finding":"Scrib negatively regulates the MAPK cascade to suppress prostate tumorigenesis; Scrib heterozygosity promotes prostate hyperplasia and biallelic Scrib loss leads to prostate intraepithelial neoplasia in mice, with elevated MAPK signaling as the mechanistic driver.","method":"Conditional/constitutive knockout mouse models, western blot (MAPK), histopathology, in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo KO with defined signaling pathway readout, single lab","pmids":["21965329"],"is_preprint":false},{"year":2011,"finding":"Missense variants in human SCRIB associated with craniorachischisis cause profound alteration in subcellular protein localization, with diminution or abolition of trafficking to the plasma membrane, identifying defective PCP protein trafficking as a pathogenic mechanism.","method":"Sequencing of patient samples, subcellular localization assays for variant proteins in cells","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment for multiple variants, single lab, mechanistic consequence defined","pmids":["22095531"],"is_preprint":false},{"year":2011,"finding":"SCRIB forms at least two distinct protein complexes: (1) SCRIB-ARHGEF7(βPIX)-GIT-PAK and (2) SCRIB-NOS1AP-VANGL; NOS1AP colocalizes with SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells. Knockdown of NOS1AP or SCRIB slows breast cancer cell migration and prevents leading-trailing polarity establishment.","method":"Mass spectrometry, confocal microscopy, shRNA knockdown, migration assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS-identified complexes with functional validation by KD, single lab","pmids":["22179838"],"is_preprint":false},{"year":2012,"finding":"Scrib targets βPIX and PAK2 to adherens junctions; a βPIX-PAK2 complex counterbalances apoptotic stimuli transduced by Scrib and elicited by cadherin-mediated cell-cell adhesion. The Scrib-βPIX-PAK2 complex at adherens junctions modulates anoikis and cell survival in response to osmotic stress.","method":"Co-immunoprecipitation, immunofluorescence at adherens junctions, siRNA knockdown, apoptosis/anoikis assays","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional epistasis via KD, single lab","pmids":["22863318"],"is_preprint":false},{"year":2012,"finding":"Scrib's leucine-rich repeat (LRR) domain associates with the co-chaperone Sgt1; HSP90 is also required for Sgt1-Scrib association, and both Sgt1 and HSP90 maintain proper Scrib protein levels. Reduced Scrib stability (following Sgt1-HSP90 inhibition) lowers the abundance of the Scrib-βPIX-PAK complex and blocks HGF-mediated epithelial morphogenesis.","method":"Co-immunoprecipitation, domain mapping, HSP90 inhibitor treatment, 3D morphogenesis assay, western blot","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-resolved Co-IP with functional consequence, single lab, multiple readouts","pmids":["22623728"],"is_preprint":false},{"year":2013,"finding":"SCRIB and MRAS form a complex with SHOC2; SCRIB functions as a PP1-regulatory protein within this complex and antagonizes SHOC2-mediated RAF dephosphorylation through competition for PP1 molecules, thereby suppressing ERK pathway activation. MRAS coordinates ERK pathway dynamics with polarity via this macromolecular complex.","method":"Co-immunoprecipitation, biochemical competition assay, phosphatase assays, western blot for RAF/ERK phosphorylation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of PP1-regulatory competition mechanism plus multiple orthogonal methods","pmids":["24211266"],"is_preprint":false},{"year":2013,"finding":"SCRIB interacts with integrin α5 (identified by Co-IP/mass spectrometry and GST pulldown); Scrib and integrin α5 colocalize at the basal plasma membrane. Scrib depletion reduces integrin α5 protein levels and surface expression by promoting its interaction with Rab7a, lysosomal translocation, and pepstatin-sensitive protease-dependent degradation. Both PDZ and LRR domains of Scrib are required for integrin α5 rescue and directional migration.","method":"Co-IP/mass spectrometry, GST pulldown, TIRF microscopy, FACS, western blot, siRNA knockdown, lysosome trafficking assays, domain-mutant rescue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including MS, pulldown, TIRF, FACS, domain mutagenesis, and functional rescue in one study","pmids":["23362312"],"is_preprint":false},{"year":2013,"finding":"In vivo zebrafish knockdown of scrib causes defects in convergence and extension (C&E) movements during gastrulation; Lpp interacts with Scrib (PCP protein) and cooperates with Scrib to mediate C&E, placing Scrib in the noncanonical Wnt/PCP pathway in vertebrates.","method":"Morpholino knockdown in zebrafish, co-immunoprecipitation, time-lapse analysis, genetic interaction","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with phenotype + Co-IP, single lab","pmids":["18582857"],"is_preprint":false},{"year":2013,"finding":"Scrib loss in mouse lens and corneal epithelium leads to epithelial-to-mesenchymal transition (EMT); mechanistically, Scrib deficiency causes nuclear accumulation of Smad3/Smad4 (TGFβ intermediates), upregulation of Snail, downregulation of E-cadherin and ZO-1, and upregulation of αSMA, placing Scrib as a suppressor of TGFβ-mediated EMT.","method":"Conditional Cre-loxP Scrib deletion in lens/cornea, immunofluorescence for EMT markers, western blot, nuclear Smad localization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with pathway markers, single lab","pmids":["24095903"],"is_preprint":false},{"year":2013,"finding":"In vivo loss of Scrib in mice (Scrib+/- and Scrib-specific KO) combined with oncogenic KRas(G12D) promotes lung cancer progression, likely through synergistic elevation of RAS-MAPK signaling, showing Scrib acts as a tumor suppressor that limits MAPK output.","method":"LSL-KRas(G12D) mouse model crossed with Scrib heterozygous mice, western blot for MAPK pathway, histopathology","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic interaction with signaling pathway readout, single lab","pmids":["24276238"],"is_preprint":false},{"year":2013,"finding":"In zebrafish, in vivo dissection of the 8q24.3 CNV shows that SCRIB (as a planar cell polarity effector) and PUF60 (splicing factor) make discrete contributions to a multisystem syndromic phenotype, and their combined suppression exacerbates some phenotypic components, demonstrating a binary genetic interaction.","method":"Zebrafish morpholino knockdown, combinatorial suppression, phenotypic rescue","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo morpholino with combinatorial genetic dissection, single lab","pmids":["24140112"],"is_preprint":false},{"year":2014,"finding":"Scrib interacts physically with Rac1 in embryonic cardiomyocytes (but not with Vangl2 in this tissue); genetic interaction between Scrib and Rac1 is required for proper cytoarchitecture of ventricular trabeculae. Cardiac-specific deletion of Scrib (Nkx2.5-Cre) causes trabecular disruption, ventricular septal defects, and cardiac fibrosis.","method":"Conditional Cre-loxP KO, co-immunoprecipitation for Scrib-Rac1 and Scrib-Vangl2, histopathology, cardiac morphology analysis","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding partner plus conditional KO with defined phenotype, single lab","pmids":["25139745"],"is_preprint":false},{"year":2015,"finding":"Scrib is asymmetrically distributed in dividing satellite (muscle stem) cells, with high Scrib levels in daughter cells committed to myogenic differentiation. Satellite-cell-specific Scrib KO causes a severe defect in muscle regeneration, demonstrating Scrib controls muscle stem cell fate decisions (self-renewal vs. differentiation).","method":"Conditional satellite-cell-specific Scrib KO mice, immunofluorescence for asymmetric distribution, muscle injury/regeneration assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with clear asymmetric localization and functional stem cell fate readout, multiple orthogonal analyses","pmids":["25704816"],"is_preprint":false},{"year":2016,"finding":"Plexin-B1 binding to transmembrane Sema4A triggers reverse signaling; Scrib is a downstream effector of Sema4A identified by mass spectrometry + siRNA screening. Plexin-B1 binding to Sema4A promotes the Sema4A-Scrib interaction, thereby removing Scrib from its βPIX complex, decreasing Rac1 and Cdc42 activity and inhibiting cell migration.","method":"Mass spectrometry, siRNA screening, co-immunoprecipitation, Rac1/Cdc42 activity assays, cell migration assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification with functional Co-IP and GTPase activity validation, single lab","pmids":["28007914"],"is_preprint":false},{"year":2017,"finding":"Scrib overexpression in hepatocellular carcinoma cells suppresses proliferation by simultaneously regulating MAPK/ERK and Hippo signaling pathways, disrupting a positive feedback loop between Yap1 and c-Myc, and suppressing expression of Yap1, c-Myc, and cyclin D1.","method":"Scrib overexpression and knockdown in HCC cells, western blot for Yap1/c-Myc/cyclin D1/ERK/Hippo pathway, in vivo mouse liver tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo gain/loss of function with multiple signaling pathway readouts, single lab","pmids":["28460446"],"is_preprint":false},{"year":2019,"finding":"SCRIB associates with the β-catenin destruction complex under proteasome inhibition; the SCRIB/β-catenin interaction is potentiated upon Wnt3a stimulation; SCRIB plays a repressing role on Wnt/β-catenin signaling.","method":"Proteomic interactome (mass spectrometry), co-immunoprecipitation, Wnt reporter assay, western blot","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS interactome with functional Co-IP and reporter assay, single lab","pmids":["31513346"],"is_preprint":false},{"year":2019,"finding":"Scrib interacts with Arhgef7 (βPIX) in primary carotid endothelial cells (identified by Co-IP/MS); siRNA knockdown of Scrib or Arhgef7 reduces endothelial barrier function. Scrib KO reduces AKT phosphorylation and endothelium-dependent relaxation while increasing vascular permeability and leukocyte extravasation. Scrib also interacts with the transcription factor GATA-like protein-1 (GLP1) and maintains its protein abundance.","method":"Co-IP/mass spectrometry, siRNA knockdown, endothelial barrier function assay, conditional endothelial KO mice, western blot (AKT), in vivo atherosclerosis models","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interactors with in vivo conditional KO and multiple functional readouts, single lab","pmids":["30949676"],"is_preprint":false},{"year":2020,"finding":"In Drosophila follicle epithelium, Scrib module proteins have distinct activities: cortical recruitment of Scrib requires an independent cortical stabilizing activity of Dlg (not palmitoylation or polar phospholipid binding). Scrib and Dlg do not directly antagonize aPKC but instead restrict aPKC localization by enabling Lgl's aPKC-inhibiting activity. Lgl is not part of the Scrib-Dlg complex at the lateral domain.","method":"Drosophila genetics, fluorescence recovery after photobleaching (FRAP), optogenetics, loss-of-function mutants, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including FRAP, optogenetics, and epistatic genetics; rigorous mechanistic dissection","pmids":["32414916"],"is_preprint":false},{"year":2020,"finding":"Lgl does not form immobile complexes with Scrib-Dlg at the lateral domain of Drosophila follicle cells (shown by FRAP); Dlg and Scrib are required only for Lgl localization and dynamics in the presence of aPKC function. Light-induced oligomerization confirms Lgl is not part of the Scrib-Dlg complex.","method":"FRAP, optogenetic depletion of plasma membrane PIP2, optogenetic oligomerization of basolateral proteins, genetic mutants","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — FRAP and optogenetics provide direct biophysical evidence; negative finding robustly established","pmids":["32665243"],"is_preprint":false},{"year":2021,"finding":"SCRIB's PDZ domains interact with the C-terminal PDZ-binding motif of the sodium/iodide symporter (NIS), retaining NIS at the basolateral plasma membrane; CRISPR/Cas9-based SCRIB knockout causes NIS mislocalization to intracellular vesicular compartments (late endosomes/lysosomes), impairing iodide transport.","method":"PDZ domain array binding assay, co-immunoprecipitation, CRISPR/Cas9 KO cells, immunofluorescence, iodide transport assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PDZ array + Co-IP binding + CRISPR KO with direct functional transport readout, multiple orthogonal methods","pmids":["34196428"],"is_preprint":false},{"year":2022,"finding":"SCRIB interacts with SLC3A2 (heteromeric component of leucine amino acid transporter SLC7A5) via the N-terminus of SCRIB, facilitating formation of a SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the amino acid transporter; both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ breast cancer cells.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, membrane fractionation, proliferation assay, tamoxifen resistance assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and functional knockdown, single lab","pmids":["35501367"],"is_preprint":false},{"year":2023,"finding":"SCRIB serves as a molecular scaffold for SHROOM2/4 and ROCK1 through an evolutionary conserved SHROOM-binding site in the SCRIB C-terminus; SCRIB KO gut epithelia show reduced apical cell shape area and impaired basoapical polarization of myosin light chain localization and activity, demonstrating SCRIB controls epithelial apical contractility during differentiation.","method":"Organ-on-chip model, SCRIB KO, immunofluorescence for myosin light chain, co-immunoprecipitation for SHROOM/ROCK1, domain mutagenesis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis combined with KO functional readout and mechanistic scaffold identification using multiple orthogonal methods","pmids":["37930352"],"is_preprint":false},{"year":2023,"finding":"hnRNP A1 promotes SCRIB exon 16 skipping by binding an 'AG'-rich sequence on intron 15 of SCRIB pre-mRNA, generating a truncated SCRIB-S isoform; SCRIB-S has lower affinity for the phosphatase subunit PPP1CA compared to full-length SCRIB-L, and promotes breast cancer metastasis through ERK pathway activation.","method":"CLIP, RIP, MS2-GFP-based RNA binding assay, affinity pulldown for PPP1CA, siRNA/antisense oligonucleotide manipulation, ERK western blot, metastasis assay","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP/RIP for RNA binding, biochemical affinity comparison, and functional antisense rescue; single lab","pmids":["37402999"],"is_preprint":false},{"year":2023,"finding":"OTULIN (Met1-Ub deubiquitinase) interacts with SCRIB; Met1-Ub chains associate with VANGL2 and PRICKLE1 (but not SCRIB) and can direct VANGL2 surface presentation, suggesting linear ubiquitination of PCP complex components is regulated in part through SCRIB-associated machinery.","method":"HEK293 cell interactomic analysis, co-immunoprecipitation, MDCK cell VANGL2-GFP trafficking assay, OTULIN KO mouse neural tube analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction with functional trafficking assay and in vivo KO, single lab","pmids":["37589075"],"is_preprint":false},{"year":2024,"finding":"Scrib controls reactive oxygen species production in microglia by regulating Scrib-associated NADPH oxidase (p22phox expression); suppression of Scrib reduces ROS and NLRP3 inflammasome activation.","method":"Scrib siRNA knockdown in primary microglia, ROS measurement, western blot for p22phox and NLRP3 components","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with ROS readout, limited mechanistic resolution of direct vs. indirect NADPH oxidase regulation","pmids":["39522252"],"is_preprint":false},{"year":2026,"finding":"Scrib directly interacts with VE-cadherin (identified by proximity ligation mass spectrometry) and organizes cortical actomyosin clusters at endothelial cell-cell junctions; Scrib depletion decreases junctional actomyosin without affecting catenin-dependent VE-cadherin-actin coupling. Myosin-1c is identified as a critical effector linking Scrib cortical dynamics and VE-cadherin to stabilize adherens junctions during angiogenesis.","method":"VE-cadherin proximity ligation mass spectrometry, 3D angiogenesis-on-chip, siRNA knockdown, actomyosin immunofluorescence, TIRF, co-immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — proximity proteomics, 3D functional model, and multiple mechanistic validations including effector identification; single lab but rigorous multi-method study","pmids":["42043432"],"is_preprint":false},{"year":2020,"finding":"FAM83H, SCRIB, and β-catenin form a complex (co-immunoprecipitation); knockdown of either FAM83H or SCRIB accelerates proteasomal degradation of β-catenin, indicating SCRIB participates in stabilizing β-catenin.","method":"Co-immunoprecipitation, siRNA knockdown, western blot for β-catenin, proteasome inhibitor treatment","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with functional KD readout for β-catenin stability, single lab","pmids":["32564009"],"is_preprint":false},{"year":2015,"finding":"Conditional biallelic loss of Scrib in mouse epidermis significantly enhances tumor multiplicity and progression in an autochthonous skin carcinogenesis model; mechanistically, apoptosis is identified as the critical effector of Scrib tumor suppressor activity during skin carcinogenesis.","method":"Cre-loxP conditional Scrib KO in epidermis, DMBA/TPA skin carcinogenesis model, apoptosis markers (immunofluorescence/western blot)","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with defined mechanistic apoptosis readout, single lab","pmids":["26376988"],"is_preprint":false}],"current_model":"SCRIB is a scaffold protein containing leucine-rich repeats and PDZ domains that localizes to basolateral membranes of polarized epithelial cells, where it organizes multiple signaling complexes: it recruits βPIX/GIT/PAK to control Cdc42/Rac1 activation and localization during cell migration and polarity; antagonizes SHOC2-mediated RAF/ERK activation by competing for PP1 within the MRAS-SHOC2-SCRIB complex; suppresses Wnt/β-catenin, Hippo/YAP, and TGFβ signaling; retains cargo such as NIS and integrin α5 at the plasma membrane by PDZ-mediated interactions; organizes cortical actomyosin at adherens junctions via myosin-1c; controls apical contractility by scaffolding SHROOM2/4 and ROCK1; is targeted for ubiquitin-mediated proteasomal degradation by HPV E6/E6AP; and functions as a planar cell polarity gene through genetic interaction with VANGL2 during neural tube closure and cochlear hair cell polarization."},"narrative":{"mechanistic_narrative":"SCRIB is a leucine-rich-repeat and PDZ-domain scaffold protein that organizes polarity- and migration-controlling signaling complexes at the basolateral membrane and cell-cell junctions of polarized epithelia and endothelia [PMID:17081755, PMID:23362312]. It functions as a core planar cell polarity (PCP) gene, acting in the same pathway as VANGL2 to control neural tube closure and cochlear hair-cell stereociliary polarization, with PCP-associated human missense variants disrupting SCRIB trafficking to the plasma membrane [PMID:12724779, PMID:12499390, PMID:22095531]. A central mechanistic theme is its recruitment of the βPIX(ARHGEF7)/GIT/PAK module to the leading edge and to adherens junctions, where it controls polarized Cdc42 and Rac1 activation during directed migration and modulates anoikis [PMID:17081755, PMID:18716323, PMID:22863318]; Semaphorin-4A/Plexin-B1 reverse signaling antagonizes migration by stripping SCRIB from this βPIX complex [PMID:28007914]. SCRIB also acts as a tumor suppressor that restrains the RAS-MAPK/ERK pathway — it serves as a PP1-regulatory protein within an MRAS-SHOC2-SCRIB complex, competing for PP1 to antagonize SHOC2-mediated RAF activation — and its loss synergizes with oncogenic KRAS to drive tumorigenesis [PMID:24211266, PMID:21965329, PMID:24276238]. Through PDZ- and LRR-mediated cargo retention it stabilizes membrane proteins including integrin α5, the sodium/iodide symporter NIS, and the SLC7A5/SLC3A2 amino acid transporter, preventing their lysosomal degradation or mislocalization [PMID:23362312, PMID:34196428, PMID:35501367]. At junctions SCRIB organizes cortical actomyosin via VE-cadherin and myosin-1c and scaffolds SHROOM2/4-ROCK1 to control apical contractility [PMID:42043432, PMID:37930352], and it additionally represses Wnt/β-catenin, Hippo/YAP, and TGFβ/Smad-driven EMT signaling [PMID:31513346, PMID:28460446, PMID:24095903]. SCRIB protein stability is maintained by the Sgt1-HSP90 chaperone system acting on its LRR domain, and it is targeted for E6AP-dependent ubiquitin-mediated degradation by high-risk HPV E6 proteins [PMID:22623728, PMID:11027293].","teleology":[{"year":2000,"claim":"Established that human Scrib is a direct target of viral oncoprotein-driven degradation, linking it to epithelial junction integrity and the first mechanistic handle on its destruction.","evidence":"In vitro ubiquitination, Co-IP, and E6 expression with ZO-1 immunofluorescence in MDCK cells","pmids":["11027293"],"confidence":"High","gaps":["Did not define SCRIB's normal cellular function beyond junction maintenance","Endogenous (non-viral) ubiquitin ligase for SCRIB not identified"]},{"year":2003,"claim":"Genetic epistasis in mouse and Drosophila placed Scrib in the planar cell polarity pathway with Vangl2 and revealed its role in asymmetric division and neural tube closure, defining it as a polarity gene rather than only an HPV target.","evidence":"Mouse Scrb1 × Vangl2 double heterozygotes, circletail positional cloning, and Drosophila scrib loss-of-function neuroblast analysis","pmids":["12724779","12499390","12545176"],"confidence":"High","gaps":["Molecular mechanism connecting Scrib to Vangl2 not resolved","Whether interaction with Vangl2 is direct was not established"]},{"year":2006,"claim":"Identified the βPIX/GIT/PAK module as the effector complex through which SCRIB controls polarized Cdc42/Rac1 activation, providing the molecular mechanism for SCRIB's role in directed migration.","evidence":"siRNA, dominant-negative constructs, GTPase activity assays, and scratch-wound migration in astrocytes; reciprocal Co-IP in T47D cells and MEFs","pmids":["17081755","18716323"],"confidence":"High","gaps":["Stoichiometry and assembly hierarchy of the SCRIB-βPIX-GIT-PAK complex not defined","How SCRIB itself is polarized to the leading edge unresolved"]},{"year":2011,"claim":"In vivo knockout models defined SCRIB as a tumor suppressor that restrains MAPK output, and proteomics resolved it into distinct βPIX-PAK and VANGL-NOS1AP complexes, separating its signaling and polarity functions.","evidence":"Conditional/constitutive Scrib KO mouse prostate models with MAPK western blots; mass spectrometry and shRNA in metastatic breast cancer cells","pmids":["21965329","22179838"],"confidence":"Medium","gaps":["Direct biochemical mechanism by which SCRIB suppresses MAPK not yet established in 2011","Functional separation of the two complexes incompletely mapped"]},{"year":2013,"claim":"Biochemical reconstitution revealed how SCRIB suppresses ERK signaling — as a PP1-regulatory protein in the MRAS-SHOC2 complex that competes for PP1 to block RAF dephosphorylation — and KRAS-cooperation models confirmed the tumor-suppressor mechanism in vivo.","evidence":"Co-IP, phosphatase and competition assays, RAF/ERK phospho-westerns; LSL-KRas(G12D);Scrib mouse lung cancer model","pmids":["24211266","24276238"],"confidence":"High","gaps":["Quantitative PP1 partitioning between SCRIB and SHOC2 in cells not measured","Cell-context dependence of the competition mechanism unresolved"]},{"year":2013,"claim":"Demonstrated SCRIB acts as a cargo-retention scaffold, stabilizing integrin α5 at the basal membrane by preventing Rab7a-dependent lysosomal degradation, extending its role from signaling to membrane protein homeostasis.","evidence":"Co-IP/MS, GST pulldown, TIRF, FACS, lysosome trafficking assays, and domain-mutant rescue","pmids":["23362312"],"confidence":"High","gaps":["Whether retention is direct PDZ binding or via an adaptor not fully resolved","Generality of the lysosomal-rescue mechanism to other cargo not yet tested in this study"]},{"year":2013,"claim":"Linked SCRIB loss to TGFβ/Smad-driven EMT and to vertebrate convergence-extension, broadening its tumor-suppressor and PCP roles to defined transcriptional and morphogenetic outputs.","evidence":"Conditional Scrib deletion in mouse lens/cornea with EMT marker and nuclear Smad analysis; zebrafish scrib morpholino with Lpp Co-IP","pmids":["24095903","18582857"],"confidence":"Medium","gaps":["Direct molecular link between SCRIB and Smad regulation not defined","Whether EMT suppression is cell-autonomous unresolved"]},{"year":2015,"claim":"Established SCRIB control of stem-cell fate and apoptosis-dependent tumor suppression, showing asymmetric SCRIB partitioning instructs muscle stem cell differentiation and that apoptosis is the critical effector of its skin tumor-suppressor activity.","evidence":"Satellite-cell-specific and epidermal conditional Scrib KO mice with regeneration and DMBA/TPA carcinogenesis assays","pmids":["25704816","26376988"],"confidence":"High","gaps":["Mechanism establishing asymmetric SCRIB inheritance unknown","Molecular pathway connecting SCRIB to apoptosis regulation not defined"]},{"year":2020,"claim":"Rigorous biophysical dissection in Drosophila redefined Scrib module assembly, showing Lgl is not a stable Scrib-Dlg complex member and that Scrib/Dlg restrict aPKC indirectly by enabling Lgl activity.","evidence":"FRAP, optogenetic oligomerization and PIP2 depletion, and epistatic genetics in follicle epithelium","pmids":["32414916","32665243"],"confidence":"High","gaps":["Mammalian generality of this Lgl-independent assembly not tested","The cortical stabilizing activity of Dlg molecularly undefined"]},{"year":2021,"claim":"Confirmed PDZ-dependent cargo retention as a recurring SCRIB mechanism, showing it holds the iodide symporter NIS and the SLC7A5/SLC3A2 transporter at the membrane, with proliferation and drug-resistance consequences.","evidence":"PDZ array binding, Co-IP, CRISPR KO with iodide transport assay (NIS); domain-mapped Co-IP and proliferation/tamoxifen assays (SLC3A2)","pmids":["34196428","35501367"],"confidence":"High","gaps":["Whether NIS and amino acid transporter retention share a common mechanism untested","In vivo relevance of transporter retention not established"]},{"year":2023,"claim":"Identified SCRIB as the scaffold for SHROOM2/4-ROCK1 apical contractility machinery and characterized a splicing-generated SCRIB-S isoform with reduced PP1 affinity that drives ERK-dependent metastasis, connecting isoform choice to signaling output.","evidence":"Organ-on-chip SCRIB KO with myosin light chain analysis and domain mutagenesis; CLIP/RIP, PPP1CA affinity pulldown, and metastasis assays for SCRIB-S","pmids":["37930352","37402999"],"confidence":"Medium","gaps":["Regulation of SCRIB splice-isoform ratio in normal tissue unclear","Structural basis of SHROOM-binding-site engagement of ROCK1 not resolved"]},{"year":2026,"claim":"Resolved a junction-stabilizing mechanism in endothelium, showing SCRIB binds VE-cadherin and uses myosin-1c to organize cortical actomyosin independently of catenin-mediated cadherin-actin coupling during angiogenesis.","evidence":"VE-cadherin proximity ligation mass spectrometry, 3D angiogenesis-on-chip, TIRF, Co-IP, and siRNA","pmids":["42043432"],"confidence":"High","gaps":["Whether myosin-1c effector role generalizes to epithelial junctions untested","Direct vs adaptor-mediated SCRIB-VE-cadherin binding not fully resolved"]},{"year":null,"claim":"How SCRIB selects among its many parallel functions — PCP, βPIX/Rac signaling, ERK suppression, cargo retention, junction actomyosin, and Wnt/Hippo/TGFβ regulation — within a single polarized cell, and what spatiotemporal cues partition its scaffold pool, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated model of how distinct SCRIB complexes are spatially or temporally segregated","Endogenous regulators of SCRIB localization and abundance incompletely mapped","Structural basis of multi-complex assembly on the LRR/PDZ scaffold undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7,14,30,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,28,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[34,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,15,28,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,6,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,3,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,9,18,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,36]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[15,28,29]}],"complexes":["SCRIB-ARHGEF7(βPIX)-GIT-PAK","MRAS-SHOC2-SCRIB","SCRIB-NOS1AP-VANGL","SCRIB/SLC3A2/LLGL2/SLC7A5"],"partners":["ARHGEF7","PAK","SHOC2","MRAS","VANGL2","VE-CADHERIN","SHROOM2","ROCK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"C0HLS1","full_name":"SCRIB overlapping open reading frame protein","aliases":[],"length_aa":120,"mass_kda":12.0,"function":"Represses translation of the downstream SCRIB protein (PubMed:34535749). 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cells.","date":"2020","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/32293058","citation_count":5,"is_preprint":false},{"pmid":"35692812","id":"PMC_35692812","title":"Neuron-Specific Deletion of Scrib in Mice Leads to Neuroanatomical and Locomotor Deficits.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35692812","citation_count":5,"is_preprint":false},{"pmid":"33962021","id":"PMC_33962021","title":"Scrib module proteins: Control of epithelial architecture and planar spindle orientation.","date":"2021","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33962021","citation_count":4,"is_preprint":false},{"pmid":"35885485","id":"PMC_35885485","title":"Individual and Co-Expression Patterns of FAM83H and SCRIB at Diagnosis Are Associated with the Survival of Colorectal Carcinoma Patients.","date":"2022","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35885485","citation_count":4,"is_preprint":false},{"pmid":"20936341","id":"PMC_20936341","title":"No association of polymorphisms in the cell polarity gene SCRIB with breast cancer risk.","date":"2010","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/20936341","citation_count":2,"is_preprint":false},{"pmid":"30083817","id":"PMC_30083817","title":"Diverging impact of cell fate determinants Scrib and Llgl1 on adhesion and migration of hematopoietic stem cells.","date":"2018","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30083817","citation_count":2,"is_preprint":false},{"pmid":"24705163","id":"PMC_24705163","title":"Molecular Expression of the Scribble Complex Genes, Dlg, Scrib and Lgl, in Silkworm, Bombyx mori.","date":"2013","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/24705163","citation_count":2,"is_preprint":false},{"pmid":"37589075","id":"PMC_37589075","title":"An interaction between OTULIN and SCRIB uncovers roles for linear ubiquitination in planar cell polarity.","date":"2023","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/37589075","citation_count":1,"is_preprint":false},{"pmid":"42043432","id":"PMC_42043432","title":"Scrib organizes cortical actomyosin clusters to maintain adherens junctions and angiogenic sprouting.","date":"2026","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/42043432","citation_count":1,"is_preprint":false},{"pmid":"35648249","id":"PMC_35648249","title":"Designing of disruptor molecules to restrain the protein-protein interaction network of VANG1/SCRIB/NOS1AP using fragment-based drug discovery techniques.","date":"2022","source":"Molecular diversity","url":"https://pubmed.ncbi.nlm.nih.gov/35648249","citation_count":1,"is_preprint":false},{"pmid":"18198112","id":"PMC_18198112","title":"[Scrib, a tumor suppressor gene involved in cell polarity].","date":"2008","source":"Medecine sciences : M/S","url":"https://pubmed.ncbi.nlm.nih.gov/18198112","citation_count":0,"is_preprint":false},{"pmid":"41690165","id":"PMC_41690165","title":"Potential anticancer activity of Shulva Yoga, a herbo-metallic compound, in loss of scrib induced cancer in Drosophila melanogaster.","date":"2026","source":"Journal of Ayurveda and integrative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41690165","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.16.628746","title":"Localized translation of cell junction mRNAs is required for epithelial cell polarity","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.628746","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.26.650750","title":"Actin cytoskeletal deregulation, caused by RhoGEF2 overexpression, induces cell competition dependent on Ptp10D, Crumbs, and the Hippo signaling pathway","date":"2025-04-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.26.650750","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.05.606658","title":"A JAK/STAT-Pdk1-S6K axis bypasses systemic growth restrictions to promote regeneration","date":"2024-08-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.05.606658","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.06.611647","title":"EyaHOST, a modular genetic system for investigation of intercellular and tumor-host interactions  <i>in Drosophila melanogaster</i>","date":"2024-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.06.611647","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.17.649307","title":"Apical-basal polarity regulates Collagen IV-dependent cell-cell adhesion in the  <i>Drosophila</i>  adipose tissue","date":"2025-04-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.17.649307","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36958,"output_tokens":8900,"usd":0.122187,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18985,"output_tokens":4968,"usd":0.109562,"stage2_stop_reason":"end_turn"},"total_usd":0.231749,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Human Scrib (hScrib) is targeted for ubiquitin-mediated degradation by high-risk HPV E6 proteins in complex with the E6AP ubiquitin-protein ligase; hScrib binds directly to E6 via its PDZ domains interacting with a conserved C-terminal PDZ-binding motif on E6. E6 expression induces degradation of hScrib in vivo and loss of tight junction integrity (ZO-1 mislocalization), dependent on the PDZ-binding epitope of E6.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, GFP-hScrib localization in MDCK cells, E6 expression with ZO-1 immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution plus in vivo degradation assay with domain-mapping; foundational mechanistic paper replicated by subsequent work\",\n      \"pmids\": [\"11027293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mutation in mouse Scrb1 causes defects in polarization of stereociliary bundles in cochlear hair cells, and Scrb1 genetically interacts with Vangl2 (Loop-tail) in regulating planar cell polarity (PCP) in mammals; double heterozygotes show phenotypes comparable to Vangl2 homozygotes, establishing Scrb1 as a PCP gene.\",\n      \"method\": \"Mouse genetics, genetic epistasis (Scrb1 × Vangl2 double heterozygotes), cochlear hair cell morphology analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with quantitative phenotypic readout, replicated by independent labs\",\n      \"pmids\": [\"12724779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Disruption of Scrb1 in the circletail mouse (single-base insertion causing frameshift and premature stop) causes craniorachischisis; Scrb1 expression overlaps with Vangl2 expression and circletail genetically interacts with loop-tail (Vangl2), placing Scrb1 in the same pathway as Vangl2 for neural tube closure initiation.\",\n      \"method\": \"Positional cloning, sequencing, expression analysis, genetic interaction (Crc × loop-tail cross)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning plus genetic epistasis, independently confirmed by subsequent studies\",\n      \"pmids\": [\"12499390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Drosophila Scrib (with Dlg and Lgl) regulates neuroblast asymmetric cell division: Scrib shows apical cortical enrichment at prophase/metaphase, and scrib mutants display defects in basal protein targeting, reduced apical cortical domain size, and asymmetric mitotic spindle defects leading to symmetric or inverted cell divisions.\",\n      \"method\": \"Drosophila genetics, immunofluorescence, loss-of-function mutant analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with multiple quantitative phenotypic readouts, ortholog of mammalian SCRIB\",\n      \"pmids\": [\"12545176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Scrib directly interacts with the zyxin family member LPP via its PDZ domains binding to the C-terminus of LPP; both proteins colocalize at cell-cell contacts. The interaction links Scrib to a signaling pathway between cell-cell contacts and the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, immunofluorescence colocalization in MDCKII and CV-1 cells\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal binding assays (Co-IP and GST pulldown) in a single lab with colocalization\",\n      \"pmids\": [\"15649318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Scrib also interacts with TRIP6 (another zyxin family member) via its third PDZ domain binding to the TRIP6 C-terminus, but does not interact with zyxin, ajuba, or LIMD1, demonstrating selectivity in Scrib PDZ-domain interactions.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown with deletion constructs, immunofluorescence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding with domain mapping, single lab, two orthogonal methods\",\n      \"pmids\": [\"16137684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mammalian Scrib controls Cdc42 localization and activation during astrocyte polarized migration by interacting and colocalizing with βPIX (a GEF for Rac/Cdc42) at the leading edge; perturbation of Scrib localization or Scrib-βPIX interaction inhibits βPIX polarized recruitment and Cdc42 activation, which in turn impairs APC and Dlg1 recruitment to the leading edge.\",\n      \"method\": \"siRNA knockdown, dominant-negative constructs, immunofluorescence, scratch-wound migration assay, Cdc42 activity assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, DN, interaction mapping, GTPase activity) with clear epistatic pathway placement\",\n      \"pmids\": [\"17081755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Scrib associates with PAK (a serine-threonine kinase) through the βPIX/GIT1 scaffold complex at the leading edge; Scrib-deficient cells show decreased cortical PAK, impaired PAK activation by Rac, and loss of polarized active Rac at the leading edge, demonstrating that Scrib is required for PAK and Rac function during cell migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown in T47D cells and primary MEFs, chemotaxis assay, active Rac immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, reciprocal Co-IP, functional assays with clear mechanistic readout\",\n      \"pmids\": [\"18716323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Scrib interacts with MCC (a binding partner for β-catenin) in a PDZ-dependent manner; MCC and Scrib colocalize at the cell membrane, and reduced MCC expression impairs directed cell migration independently of Rac1, Cdc42, and PAK activation.\",\n      \"method\": \"Yeast two-hybrid (isolation), co-immunoprecipitation, immunofluorescence, siRNA knockdown, migration assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain validation, single lab, functional knockdown with mechanistic nuance\",\n      \"pmids\": [\"19555689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Scrib negatively regulates the MAPK cascade to suppress prostate tumorigenesis; Scrib heterozygosity promotes prostate hyperplasia and biallelic Scrib loss leads to prostate intraepithelial neoplasia in mice, with elevated MAPK signaling as the mechanistic driver.\",\n      \"method\": \"Conditional/constitutive knockout mouse models, western blot (MAPK), histopathology, in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KO with defined signaling pathway readout, single lab\",\n      \"pmids\": [\"21965329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Missense variants in human SCRIB associated with craniorachischisis cause profound alteration in subcellular protein localization, with diminution or abolition of trafficking to the plasma membrane, identifying defective PCP protein trafficking as a pathogenic mechanism.\",\n      \"method\": \"Sequencing of patient samples, subcellular localization assays for variant proteins in cells\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment for multiple variants, single lab, mechanistic consequence defined\",\n      \"pmids\": [\"22095531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SCRIB forms at least two distinct protein complexes: (1) SCRIB-ARHGEF7(βPIX)-GIT-PAK and (2) SCRIB-NOS1AP-VANGL; NOS1AP colocalizes with SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells. Knockdown of NOS1AP or SCRIB slows breast cancer cell migration and prevents leading-trailing polarity establishment.\",\n      \"method\": \"Mass spectrometry, confocal microscopy, shRNA knockdown, migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS-identified complexes with functional validation by KD, single lab\",\n      \"pmids\": [\"22179838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Scrib targets βPIX and PAK2 to adherens junctions; a βPIX-PAK2 complex counterbalances apoptotic stimuli transduced by Scrib and elicited by cadherin-mediated cell-cell adhesion. The Scrib-βPIX-PAK2 complex at adherens junctions modulates anoikis and cell survival in response to osmotic stress.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence at adherens junctions, siRNA knockdown, apoptosis/anoikis assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional epistasis via KD, single lab\",\n      \"pmids\": [\"22863318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Scrib's leucine-rich repeat (LRR) domain associates with the co-chaperone Sgt1; HSP90 is also required for Sgt1-Scrib association, and both Sgt1 and HSP90 maintain proper Scrib protein levels. Reduced Scrib stability (following Sgt1-HSP90 inhibition) lowers the abundance of the Scrib-βPIX-PAK complex and blocks HGF-mediated epithelial morphogenesis.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, HSP90 inhibitor treatment, 3D morphogenesis assay, western blot\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-resolved Co-IP with functional consequence, single lab, multiple readouts\",\n      \"pmids\": [\"22623728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCRIB and MRAS form a complex with SHOC2; SCRIB functions as a PP1-regulatory protein within this complex and antagonizes SHOC2-mediated RAF dephosphorylation through competition for PP1 molecules, thereby suppressing ERK pathway activation. MRAS coordinates ERK pathway dynamics with polarity via this macromolecular complex.\",\n      \"method\": \"Co-immunoprecipitation, biochemical competition assay, phosphatase assays, western blot for RAF/ERK phosphorylation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of PP1-regulatory competition mechanism plus multiple orthogonal methods\",\n      \"pmids\": [\"24211266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCRIB interacts with integrin α5 (identified by Co-IP/mass spectrometry and GST pulldown); Scrib and integrin α5 colocalize at the basal plasma membrane. Scrib depletion reduces integrin α5 protein levels and surface expression by promoting its interaction with Rab7a, lysosomal translocation, and pepstatin-sensitive protease-dependent degradation. Both PDZ and LRR domains of Scrib are required for integrin α5 rescue and directional migration.\",\n      \"method\": \"Co-IP/mass spectrometry, GST pulldown, TIRF microscopy, FACS, western blot, siRNA knockdown, lysosome trafficking assays, domain-mutant rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including MS, pulldown, TIRF, FACS, domain mutagenesis, and functional rescue in one study\",\n      \"pmids\": [\"23362312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In vivo zebrafish knockdown of scrib causes defects in convergence and extension (C&E) movements during gastrulation; Lpp interacts with Scrib (PCP protein) and cooperates with Scrib to mediate C&E, placing Scrib in the noncanonical Wnt/PCP pathway in vertebrates.\",\n      \"method\": \"Morpholino knockdown in zebrafish, co-immunoprecipitation, time-lapse analysis, genetic interaction\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with phenotype + Co-IP, single lab\",\n      \"pmids\": [\"18582857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Scrib loss in mouse lens and corneal epithelium leads to epithelial-to-mesenchymal transition (EMT); mechanistically, Scrib deficiency causes nuclear accumulation of Smad3/Smad4 (TGFβ intermediates), upregulation of Snail, downregulation of E-cadherin and ZO-1, and upregulation of αSMA, placing Scrib as a suppressor of TGFβ-mediated EMT.\",\n      \"method\": \"Conditional Cre-loxP Scrib deletion in lens/cornea, immunofluorescence for EMT markers, western blot, nuclear Smad localization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with pathway markers, single lab\",\n      \"pmids\": [\"24095903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In vivo loss of Scrib in mice (Scrib+/- and Scrib-specific KO) combined with oncogenic KRas(G12D) promotes lung cancer progression, likely through synergistic elevation of RAS-MAPK signaling, showing Scrib acts as a tumor suppressor that limits MAPK output.\",\n      \"method\": \"LSL-KRas(G12D) mouse model crossed with Scrib heterozygous mice, western blot for MAPK pathway, histopathology\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic interaction with signaling pathway readout, single lab\",\n      \"pmids\": [\"24276238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In zebrafish, in vivo dissection of the 8q24.3 CNV shows that SCRIB (as a planar cell polarity effector) and PUF60 (splicing factor) make discrete contributions to a multisystem syndromic phenotype, and their combined suppression exacerbates some phenotypic components, demonstrating a binary genetic interaction.\",\n      \"method\": \"Zebrafish morpholino knockdown, combinatorial suppression, phenotypic rescue\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo morpholino with combinatorial genetic dissection, single lab\",\n      \"pmids\": [\"24140112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Scrib interacts physically with Rac1 in embryonic cardiomyocytes (but not with Vangl2 in this tissue); genetic interaction between Scrib and Rac1 is required for proper cytoarchitecture of ventricular trabeculae. Cardiac-specific deletion of Scrib (Nkx2.5-Cre) causes trabecular disruption, ventricular septal defects, and cardiac fibrosis.\",\n      \"method\": \"Conditional Cre-loxP KO, co-immunoprecipitation for Scrib-Rac1 and Scrib-Vangl2, histopathology, cardiac morphology analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding partner plus conditional KO with defined phenotype, single lab\",\n      \"pmids\": [\"25139745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Scrib is asymmetrically distributed in dividing satellite (muscle stem) cells, with high Scrib levels in daughter cells committed to myogenic differentiation. Satellite-cell-specific Scrib KO causes a severe defect in muscle regeneration, demonstrating Scrib controls muscle stem cell fate decisions (self-renewal vs. differentiation).\",\n      \"method\": \"Conditional satellite-cell-specific Scrib KO mice, immunofluorescence for asymmetric distribution, muscle injury/regeneration assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with clear asymmetric localization and functional stem cell fate readout, multiple orthogonal analyses\",\n      \"pmids\": [\"25704816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Plexin-B1 binding to transmembrane Sema4A triggers reverse signaling; Scrib is a downstream effector of Sema4A identified by mass spectrometry + siRNA screening. Plexin-B1 binding to Sema4A promotes the Sema4A-Scrib interaction, thereby removing Scrib from its βPIX complex, decreasing Rac1 and Cdc42 activity and inhibiting cell migration.\",\n      \"method\": \"Mass spectrometry, siRNA screening, co-immunoprecipitation, Rac1/Cdc42 activity assays, cell migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification with functional Co-IP and GTPase activity validation, single lab\",\n      \"pmids\": [\"28007914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Scrib overexpression in hepatocellular carcinoma cells suppresses proliferation by simultaneously regulating MAPK/ERK and Hippo signaling pathways, disrupting a positive feedback loop between Yap1 and c-Myc, and suppressing expression of Yap1, c-Myc, and cyclin D1.\",\n      \"method\": \"Scrib overexpression and knockdown in HCC cells, western blot for Yap1/c-Myc/cyclin D1/ERK/Hippo pathway, in vivo mouse liver tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo gain/loss of function with multiple signaling pathway readouts, single lab\",\n      \"pmids\": [\"28460446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SCRIB associates with the β-catenin destruction complex under proteasome inhibition; the SCRIB/β-catenin interaction is potentiated upon Wnt3a stimulation; SCRIB plays a repressing role on Wnt/β-catenin signaling.\",\n      \"method\": \"Proteomic interactome (mass spectrometry), co-immunoprecipitation, Wnt reporter assay, western blot\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS interactome with functional Co-IP and reporter assay, single lab\",\n      \"pmids\": [\"31513346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Scrib interacts with Arhgef7 (βPIX) in primary carotid endothelial cells (identified by Co-IP/MS); siRNA knockdown of Scrib or Arhgef7 reduces endothelial barrier function. Scrib KO reduces AKT phosphorylation and endothelium-dependent relaxation while increasing vascular permeability and leukocyte extravasation. Scrib also interacts with the transcription factor GATA-like protein-1 (GLP1) and maintains its protein abundance.\",\n      \"method\": \"Co-IP/mass spectrometry, siRNA knockdown, endothelial barrier function assay, conditional endothelial KO mice, western blot (AKT), in vivo atherosclerosis models\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interactors with in vivo conditional KO and multiple functional readouts, single lab\",\n      \"pmids\": [\"30949676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Drosophila follicle epithelium, Scrib module proteins have distinct activities: cortical recruitment of Scrib requires an independent cortical stabilizing activity of Dlg (not palmitoylation or polar phospholipid binding). Scrib and Dlg do not directly antagonize aPKC but instead restrict aPKC localization by enabling Lgl's aPKC-inhibiting activity. Lgl is not part of the Scrib-Dlg complex at the lateral domain.\",\n      \"method\": \"Drosophila genetics, fluorescence recovery after photobleaching (FRAP), optogenetics, loss-of-function mutants, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including FRAP, optogenetics, and epistatic genetics; rigorous mechanistic dissection\",\n      \"pmids\": [\"32414916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lgl does not form immobile complexes with Scrib-Dlg at the lateral domain of Drosophila follicle cells (shown by FRAP); Dlg and Scrib are required only for Lgl localization and dynamics in the presence of aPKC function. Light-induced oligomerization confirms Lgl is not part of the Scrib-Dlg complex.\",\n      \"method\": \"FRAP, optogenetic depletion of plasma membrane PIP2, optogenetic oligomerization of basolateral proteins, genetic mutants\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — FRAP and optogenetics provide direct biophysical evidence; negative finding robustly established\",\n      \"pmids\": [\"32665243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCRIB's PDZ domains interact with the C-terminal PDZ-binding motif of the sodium/iodide symporter (NIS), retaining NIS at the basolateral plasma membrane; CRISPR/Cas9-based SCRIB knockout causes NIS mislocalization to intracellular vesicular compartments (late endosomes/lysosomes), impairing iodide transport.\",\n      \"method\": \"PDZ domain array binding assay, co-immunoprecipitation, CRISPR/Cas9 KO cells, immunofluorescence, iodide transport assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PDZ array + Co-IP binding + CRISPR KO with direct functional transport readout, multiple orthogonal methods\",\n      \"pmids\": [\"34196428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SCRIB interacts with SLC3A2 (heteromeric component of leucine amino acid transporter SLC7A5) via the N-terminus of SCRIB, facilitating formation of a SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the amino acid transporter; both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, membrane fractionation, proliferation assay, tamoxifen resistance assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and functional knockdown, single lab\",\n      \"pmids\": [\"35501367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SCRIB serves as a molecular scaffold for SHROOM2/4 and ROCK1 through an evolutionary conserved SHROOM-binding site in the SCRIB C-terminus; SCRIB KO gut epithelia show reduced apical cell shape area and impaired basoapical polarization of myosin light chain localization and activity, demonstrating SCRIB controls epithelial apical contractility during differentiation.\",\n      \"method\": \"Organ-on-chip model, SCRIB KO, immunofluorescence for myosin light chain, co-immunoprecipitation for SHROOM/ROCK1, domain mutagenesis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis combined with KO functional readout and mechanistic scaffold identification using multiple orthogonal methods\",\n      \"pmids\": [\"37930352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hnRNP A1 promotes SCRIB exon 16 skipping by binding an 'AG'-rich sequence on intron 15 of SCRIB pre-mRNA, generating a truncated SCRIB-S isoform; SCRIB-S has lower affinity for the phosphatase subunit PPP1CA compared to full-length SCRIB-L, and promotes breast cancer metastasis through ERK pathway activation.\",\n      \"method\": \"CLIP, RIP, MS2-GFP-based RNA binding assay, affinity pulldown for PPP1CA, siRNA/antisense oligonucleotide manipulation, ERK western blot, metastasis assay\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP/RIP for RNA binding, biochemical affinity comparison, and functional antisense rescue; single lab\",\n      \"pmids\": [\"37402999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTULIN (Met1-Ub deubiquitinase) interacts with SCRIB; Met1-Ub chains associate with VANGL2 and PRICKLE1 (but not SCRIB) and can direct VANGL2 surface presentation, suggesting linear ubiquitination of PCP complex components is regulated in part through SCRIB-associated machinery.\",\n      \"method\": \"HEK293 cell interactomic analysis, co-immunoprecipitation, MDCK cell VANGL2-GFP trafficking assay, OTULIN KO mouse neural tube analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction with functional trafficking assay and in vivo KO, single lab\",\n      \"pmids\": [\"37589075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Scrib controls reactive oxygen species production in microglia by regulating Scrib-associated NADPH oxidase (p22phox expression); suppression of Scrib reduces ROS and NLRP3 inflammasome activation.\",\n      \"method\": \"Scrib siRNA knockdown in primary microglia, ROS measurement, western blot for p22phox and NLRP3 components\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with ROS readout, limited mechanistic resolution of direct vs. indirect NADPH oxidase regulation\",\n      \"pmids\": [\"39522252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Scrib directly interacts with VE-cadherin (identified by proximity ligation mass spectrometry) and organizes cortical actomyosin clusters at endothelial cell-cell junctions; Scrib depletion decreases junctional actomyosin without affecting catenin-dependent VE-cadherin-actin coupling. Myosin-1c is identified as a critical effector linking Scrib cortical dynamics and VE-cadherin to stabilize adherens junctions during angiogenesis.\",\n      \"method\": \"VE-cadherin proximity ligation mass spectrometry, 3D angiogenesis-on-chip, siRNA knockdown, actomyosin immunofluorescence, TIRF, co-immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — proximity proteomics, 3D functional model, and multiple mechanistic validations including effector identification; single lab but rigorous multi-method study\",\n      \"pmids\": [\"42043432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM83H, SCRIB, and β-catenin form a complex (co-immunoprecipitation); knockdown of either FAM83H or SCRIB accelerates proteasomal degradation of β-catenin, indicating SCRIB participates in stabilizing β-catenin.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blot for β-catenin, proteasome inhibitor treatment\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with functional KD readout for β-catenin stability, single lab\",\n      \"pmids\": [\"32564009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional biallelic loss of Scrib in mouse epidermis significantly enhances tumor multiplicity and progression in an autochthonous skin carcinogenesis model; mechanistically, apoptosis is identified as the critical effector of Scrib tumor suppressor activity during skin carcinogenesis.\",\n      \"method\": \"Cre-loxP conditional Scrib KO in epidermis, DMBA/TPA skin carcinogenesis model, apoptosis markers (immunofluorescence/western blot)\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with defined mechanistic apoptosis readout, single lab\",\n      \"pmids\": [\"26376988\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCRIB is a scaffold protein containing leucine-rich repeats and PDZ domains that localizes to basolateral membranes of polarized epithelial cells, where it organizes multiple signaling complexes: it recruits βPIX/GIT/PAK to control Cdc42/Rac1 activation and localization during cell migration and polarity; antagonizes SHOC2-mediated RAF/ERK activation by competing for PP1 within the MRAS-SHOC2-SCRIB complex; suppresses Wnt/β-catenin, Hippo/YAP, and TGFβ signaling; retains cargo such as NIS and integrin α5 at the plasma membrane by PDZ-mediated interactions; organizes cortical actomyosin at adherens junctions via myosin-1c; controls apical contractility by scaffolding SHROOM2/4 and ROCK1; is targeted for ubiquitin-mediated proteasomal degradation by HPV E6/E6AP; and functions as a planar cell polarity gene through genetic interaction with VANGL2 during neural tube closure and cochlear hair cell polarization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCRIB is a leucine-rich-repeat and PDZ-domain scaffold protein that organizes polarity- and migration-controlling signaling complexes at the basolateral membrane and cell-cell junctions of polarized epithelia and endothelia [#6, #15]. It functions as a core planar cell polarity (PCP) gene, acting in the same pathway as VANGL2 to control neural tube closure and cochlear hair-cell stereociliary polarization, with PCP-associated human missense variants disrupting SCRIB trafficking to the plasma membrane [#1, #2, #10]. A central mechanistic theme is its recruitment of the βPIX(ARHGEF7)/GIT/PAK module to the leading edge and to adherens junctions, where it controls polarized Cdc42 and Rac1 activation during directed migration and modulates anoikis [#6, #7, #12]; Semaphorin-4A/Plexin-B1 reverse signaling antagonizes migration by stripping SCRIB from this βPIX complex [#22]. SCRIB also acts as a tumor suppressor that restrains the RAS-MAPK/ERK pathway — it serves as a PP1-regulatory protein within an MRAS-SHOC2-SCRIB complex, competing for PP1 to antagonize SHOC2-mediated RAF activation — and its loss synergizes with oncogenic KRAS to drive tumorigenesis [#14, #9, #18]. Through PDZ- and LRR-mediated cargo retention it stabilizes membrane proteins including integrin α5, the sodium/iodide symporter NIS, and the SLC7A5/SLC3A2 amino acid transporter, preventing their lysosomal degradation or mislocalization [#15, #28, #29]. At junctions SCRIB organizes cortical actomyosin via VE-cadherin and myosin-1c and scaffolds SHROOM2/4-ROCK1 to control apical contractility [#34, #30], and it additionally represses Wnt/β-catenin, Hippo/YAP, and TGFβ/Smad-driven EMT signaling [#24, #23, #17]. SCRIB protein stability is maintained by the Sgt1-HSP90 chaperone system acting on its LRR domain, and it is targeted for E6AP-dependent ubiquitin-mediated degradation by high-risk HPV E6 proteins [#13, #0].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that human Scrib is a direct target of viral oncoprotein-driven degradation, linking it to epithelial junction integrity and the first mechanistic handle on its destruction.\",\n      \"evidence\": \"In vitro ubiquitination, Co-IP, and E6 expression with ZO-1 immunofluorescence in MDCK cells\",\n      \"pmids\": [\"11027293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define SCRIB's normal cellular function beyond junction maintenance\", \"Endogenous (non-viral) ubiquitin ligase for SCRIB not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic epistasis in mouse and Drosophila placed Scrib in the planar cell polarity pathway with Vangl2 and revealed its role in asymmetric division and neural tube closure, defining it as a polarity gene rather than only an HPV target.\",\n      \"evidence\": \"Mouse Scrb1 × Vangl2 double heterozygotes, circletail positional cloning, and Drosophila scrib loss-of-function neuroblast analysis\",\n      \"pmids\": [\"12724779\", \"12499390\", \"12545176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting Scrib to Vangl2 not resolved\", \"Whether interaction with Vangl2 is direct was not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the βPIX/GIT/PAK module as the effector complex through which SCRIB controls polarized Cdc42/Rac1 activation, providing the molecular mechanism for SCRIB's role in directed migration.\",\n      \"evidence\": \"siRNA, dominant-negative constructs, GTPase activity assays, and scratch-wound migration in astrocytes; reciprocal Co-IP in T47D cells and MEFs\",\n      \"pmids\": [\"17081755\", \"18716323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly hierarchy of the SCRIB-βPIX-GIT-PAK complex not defined\", \"How SCRIB itself is polarized to the leading edge unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo knockout models defined SCRIB as a tumor suppressor that restrains MAPK output, and proteomics resolved it into distinct βPIX-PAK and VANGL-NOS1AP complexes, separating its signaling and polarity functions.\",\n      \"evidence\": \"Conditional/constitutive Scrib KO mouse prostate models with MAPK western blots; mass spectrometry and shRNA in metastatic breast cancer cells\",\n      \"pmids\": [\"21965329\", \"22179838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism by which SCRIB suppresses MAPK not yet established in 2011\", \"Functional separation of the two complexes incompletely mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Biochemical reconstitution revealed how SCRIB suppresses ERK signaling — as a PP1-regulatory protein in the MRAS-SHOC2 complex that competes for PP1 to block RAF dephosphorylation — and KRAS-cooperation models confirmed the tumor-suppressor mechanism in vivo.\",\n      \"evidence\": \"Co-IP, phosphatase and competition assays, RAF/ERK phospho-westerns; LSL-KRas(G12D);Scrib mouse lung cancer model\",\n      \"pmids\": [\"24211266\", \"24276238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative PP1 partitioning between SCRIB and SHOC2 in cells not measured\", \"Cell-context dependence of the competition mechanism unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated SCRIB acts as a cargo-retention scaffold, stabilizing integrin α5 at the basal membrane by preventing Rab7a-dependent lysosomal degradation, extending its role from signaling to membrane protein homeostasis.\",\n      \"evidence\": \"Co-IP/MS, GST pulldown, TIRF, FACS, lysosome trafficking assays, and domain-mutant rescue\",\n      \"pmids\": [\"23362312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether retention is direct PDZ binding or via an adaptor not fully resolved\", \"Generality of the lysosomal-rescue mechanism to other cargo not yet tested in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked SCRIB loss to TGFβ/Smad-driven EMT and to vertebrate convergence-extension, broadening its tumor-suppressor and PCP roles to defined transcriptional and morphogenetic outputs.\",\n      \"evidence\": \"Conditional Scrib deletion in mouse lens/cornea with EMT marker and nuclear Smad analysis; zebrafish scrib morpholino with Lpp Co-IP\",\n      \"pmids\": [\"24095903\", \"18582857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between SCRIB and Smad regulation not defined\", \"Whether EMT suppression is cell-autonomous unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established SCRIB control of stem-cell fate and apoptosis-dependent tumor suppression, showing asymmetric SCRIB partitioning instructs muscle stem cell differentiation and that apoptosis is the critical effector of its skin tumor-suppressor activity.\",\n      \"evidence\": \"Satellite-cell-specific and epidermal conditional Scrib KO mice with regeneration and DMBA/TPA carcinogenesis assays\",\n      \"pmids\": [\"25704816\", \"26376988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism establishing asymmetric SCRIB inheritance unknown\", \"Molecular pathway connecting SCRIB to apoptosis regulation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Rigorous biophysical dissection in Drosophila redefined Scrib module assembly, showing Lgl is not a stable Scrib-Dlg complex member and that Scrib/Dlg restrict aPKC indirectly by enabling Lgl activity.\",\n      \"evidence\": \"FRAP, optogenetic oligomerization and PIP2 depletion, and epistatic genetics in follicle epithelium\",\n      \"pmids\": [\"32414916\", \"32665243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian generality of this Lgl-independent assembly not tested\", \"The cortical stabilizing activity of Dlg molecularly undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed PDZ-dependent cargo retention as a recurring SCRIB mechanism, showing it holds the iodide symporter NIS and the SLC7A5/SLC3A2 transporter at the membrane, with proliferation and drug-resistance consequences.\",\n      \"evidence\": \"PDZ array binding, Co-IP, CRISPR KO with iodide transport assay (NIS); domain-mapped Co-IP and proliferation/tamoxifen assays (SLC3A2)\",\n      \"pmids\": [\"34196428\", \"35501367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NIS and amino acid transporter retention share a common mechanism untested\", \"In vivo relevance of transporter retention not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SCRIB as the scaffold for SHROOM2/4-ROCK1 apical contractility machinery and characterized a splicing-generated SCRIB-S isoform with reduced PP1 affinity that drives ERK-dependent metastasis, connecting isoform choice to signaling output.\",\n      \"evidence\": \"Organ-on-chip SCRIB KO with myosin light chain analysis and domain mutagenesis; CLIP/RIP, PPP1CA affinity pulldown, and metastasis assays for SCRIB-S\",\n      \"pmids\": [\"37930352\", \"37402999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation of SCRIB splice-isoform ratio in normal tissue unclear\", \"Structural basis of SHROOM-binding-site engagement of ROCK1 not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved a junction-stabilizing mechanism in endothelium, showing SCRIB binds VE-cadherin and uses myosin-1c to organize cortical actomyosin independently of catenin-mediated cadherin-actin coupling during angiogenesis.\",\n      \"evidence\": \"VE-cadherin proximity ligation mass spectrometry, 3D angiogenesis-on-chip, TIRF, Co-IP, and siRNA\",\n      \"pmids\": [\"42043432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether myosin-1c effector role generalizes to epithelial junctions untested\", \"Direct vs adaptor-mediated SCRIB-VE-cadherin binding not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SCRIB selects among its many parallel functions — PCP, βPIX/Rac signaling, ERK suppression, cargo retention, junction actomyosin, and Wnt/Hippo/TGFβ regulation — within a single polarized cell, and what spatiotemporal cues partition its scaffold pool, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated model of how distinct SCRIB complexes are spatially or temporally segregated\", \"Endogenous regulators of SCRIB localization and abundance incompletely mapped\", \"Structural basis of multi-complex assembly on the LRR/PDZ scaffold undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7, 14, 30, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 28, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [34, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 15, 28, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 6, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 3, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 9, 18, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 36]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [15, 28, 29]}\n    ],\n    \"complexes\": [\n      \"SCRIB-ARHGEF7(βPIX)-GIT-PAK\",\n      \"MRAS-SHOC2-SCRIB\",\n      \"SCRIB-NOS1AP-VANGL\",\n      \"SCRIB/SLC3A2/LLGL2/SLC7A5\"\n    ],\n    \"partners\": [\n      \"ARHGEF7\",\n      \"PAK\",\n      \"SHOC2\",\n      \"MRAS\",\n      \"VANGL2\",\n      \"VE-cadherin\",\n      \"SHROOM2\",\n      \"ROCK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}