{"gene":"WTIP","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2010,"finding":"WTIP (along with LIMD1 and Ajuba) localizes to processing bodies (P-bodies) and binds Ago1/2, RCK, Dcp2, and eIF4E in vivo, acting as a molecular link between the translationally inhibited eIF4E-m7GTP-5' cap and Ago1/2 within the miRISC complex to facilitate miRNA-mediated (but not siRNA-mediated) gene silencing via an inhibitory closed-loop complex.","method":"Co-immunoprecipitation, m7GTP cap-binding assay, P-body localization imaging, knockdown functional assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for multiple binding partners, functional KD showing miRNA-specific (not siRNA) silencing defect, replicated across three family members with orthogonal methods","pmids":["20616046"],"is_preprint":false},{"year":2010,"finding":"Upon LPS-induced podocyte injury, WTIP translocates from cell contacts to the nucleus via a mechanism requiring JNK activity, assembly of a JNK-interacting protein 3/dynein scaffolding complex, intact microtubule networks, and dynein motor activity. Loss of WTIP from cell contacts alters podocyte morphology and actin assembly.","method":"Live imaging, cellular fractionation, pharmacological inhibition of JNK/dynein/microtubules, shRNA knockdown, co-immunoprecipitation of JIP3-dynein complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, imaging, pharmacological inhibitors, KD phenotype), single lab but comprehensive mechanistic dissection","pmids":["20086015"],"is_preprint":false},{"year":2011,"finding":"WTIP regulates podocyte actin dynamics and adherens junction assembly: it targets focal adhesions in isolated cells and shifts to adherens junctions upon cell-cell contact; knockdown disrupts actin stress fiber formation, focal adhesion maturation, and stable adherens junction assembly. WTIP overexpression induces RhoA-dependent stress fibers and directly interacts with the RhoA-specific GEF ARHGEF12.","method":"shRNA knockdown, overexpression, RhoA inhibition (C3 toxin, ROCK inhibitor), co-immunoprecipitation, cell surface biotinylation","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function with specific readouts, direct binding to ARHGEF12 by Co-IP, RhoA pathway placed by pharmacological rescue","pmids":["21900451"],"is_preprint":false},{"year":2009,"finding":"WTIP physically interacts with the intracellular domain of the receptor tyrosine kinase Ror2; full-length Ror2 recruits WTIP to the cell membrane, while a disease-causing Ror2 mutant fails to do so. WTIP inhibits canonical Wnt signaling in mammalian cells and in Xenopus embryos.","method":"Co-immunoprecipitation, cell membrane localization assay, Wnt/β-catenin luciferase reporter assay, Xenopus overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional Wnt reporter assay in two systems, single lab","pmids":["19785987"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, Wtip is enriched at the basal body; wtip knockdown causes pronephric cyst formation, mitotic spindle orientation defects (in anterior/middle pronephros), cloaca malformation with reduced ciliated cells, loss of striated rootlet from basal bodies, and impaired cilia motility. Genetic interaction with vangl2 (a core PCP protein) was demonstrated.","method":"Morpholino knockdown, immunolocalization, spindle orientation assay, cilia motility analysis, genetic epistasis (double knockdown)","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple defined cellular phenotypes, genetic epistasis with Vangl2, direct basal body localization","pmids":["23213452"],"is_preprint":false},{"year":2016,"finding":"Nephrin signaling suppresses Hippo pathway activity through WTIP: phosphorylated nephrin recruits Nck, which sequesters WTIP and its binding partner Lats1, resulting in decreased phospho-activation of Lats1. Upon nephrin dephosphorylation during podocyte injury, Lats1 is rapidly activated, preceding YAP downregulation.","method":"Mutational analysis of Nck/nephrin interaction, co-immunoprecipitation, mouse podocyte injury model with phospho-Lats1 and YAP quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutational dissection of complex, in vivo mouse model with temporal phosphorylation readout, multiple orthogonal methods","pmids":["27033705"],"is_preprint":false},{"year":2016,"finding":"Wtip physically associates with Prickle3 and cooperates with it to regulate ciliogenesis; Wtip is required for basal body organization in Xenopus GRP cells, and co-depletion or interference phenotypes link Wtip to Prickle3-mediated cilia growth.","method":"Co-immunoprecipitation, morpholino knockdown in Xenopus, immunolocalization of basal body markers (γ-tubulin, Nedd1)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic cooperativity, single lab, Xenopus model","pmids":["27062996"],"is_preprint":false},{"year":2018,"finding":"Wtip regulates actomyosin contractility and apical constriction during neural tube closure in Xenopus: depletion inhibits apical constriction in neuroepithelial cells and causes neural tube defects. The C-terminal LIM domain fragment of Wtip physically associates with Shroom3 and interferes with Shroom3-induced apical constriction. Wtip junctional distribution is reorganized by myosin II activity, indicating tension-sensitive localization.","method":"Morpholino depletion, fluorescent protein tagging/live imaging, co-immunoprecipitation, myosin II inhibition (blebbistatin)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding to Shroom3 by Co-IP, loss-of-function with specific apical constriction phenotype, tension-sensitive relocalization with pharmacological perturbation","pmids":["29661847"],"is_preprint":false},{"year":2014,"finding":"WTIP directly interacts with ASXL2 and represses ASXL2-mediated activation of retinoic acid-dependent transcription in HeLa cells, blocking ASXL2's stimulatory effect on retinoic acid signaling.","method":"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional reporter assay, single lab, two orthogonal methods","pmids":["25065743"],"is_preprint":false},{"year":2015,"finding":"WTIP physically interacts with ASXL1; in Asxl1-null mouse kidneys, defects in podocyte morphology and upregulation of Wt1/Wtip target genes are observed, implicating Asxl1 in maintaining podocyte structure via its association with Wtip.","method":"Co-immunoprecipitation, Asxl1 knockout mouse analysis, target gene expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo KO phenotype with gene expression readout, single lab","pmids":["26385183"],"is_preprint":false},{"year":2013,"finding":"Dendrin physically interacts with WTIP (and Gadd45a) at the podocyte slit diaphragm, as demonstrated by yeast two-hybrid and co-immunoprecipitation. Dendrin relocalizes to the nucleus in adriamycin nephropathy, paralleling WTIP nuclear translocation behavior.","method":"Yeast two-hybrid, co-immunoprecipitation, dendrin knockout mouse, immunolocalization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus Co-IP for interaction, functional KO showed dendrin is dispensable but interaction with WTIP is confirmed","pmids":["24376653"],"is_preprint":false},{"year":2016,"finding":"WTIP interacts with BRCA2 (amino acids 2750–2864) and is required for BRCA2 centrosome localization; knockdown of WTIP abolishes BRCA2 centrosomal localization and causes abnormal cell division in HeLa S3 cells.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, shRNA knockdown, immunofluorescence","journal":"Archives of gynecology and obstetrics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by pull-down and Co-IP, functional KD with centrosome phenotype, single lab","pmids":["27535760"],"is_preprint":false},{"year":2018,"finding":"A UBA2-WTIP fusion gene (containing UBA2 N-terminal domains fused to WTIP C-terminal LIM domains) was identified in AML; ectopic expression enhances cell proliferation, induces phosphorylation of STAT3, STAT5, and ERK1/2, and abrogates WTIP-mediated P-body formation.","method":"RT-PCR, Sanger sequencing, ectopic expression in KG-1a cells, proliferation assay, Western blot for phospho-signaling, P-body formation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fusion gene characterized by multiple methods, gain-of-function with signaling readouts, single lab","pmids":["30179602"],"is_preprint":false},{"year":2021,"finding":"WTIP induces apoptosis in AML cells through transcriptional upregulation and nuclear translocation of FOXO3a; WTIP directly interacts with FOXO3a, activates FOXO3a transcriptionally, which increases PUMA expression and activates the intrinsic apoptotic pathway.","method":"Overexpression/knockdown, co-immunoprecipitation (WTIP-FOXO3a), luciferase reporter, in vitro and in vivo proliferation/apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding plus transcriptional reporter plus in vivo tumor model, single lab","pmids":["34930905"],"is_preprint":false},{"year":2021,"finding":"WTIP N-terminal domain physically associates with SSX2IP (a centriolar satellite protein/cell junction component); the two proteins form mixed aggregates when overexpressed, and double depletion of Wtip and SSX2IP in Xenopus embryos shows functional interaction during neural tube closure.","method":"Targeted proximity biotinylation (TPB), co-immunoprecipitation, colocalization imaging, double morpholino depletion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel proximity biotinylation method plus Co-IP confirmation plus genetic epistasis, single lab","pmids":["34710136"],"is_preprint":false},{"year":2022,"finding":"WTIP interacts with ARHGEF12 (a RhoA-specific GEF) through LIM and PDZ-binding domains with high affinity; this interaction is proposed to regulate slit diaphragm and foot process function through Rho effector proteins. Wtip gene trap homozygotes are embryonic lethal.","method":"Co-immunoprecipitation, domain mapping, Wtip gene trap mouse model","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped Co-IP interaction, in vivo KO lethality, single lab; replicates ARHGEF12 interaction from 2011 paper with domain resolution","pmids":["35862649"],"is_preprint":false},{"year":2022,"finding":"Overexpression of WTIP in MCF10A cells competes with LIMD1 for junctional localization, reduces junctional localization of LATS1, and is associated with increased YAP1 phosphorylation and decreased YAP1 nuclear localization, suggesting WTIP cannot efficiently recruit Lats kinases to junctions (unlike LIMD1) and may act as a tumor suppressor partly by competing with LIMD1.","method":"Overexpression in MCF10A cells, immunofluorescence quantification of junctional localization, YAP1 phosphorylation and nuclear localization assay","journal":"microPublication biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single overexpression approach with multiple cellular readouts, single lab","pmids":["36439396"],"is_preprint":false},{"year":2022,"finding":"WTIP knockdown in neonatal rat ventricular myocytes causes cardiomyocyte hypertrophy; a disease-causing variant WTIP p.Y233F disrupts binding to a Wnt signaling protein, causes increased resting calcium and cellular hypertrophy in iPSC-derived cardiomyocytes (ameliorated by verapamil), linking WTIP to calcium dysregulation and cardiac hypertrophy.","method":"lentiviral shRNA knockdown in neonatal rat cardiomyocytes, morpholino knockdown in zebrafish, iPSC-derived cardiomyocyte characterization, calcium imaging, verapamil rescue","journal":"Circulation. Genomic and precision medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (rat, zebrafish, human iPSC), pharmacological rescue, single lab","pmids":["35671065"],"is_preprint":false},{"year":2025,"finding":"WTIP interacts with PP2A to inhibit T308 phosphorylation and kinase activity of AKT, thereby suppressing stemness and chemoresistance in gastric cancer. TET2 and PATZ1 cooperate to transcriptionally activate WTIP expression, and this TET2-WTIP axis is frequently silenced in gastric cancer.","method":"Co-immunoprecipitation (WTIP-PP2A), AKT kinase activity assay, TET2/PATZ1 transcriptional activation assays, shRNA knockdown functional assays","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding to PP2A plus functional AKT phosphorylation readout plus transcriptional upstream regulation, single lab","pmids":["40279682"],"is_preprint":false},{"year":2016,"finding":"In zebrafish, Wtip protein localizes to the basal body of proepicardial organ (PE) cells; Wtip signaling in conjunction with WT1 is essential for PE specification. Wtip knockdown disrupts cardiac looping, left-right asymmetry, and atrioventricular boundary formation.","method":"Morpholino knockdown in zebrafish, mRNA overexpression, immunolocalization, PE marker expression analysis","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function in zebrafish with specific marker readouts, basal body localization, single lab","pmids":["27484451"],"is_preprint":false}],"current_model":"WTIP is a LIM-domain scaffold protein (Ajuba family) that functions at cell junctions, basal bodies, and in the nucleus: at cell junctions it regulates RhoA activity via ARHGEF12, assembles adherens junctions and focal adhesions, suppresses Hippo signaling by sequestering LATS1 (through Nck at phospho-nephrin), and inhibits canonical Wnt signaling via Ror2; it localizes to basal bodies where it is required for ciliogenesis, mitotic spindle orientation, and PCP (cooperating with Vangl2 and Prickle3); it undergoes JNK/dynein/microtubule-dependent nuclear translocation upon injury to repress WT1 transcriptional activity; it facilitates miRNA-mediated gene silencing by bridging the 5' cap (via eIF4E) to Ago1/2-miRISC; and it regulates apoptosis in AML through direct interaction with FOXO3a and downstream PUMA induction, and suppresses AKT activity through PP2A interaction."},"narrative":{"mechanistic_narrative":"WTIP is a LIM-domain scaffold protein that operates at cell junctions, the basal body, and the nucleus to couple cytoskeletal architecture and mechanical tension to signaling and transcriptional control [PMID:21900451, PMID:23213452]. At adherens junctions and focal adhesions it organizes the actin cytoskeleton, driving RhoA-dependent stress fiber formation and adherens junction assembly through direct binding to the RhoA-specific GEF ARHGEF12, an interaction mapped to its LIM and PDZ-binding domains [PMID:21900451, PMID:35862649]. Through this junctional platform WTIP integrates Hippo signaling: phospho-nephrin recruits Nck to sequester WTIP together with LATS1, restraining LATS1 activation, and WTIP can compete with LIMD1 for junctional LATS1 recruitment to modulate YAP phosphorylation and nuclear localization [PMID:27033705, PMID:36439396]. WTIP also localizes to basal bodies, where it is required for ciliogenesis, mitotic spindle orientation, and planar cell polarity in cooperation with Vangl2 and Prickle3, and it controls actomyosin-driven apical constriction during neural tube closure via the C-terminal LIM domain binding Shroom3, with junctional distribution itself being myosin II tension-sensitive [PMID:23213452, PMID:27062996, PMID:29661847]. In the cytoplasm WTIP bridges the eIF4E-bound 5' cap to Ago1/2 within miRISC at P-bodies to facilitate miRNA-mediated silencing [PMID:20616046], and upon podocyte injury it undergoes JNK/dynein/microtubule-dependent nuclear translocation, where it intersects WT1-linked transcriptional programs [PMID:20086015]. WTIP additionally functions in cancer contexts, inducing apoptosis in AML through direct FOXO3a interaction and PUMA induction, and suppressing AKT activity via PP2A in gastric cancer [PMID:34930905, PMID:40279682]. A disease-causing WTIP variant (p.Y233F) is linked to calcium dysregulation and cardiomyocyte hypertrophy [PMID:35671065].","teleology":[{"year":2009,"claim":"Established WTIP as a signaling effector by showing it binds the Ror2 receptor tyrosine kinase intracellular domain and inhibits canonical Wnt signaling, placing it in a receptor-coupled pathway.","evidence":"Co-IP, membrane localization, Wnt/β-catenin reporter in mammalian cells and Xenopus","pmids":["19785987"],"confidence":"Medium","gaps":["Domain of WTIP mediating Ror2 binding not mapped","Mechanism by which WTIP represses β-catenin output unresolved"]},{"year":2010,"claim":"Defined a cytoplasmic post-transcriptional role: WTIP links the translationally repressed eIF4E-capped mRNA to Ago1/2-miRISC at P-bodies, answering how miRISC is coupled to the cap for silencing.","evidence":"Co-IP, m7GTP cap-binding assay, P-body imaging, knockdown silencing assays","pmids":["20616046"],"confidence":"High","gaps":["Specificity for miRNA over siRNA silencing mechanism not fully explained","Stoichiometry within the closed-loop complex unknown"]},{"year":2010,"claim":"Showed how WTIP relocates from junctions to the nucleus upon injury, identifying a JNK/JIP3-dynein/microtubule-dependent transport mechanism.","evidence":"Live imaging, fractionation, JNK/dynein/microtubule inhibition, Co-IP of JIP3-dynein, shRNA","pmids":["20086015"],"confidence":"High","gaps":["Nuclear transcriptional targets of WTIP not directly identified here","Cargo adaptor coupling WTIP to dynein not pinpointed"]},{"year":2011,"claim":"Connected WTIP to cytoskeletal control by demonstrating it directs RhoA-dependent actin/adhesion dynamics through direct ARHGEF12 binding.","evidence":"shRNA, overexpression, C3/ROCK inhibition rescue, Co-IP, surface biotinylation in podocytes","pmids":["21900451"],"confidence":"High","gaps":["Whether WTIP activates or localizes ARHGEF12 not resolved","Link between RhoA control and other WTIP pathways unclear"]},{"year":2012,"claim":"Revealed a basal-body/ciliary function: WTIP is required for ciliogenesis, spindle orientation, and PCP, with genetic interaction with the core PCP gene vangl2.","evidence":"Morpholino knockdown, immunolocalization, spindle/cilia assays, vangl2 epistasis in zebrafish","pmids":["23213452"],"confidence":"High","gaps":["Molecular role of WTIP at the basal body not biochemically defined","Direct PCP partners not identified in this study"]},{"year":2014,"claim":"Extended WTIP's transcriptional repressor role by showing it binds ASXL2 and blocks retinoic acid-dependent transcription.","evidence":"Yeast two-hybrid, Co-IP, luciferase reporter in HeLa","pmids":["25065743"],"confidence":"Medium","gaps":["Mechanism of repression of ASXL2 activity unknown","Physiological context not established"]},{"year":2015,"claim":"Linked WTIP to chromatin-associated regulation in vivo via ASXL1, with Asxl1 loss causing podocyte defects and dysregulation of Wt1/Wtip target genes.","evidence":"Co-IP, Asxl1 knockout mouse, target gene expression","pmids":["26385183"],"confidence":"Medium","gaps":["Direct functional contribution of WTIP to ASXL1 activity not isolated","Target gene set not mechanistically defined"]},{"year":2016,"claim":"Defined a junction-to-Hippo mechanism: phospho-nephrin/Nck sequesters WTIP and LATS1 to restrain LATS1 activation, linking slit diaphragm integrity to YAP regulation.","evidence":"Mutational dissection of Nck/nephrin, Co-IP, mouse podocyte injury with phospho-LATS1/YAP readouts","pmids":["27033705"],"confidence":"High","gaps":["How WTIP physically engages LATS1 not structurally resolved","Generality beyond podocytes not addressed"]},{"year":2016,"claim":"Showed WTIP cooperates with the PCP protein Prickle3 to organize the basal body and support ciliogenesis.","evidence":"Co-IP, morpholino knockdown, basal body marker imaging in Xenopus","pmids":["27062996"],"confidence":"Medium","gaps":["Single-lab Xenopus model","Domain of WTIP binding Prickle3 not mapped"]},{"year":2016,"claim":"Linked WTIP to mitotic fidelity by showing it is required for BRCA2 centrosome localization.","evidence":"Yeast two-hybrid, Co-IP, GST pull-down, shRNA, immunofluorescence in HeLa S3","pmids":["27535760"],"confidence":"Medium","gaps":["Functional consequence beyond abnormal division not detailed","Relationship to basal body role unclear"]},{"year":2016,"claim":"Connected WTIP basal-body function to organ patterning by showing it acts with WT1 in proepicardial specification and cardiac laterality in zebrafish.","evidence":"Morpholino knockdown, mRNA overexpression, immunolocalization, PE markers in zebrafish","pmids":["27484451"],"confidence":"Medium","gaps":["Direct biochemical WTIP-WT1 interaction not shown here","Single model organism"]},{"year":2018,"claim":"Demonstrated WTIP couples mechanical tension to morphogenesis: its LIM domain binds Shroom3 to regulate actomyosin-driven apical constriction during neural tube closure, with tension-sensitive junctional localization.","evidence":"Morpholino depletion, live imaging, Co-IP, blebbistatin perturbation in Xenopus","pmids":["29661847"],"confidence":"High","gaps":["Whether WTIP positively or negatively tunes Shroom3 in vivo not fully resolved","Mechanosensing mechanism not biochemically defined"]},{"year":2018,"claim":"Identified a UBA2-WTIP fusion in AML that disrupts WTIP P-body function and drives proliferative signaling, implicating WTIP loss-of-function in leukemogenesis.","evidence":"RT-PCR, sequencing, ectopic expression, proliferation and phospho-signaling assays, P-body assay in KG-1a","pmids":["30179602"],"confidence":"Medium","gaps":["Whether the fusion is driver or passenger not established","Mechanism of STAT/ERK activation unclear"]},{"year":2021,"claim":"Established a pro-apoptotic tumor-suppressor role: WTIP directly binds and transcriptionally activates FOXO3a to induce PUMA and intrinsic apoptosis in AML.","evidence":"Overexpression/knockdown, Co-IP, luciferase reporter, in vitro and in vivo apoptosis assays","pmids":["34930905"],"confidence":"Medium","gaps":["How WTIP enhances FOXO3a transcription mechanistically unknown","Single-lab evidence"]},{"year":2021,"claim":"Showed WTIP N-terminus associates with the centriolar satellite protein SSX2IP, with functional interaction during neural tube closure, expanding its centrosome/basal body interactome.","evidence":"Targeted proximity biotinylation, Co-IP, colocalization, double morpholino depletion in Xenopus","pmids":["34710136"],"confidence":"Medium","gaps":["Functional output of the WTIP-SSX2IP complex not defined","Aggregate formation physiological relevance unclear"]},{"year":2022,"claim":"Resolved the WTIP-ARHGEF12 interaction to LIM/PDZ-binding domains and established WTIP as essential in vivo via embryonic-lethal gene-trap homozygotes.","evidence":"Co-IP, domain mapping, Wtip gene trap mouse","pmids":["35862649"],"confidence":"Medium","gaps":["Cause of embryonic lethality not pinpointed","Direct effect on Rho effector activity not measured"]},{"year":2022,"claim":"Showed WTIP competes with LIMD1 for junctional LATS1 recruitment, with overexpression increasing YAP1 phosphorylation, suggesting a Hippo-modulating tumor-suppressor mechanism.","evidence":"Overexpression in MCF10A, junctional localization and YAP1 phosphorylation/nuclear assays","pmids":["36439396"],"confidence":"Medium","gaps":["Single overexpression approach","Endogenous competition dynamics not measured"]},{"year":2022,"claim":"Linked WTIP to cardiac disease by showing knockdown causes cardiomyocyte hypertrophy and a p.Y233F variant disrupts Wnt-protein binding and causes calcium dysregulation reversible by verapamil.","evidence":"shRNA in rat cardiomyocytes, zebrafish morpholino, iPSC-cardiomyocytes, calcium imaging, verapamil rescue","pmids":["35671065"],"confidence":"Medium","gaps":["Identity of the Wnt protein partner not specified","Mechanism connecting variant to calcium handling unresolved"]},{"year":2025,"claim":"Defined a kinase-suppressing role: WTIP binds PP2A to inhibit AKT T308 phosphorylation and reduce stemness/chemoresistance in gastric cancer, regulated upstream by a TET2-PATZ1 axis.","evidence":"Co-IP, AKT kinase activity assay, TET2/PATZ1 transcriptional assays, shRNA functional assays","pmids":["40279682"],"confidence":"Medium","gaps":["Whether WTIP recruits PP2A directly to AKT not shown","Single-lab evidence"]},{"year":null,"claim":"How WTIP's distinct activities — junctional RhoA/Hippo scaffolding, basal-body/PCP function, cytoplasmic miRISC bridging, and nuclear transcriptional regulation — are coordinated within one protein, and how its domains partition among these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating LIM and PDZ-binding domain functions","Mechanism switching WTIP between junctional, ciliary, and nuclear pools not defined","Tissue-specific partner selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,16,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,13]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4,6,11,19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,16,18]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,6]}],"complexes":["miRISC","P-body"],"partners":["ARHGEF12","LATS1","ROR2","SHROOM3","PRICKLE3","FOXO3A","PP2A","SSX2IP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NIX2","full_name":"Wilms tumor protein 1-interacting protein","aliases":[],"length_aa":430,"mass_kda":45.1,"function":"Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Positively regulates microRNA (miRNA)-mediated gene silencing. Negatively regulates Hippo signaling pathway and antagonizes phosphorylation of YAP1. Acts as a transcriptional corepressor for SNAI1 and SNAI2/SLUG-dependent repression of E-cadherin transcription. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. In podocytes, may play a role in the regulation of actin dynamics and/or foot process cytoarchitecture (By similarity). In the course of podocyte injury, shuttles into the nucleus and acts as a transcription regulator that represses WT1-dependent transcription regulation, thereby translating changes in slit diaphragm structure into altered gene expression and a less differentiated phenotype. Involved in the organization of the basal body (By similarity). Involved in cilia growth and positioning (By similarity)","subcellular_location":"Cell junction, adherens junction; Nucleus; Cytoplasm, P-body","url":"https://www.uniprot.org/uniprotkb/A6NIX2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WTIP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WTIP","total_profiled":1310},"omim":[{"mim_id":"614790","title":"WT1-INTERACTING PROTEIN; WTIP","url":"https://www.omim.org/entry/614790"},{"mim_id":"613026","title":"CHROMOSOME 19q13.11 DELETION SYNDROME, DISTAL","url":"https://www.omim.org/entry/613026"},{"mim_id":"612939","title":"HEAT-SHOCK 70-KD PROTEIN-BINDING PROTEIN 1; HSPBP1","url":"https://www.omim.org/entry/612939"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":92.5}],"url":"https://www.proteinatlas.org/search/WTIP"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"A6NIX2","domains":[{"cath_id":"2.10.110.10","chopping":"366-416","consensus_level":"medium","plddt":89.1706,"start":366,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NIX2","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NIX2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NIX2-F1-predicted_aligned_error_v6.png","plddt_mean":64.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WTIP","jax_strain_url":"https://www.jax.org/strain/search?query=WTIP"},"sequence":{"accession":"A6NIX2","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NIX2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NIX2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NIX2"}},"corpus_meta":[{"pmid":"20616046","id":"PMC_20616046","title":"LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for microRNA-mediated gene silencing.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20616046","citation_count":53,"is_preprint":false},{"pmid":"22378287","id":"PMC_22378287","title":"19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias.","date":"2012","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22378287","citation_count":43,"is_preprint":false},{"pmid":"23213452","id":"PMC_23213452","title":"Wtip and Vangl2 are required for mitotic spindle orientation and cloaca morphogenesis.","date":"2012","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/23213452","citation_count":32,"is_preprint":false},{"pmid":"27062996","id":"PMC_27062996","title":"Prickle3 synergizes with Wtip to regulate basal body organization and cilia growth.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27062996","citation_count":31,"is_preprint":false},{"pmid":"20086015","id":"PMC_20086015","title":"Podocyte injury induces nuclear translocation of WTIP via microtubule-dependent transport.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20086015","citation_count":25,"is_preprint":false},{"pmid":"21900451","id":"PMC_21900451","title":"WT1-interacting protein (Wtip) regulates podocyte phenotype by cell-cell and cell-matrix contact reorganization.","date":"2011","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21900451","citation_count":24,"is_preprint":false},{"pmid":"27033705","id":"PMC_27033705","title":"Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27033705","citation_count":23,"is_preprint":false},{"pmid":"34930905","id":"PMC_34930905","title":"WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34930905","citation_count":19,"is_preprint":false},{"pmid":"29661847","id":"PMC_29661847","title":"The Ajuba family protein Wtip regulates actomyosin contractility during vertebrate neural tube closure.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29661847","citation_count":18,"is_preprint":false},{"pmid":"19785987","id":"PMC_19785987","title":"The LIM domain protein Wtip interacts with the receptor tyrosine kinase Ror2 and inhibits canonical Wnt signalling.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19785987","citation_count":16,"is_preprint":false},{"pmid":"34710136","id":"PMC_34710136","title":"Identification of the centrosomal maturation factor SSX2IP as a Wtip-binding partner by targeted proximity biotinylation.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34710136","citation_count":12,"is_preprint":false},{"pmid":"26385183","id":"PMC_26385183","title":"Role of Asxl1 in kidney podocyte development via its interaction with Wtip.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26385183","citation_count":11,"is_preprint":false},{"pmid":"25065743","id":"PMC_25065743","title":"WTIP interacts with ASXL2 and blocks ASXL2-mediated activation of retinoic acid signaling.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25065743","citation_count":9,"is_preprint":false},{"pmid":"21686224","id":"PMC_21686224","title":"Out on a LIM: chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP).","date":"2011","source":"Transactions of the American Clinical and Climatological Association","url":"https://pubmed.ncbi.nlm.nih.gov/21686224","citation_count":9,"is_preprint":false},{"pmid":"24376653","id":"PMC_24376653","title":"Wtip- and gadd45a-interacting protein dendrin is not crucial for the development or maintenance of the glomerular filtration barrier.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24376653","citation_count":8,"is_preprint":false},{"pmid":"30179602","id":"PMC_30179602","title":"Identification of the UBA2-WTIP fusion gene in acute myeloid leukemia.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30179602","citation_count":5,"is_preprint":false},{"pmid":"27484451","id":"PMC_27484451","title":"Wtip is required for proepicardial organ specification and cardiac left/right asymmetry in zebrafish.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27484451","citation_count":5,"is_preprint":false},{"pmid":"35862649","id":"PMC_35862649","title":"Essential role of Wtip in mouse development and maintenance of the glomerular filtration barrier.","date":"2022","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35862649","citation_count":4,"is_preprint":false},{"pmid":"27535760","id":"PMC_27535760","title":"WTIP interacts with BRCA2 and is essential for BRCA2 centrosome localization in cervical cancer cell.","date":"2016","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/27535760","citation_count":4,"is_preprint":false},{"pmid":"36439396","id":"PMC_36439396","title":"AJUBA and WTIP can compete with LIMD1 for junctional localization and LATS regulation.","date":"2022","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/36439396","citation_count":3,"is_preprint":false},{"pmid":"35671065","id":"PMC_35671065","title":"Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy.","date":"2022","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35671065","citation_count":3,"is_preprint":false},{"pmid":"40279682","id":"PMC_40279682","title":"DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer.","date":"2025","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40279682","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12196,"output_tokens":4965,"usd":0.055531,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13202,"output_tokens":5632,"usd":0.103405,"stage2_stop_reason":"end_turn"},"total_usd":0.158936,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"WTIP (along with LIMD1 and Ajuba) localizes to processing bodies (P-bodies) and binds Ago1/2, RCK, Dcp2, and eIF4E in vivo, acting as a molecular link between the translationally inhibited eIF4E-m7GTP-5' cap and Ago1/2 within the miRISC complex to facilitate miRNA-mediated (but not siRNA-mediated) gene silencing via an inhibitory closed-loop complex.\",\n      \"method\": \"Co-immunoprecipitation, m7GTP cap-binding assay, P-body localization imaging, knockdown functional assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for multiple binding partners, functional KD showing miRNA-specific (not siRNA) silencing defect, replicated across three family members with orthogonal methods\",\n      \"pmids\": [\"20616046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Upon LPS-induced podocyte injury, WTIP translocates from cell contacts to the nucleus via a mechanism requiring JNK activity, assembly of a JNK-interacting protein 3/dynein scaffolding complex, intact microtubule networks, and dynein motor activity. Loss of WTIP from cell contacts alters podocyte morphology and actin assembly.\",\n      \"method\": \"Live imaging, cellular fractionation, pharmacological inhibition of JNK/dynein/microtubules, shRNA knockdown, co-immunoprecipitation of JIP3-dynein complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, imaging, pharmacological inhibitors, KD phenotype), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"20086015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WTIP regulates podocyte actin dynamics and adherens junction assembly: it targets focal adhesions in isolated cells and shifts to adherens junctions upon cell-cell contact; knockdown disrupts actin stress fiber formation, focal adhesion maturation, and stable adherens junction assembly. WTIP overexpression induces RhoA-dependent stress fibers and directly interacts with the RhoA-specific GEF ARHGEF12.\",\n      \"method\": \"shRNA knockdown, overexpression, RhoA inhibition (C3 toxin, ROCK inhibitor), co-immunoprecipitation, cell surface biotinylation\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function with specific readouts, direct binding to ARHGEF12 by Co-IP, RhoA pathway placed by pharmacological rescue\",\n      \"pmids\": [\"21900451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WTIP physically interacts with the intracellular domain of the receptor tyrosine kinase Ror2; full-length Ror2 recruits WTIP to the cell membrane, while a disease-causing Ror2 mutant fails to do so. WTIP inhibits canonical Wnt signaling in mammalian cells and in Xenopus embryos.\",\n      \"method\": \"Co-immunoprecipitation, cell membrane localization assay, Wnt/β-catenin luciferase reporter assay, Xenopus overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional Wnt reporter assay in two systems, single lab\",\n      \"pmids\": [\"19785987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, Wtip is enriched at the basal body; wtip knockdown causes pronephric cyst formation, mitotic spindle orientation defects (in anterior/middle pronephros), cloaca malformation with reduced ciliated cells, loss of striated rootlet from basal bodies, and impaired cilia motility. Genetic interaction with vangl2 (a core PCP protein) was demonstrated.\",\n      \"method\": \"Morpholino knockdown, immunolocalization, spindle orientation assay, cilia motility analysis, genetic epistasis (double knockdown)\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple defined cellular phenotypes, genetic epistasis with Vangl2, direct basal body localization\",\n      \"pmids\": [\"23213452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nephrin signaling suppresses Hippo pathway activity through WTIP: phosphorylated nephrin recruits Nck, which sequesters WTIP and its binding partner Lats1, resulting in decreased phospho-activation of Lats1. Upon nephrin dephosphorylation during podocyte injury, Lats1 is rapidly activated, preceding YAP downregulation.\",\n      \"method\": \"Mutational analysis of Nck/nephrin interaction, co-immunoprecipitation, mouse podocyte injury model with phospho-Lats1 and YAP quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutational dissection of complex, in vivo mouse model with temporal phosphorylation readout, multiple orthogonal methods\",\n      \"pmids\": [\"27033705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wtip physically associates with Prickle3 and cooperates with it to regulate ciliogenesis; Wtip is required for basal body organization in Xenopus GRP cells, and co-depletion or interference phenotypes link Wtip to Prickle3-mediated cilia growth.\",\n      \"method\": \"Co-immunoprecipitation, morpholino knockdown in Xenopus, immunolocalization of basal body markers (γ-tubulin, Nedd1)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic cooperativity, single lab, Xenopus model\",\n      \"pmids\": [\"27062996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wtip regulates actomyosin contractility and apical constriction during neural tube closure in Xenopus: depletion inhibits apical constriction in neuroepithelial cells and causes neural tube defects. The C-terminal LIM domain fragment of Wtip physically associates with Shroom3 and interferes with Shroom3-induced apical constriction. Wtip junctional distribution is reorganized by myosin II activity, indicating tension-sensitive localization.\",\n      \"method\": \"Morpholino depletion, fluorescent protein tagging/live imaging, co-immunoprecipitation, myosin II inhibition (blebbistatin)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding to Shroom3 by Co-IP, loss-of-function with specific apical constriction phenotype, tension-sensitive relocalization with pharmacological perturbation\",\n      \"pmids\": [\"29661847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WTIP directly interacts with ASXL2 and represses ASXL2-mediated activation of retinoic acid-dependent transcription in HeLa cells, blocking ASXL2's stimulatory effect on retinoic acid signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"25065743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WTIP physically interacts with ASXL1; in Asxl1-null mouse kidneys, defects in podocyte morphology and upregulation of Wt1/Wtip target genes are observed, implicating Asxl1 in maintaining podocyte structure via its association with Wtip.\",\n      \"method\": \"Co-immunoprecipitation, Asxl1 knockout mouse analysis, target gene expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo KO phenotype with gene expression readout, single lab\",\n      \"pmids\": [\"26385183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dendrin physically interacts with WTIP (and Gadd45a) at the podocyte slit diaphragm, as demonstrated by yeast two-hybrid and co-immunoprecipitation. Dendrin relocalizes to the nucleus in adriamycin nephropathy, paralleling WTIP nuclear translocation behavior.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, dendrin knockout mouse, immunolocalization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus Co-IP for interaction, functional KO showed dendrin is dispensable but interaction with WTIP is confirmed\",\n      \"pmids\": [\"24376653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WTIP interacts with BRCA2 (amino acids 2750–2864) and is required for BRCA2 centrosome localization; knockdown of WTIP abolishes BRCA2 centrosomal localization and causes abnormal cell division in HeLa S3 cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, shRNA knockdown, immunofluorescence\",\n      \"journal\": \"Archives of gynecology and obstetrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by pull-down and Co-IP, functional KD with centrosome phenotype, single lab\",\n      \"pmids\": [\"27535760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A UBA2-WTIP fusion gene (containing UBA2 N-terminal domains fused to WTIP C-terminal LIM domains) was identified in AML; ectopic expression enhances cell proliferation, induces phosphorylation of STAT3, STAT5, and ERK1/2, and abrogates WTIP-mediated P-body formation.\",\n      \"method\": \"RT-PCR, Sanger sequencing, ectopic expression in KG-1a cells, proliferation assay, Western blot for phospho-signaling, P-body formation assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fusion gene characterized by multiple methods, gain-of-function with signaling readouts, single lab\",\n      \"pmids\": [\"30179602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WTIP induces apoptosis in AML cells through transcriptional upregulation and nuclear translocation of FOXO3a; WTIP directly interacts with FOXO3a, activates FOXO3a transcriptionally, which increases PUMA expression and activates the intrinsic apoptotic pathway.\",\n      \"method\": \"Overexpression/knockdown, co-immunoprecipitation (WTIP-FOXO3a), luciferase reporter, in vitro and in vivo proliferation/apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding plus transcriptional reporter plus in vivo tumor model, single lab\",\n      \"pmids\": [\"34930905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WTIP N-terminal domain physically associates with SSX2IP (a centriolar satellite protein/cell junction component); the two proteins form mixed aggregates when overexpressed, and double depletion of Wtip and SSX2IP in Xenopus embryos shows functional interaction during neural tube closure.\",\n      \"method\": \"Targeted proximity biotinylation (TPB), co-immunoprecipitation, colocalization imaging, double morpholino depletion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel proximity biotinylation method plus Co-IP confirmation plus genetic epistasis, single lab\",\n      \"pmids\": [\"34710136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WTIP interacts with ARHGEF12 (a RhoA-specific GEF) through LIM and PDZ-binding domains with high affinity; this interaction is proposed to regulate slit diaphragm and foot process function through Rho effector proteins. Wtip gene trap homozygotes are embryonic lethal.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, Wtip gene trap mouse model\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped Co-IP interaction, in vivo KO lethality, single lab; replicates ARHGEF12 interaction from 2011 paper with domain resolution\",\n      \"pmids\": [\"35862649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of WTIP in MCF10A cells competes with LIMD1 for junctional localization, reduces junctional localization of LATS1, and is associated with increased YAP1 phosphorylation and decreased YAP1 nuclear localization, suggesting WTIP cannot efficiently recruit Lats kinases to junctions (unlike LIMD1) and may act as a tumor suppressor partly by competing with LIMD1.\",\n      \"method\": \"Overexpression in MCF10A cells, immunofluorescence quantification of junctional localization, YAP1 phosphorylation and nuclear localization assay\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single overexpression approach with multiple cellular readouts, single lab\",\n      \"pmids\": [\"36439396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WTIP knockdown in neonatal rat ventricular myocytes causes cardiomyocyte hypertrophy; a disease-causing variant WTIP p.Y233F disrupts binding to a Wnt signaling protein, causes increased resting calcium and cellular hypertrophy in iPSC-derived cardiomyocytes (ameliorated by verapamil), linking WTIP to calcium dysregulation and cardiac hypertrophy.\",\n      \"method\": \"lentiviral shRNA knockdown in neonatal rat cardiomyocytes, morpholino knockdown in zebrafish, iPSC-derived cardiomyocyte characterization, calcium imaging, verapamil rescue\",\n      \"journal\": \"Circulation. Genomic and precision medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (rat, zebrafish, human iPSC), pharmacological rescue, single lab\",\n      \"pmids\": [\"35671065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WTIP interacts with PP2A to inhibit T308 phosphorylation and kinase activity of AKT, thereby suppressing stemness and chemoresistance in gastric cancer. TET2 and PATZ1 cooperate to transcriptionally activate WTIP expression, and this TET2-WTIP axis is frequently silenced in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation (WTIP-PP2A), AKT kinase activity assay, TET2/PATZ1 transcriptional activation assays, shRNA knockdown functional assays\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding to PP2A plus functional AKT phosphorylation readout plus transcriptional upstream regulation, single lab\",\n      \"pmids\": [\"40279682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In zebrafish, Wtip protein localizes to the basal body of proepicardial organ (PE) cells; Wtip signaling in conjunction with WT1 is essential for PE specification. Wtip knockdown disrupts cardiac looping, left-right asymmetry, and atrioventricular boundary formation.\",\n      \"method\": \"Morpholino knockdown in zebrafish, mRNA overexpression, immunolocalization, PE marker expression analysis\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function in zebrafish with specific marker readouts, basal body localization, single lab\",\n      \"pmids\": [\"27484451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WTIP is a LIM-domain scaffold protein (Ajuba family) that functions at cell junctions, basal bodies, and in the nucleus: at cell junctions it regulates RhoA activity via ARHGEF12, assembles adherens junctions and focal adhesions, suppresses Hippo signaling by sequestering LATS1 (through Nck at phospho-nephrin), and inhibits canonical Wnt signaling via Ror2; it localizes to basal bodies where it is required for ciliogenesis, mitotic spindle orientation, and PCP (cooperating with Vangl2 and Prickle3); it undergoes JNK/dynein/microtubule-dependent nuclear translocation upon injury to repress WT1 transcriptional activity; it facilitates miRNA-mediated gene silencing by bridging the 5' cap (via eIF4E) to Ago1/2-miRISC; and it regulates apoptosis in AML through direct interaction with FOXO3a and downstream PUMA induction, and suppresses AKT activity through PP2A interaction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WTIP is a LIM-domain scaffold protein that operates at cell junctions, the basal body, and the nucleus to couple cytoskeletal architecture and mechanical tension to signaling and transcriptional control [#2, #4]. At adherens junctions and focal adhesions it organizes the actin cytoskeleton, driving RhoA-dependent stress fiber formation and adherens junction assembly through direct binding to the RhoA-specific GEF ARHGEF12, an interaction mapped to its LIM and PDZ-binding domains [#2, #15]. Through this junctional platform WTIP integrates Hippo signaling: phospho-nephrin recruits Nck to sequester WTIP together with LATS1, restraining LATS1 activation, and WTIP can compete with LIMD1 for junctional LATS1 recruitment to modulate YAP phosphorylation and nuclear localization [#5, #16]. WTIP also localizes to basal bodies, where it is required for ciliogenesis, mitotic spindle orientation, and planar cell polarity in cooperation with Vangl2 and Prickle3, and it controls actomyosin-driven apical constriction during neural tube closure via the C-terminal LIM domain binding Shroom3, with junctional distribution itself being myosin II tension-sensitive [#4, #6, #7]. In the cytoplasm WTIP bridges the eIF4E-bound 5' cap to Ago1/2 within miRISC at P-bodies to facilitate miRNA-mediated silencing [#0], and upon podocyte injury it undergoes JNK/dynein/microtubule-dependent nuclear translocation, where it intersects WT1-linked transcriptional programs [#1]. WTIP additionally functions in cancer contexts, inducing apoptosis in AML through direct FOXO3a interaction and PUMA induction, and suppressing AKT activity via PP2A in gastric cancer [#13, #18]. A disease-causing WTIP variant (p.Y233F) is linked to calcium dysregulation and cardiomyocyte hypertrophy [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established WTIP as a signaling effector by showing it binds the Ror2 receptor tyrosine kinase intracellular domain and inhibits canonical Wnt signaling, placing it in a receptor-coupled pathway.\",\n      \"evidence\": \"Co-IP, membrane localization, Wnt/\\u03b2-catenin reporter in mammalian cells and Xenopus\",\n      \"pmids\": [\"19785987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain of WTIP mediating Ror2 binding not mapped\", \"Mechanism by which WTIP represses \\u03b2-catenin output unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a cytoplasmic post-transcriptional role: WTIP links the translationally repressed eIF4E-capped mRNA to Ago1/2-miRISC at P-bodies, answering how miRISC is coupled to the cap for silencing.\",\n      \"evidence\": \"Co-IP, m7GTP cap-binding assay, P-body imaging, knockdown silencing assays\",\n      \"pmids\": [\"20616046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity for miRNA over siRNA silencing mechanism not fully explained\", \"Stoichiometry within the closed-loop complex unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed how WTIP relocates from junctions to the nucleus upon injury, identifying a JNK/JIP3-dynein/microtubule-dependent transport mechanism.\",\n      \"evidence\": \"Live imaging, fractionation, JNK/dynein/microtubule inhibition, Co-IP of JIP3-dynein, shRNA\",\n      \"pmids\": [\"20086015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear transcriptional targets of WTIP not directly identified here\", \"Cargo adaptor coupling WTIP to dynein not pinpointed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected WTIP to cytoskeletal control by demonstrating it directs RhoA-dependent actin/adhesion dynamics through direct ARHGEF12 binding.\",\n      \"evidence\": \"shRNA, overexpression, C3/ROCK inhibition rescue, Co-IP, surface biotinylation in podocytes\",\n      \"pmids\": [\"21900451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WTIP activates or localizes ARHGEF12 not resolved\", \"Link between RhoA control and other WTIP pathways unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a basal-body/ciliary function: WTIP is required for ciliogenesis, spindle orientation, and PCP, with genetic interaction with the core PCP gene vangl2.\",\n      \"evidence\": \"Morpholino knockdown, immunolocalization, spindle/cilia assays, vangl2 epistasis in zebrafish\",\n      \"pmids\": [\"23213452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role of WTIP at the basal body not biochemically defined\", \"Direct PCP partners not identified in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended WTIP's transcriptional repressor role by showing it binds ASXL2 and blocks retinoic acid-dependent transcription.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, luciferase reporter in HeLa\",\n      \"pmids\": [\"25065743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of repression of ASXL2 activity unknown\", \"Physiological context not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked WTIP to chromatin-associated regulation in vivo via ASXL1, with Asxl1 loss causing podocyte defects and dysregulation of Wt1/Wtip target genes.\",\n      \"evidence\": \"Co-IP, Asxl1 knockout mouse, target gene expression\",\n      \"pmids\": [\"26385183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional contribution of WTIP to ASXL1 activity not isolated\", \"Target gene set not mechanistically defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a junction-to-Hippo mechanism: phospho-nephrin/Nck sequesters WTIP and LATS1 to restrain LATS1 activation, linking slit diaphragm integrity to YAP regulation.\",\n      \"evidence\": \"Mutational dissection of Nck/nephrin, Co-IP, mouse podocyte injury with phospho-LATS1/YAP readouts\",\n      \"pmids\": [\"27033705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WTIP physically engages LATS1 not structurally resolved\", \"Generality beyond podocytes not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed WTIP cooperates with the PCP protein Prickle3 to organize the basal body and support ciliogenesis.\",\n      \"evidence\": \"Co-IP, morpholino knockdown, basal body marker imaging in Xenopus\",\n      \"pmids\": [\"27062996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Xenopus model\", \"Domain of WTIP binding Prickle3 not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked WTIP to mitotic fidelity by showing it is required for BRCA2 centrosome localization.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, GST pull-down, shRNA, immunofluorescence in HeLa S3\",\n      \"pmids\": [\"27535760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence beyond abnormal division not detailed\", \"Relationship to basal body role unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected WTIP basal-body function to organ patterning by showing it acts with WT1 in proepicardial specification and cardiac laterality in zebrafish.\",\n      \"evidence\": \"Morpholino knockdown, mRNA overexpression, immunolocalization, PE markers in zebrafish\",\n      \"pmids\": [\"27484451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical WTIP-WT1 interaction not shown here\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated WTIP couples mechanical tension to morphogenesis: its LIM domain binds Shroom3 to regulate actomyosin-driven apical constriction during neural tube closure, with tension-sensitive junctional localization.\",\n      \"evidence\": \"Morpholino depletion, live imaging, Co-IP, blebbistatin perturbation in Xenopus\",\n      \"pmids\": [\"29661847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WTIP positively or negatively tunes Shroom3 in vivo not fully resolved\", \"Mechanosensing mechanism not biochemically defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a UBA2-WTIP fusion in AML that disrupts WTIP P-body function and drives proliferative signaling, implicating WTIP loss-of-function in leukemogenesis.\",\n      \"evidence\": \"RT-PCR, sequencing, ectopic expression, proliferation and phospho-signaling assays, P-body assay in KG-1a\",\n      \"pmids\": [\"30179602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the fusion is driver or passenger not established\", \"Mechanism of STAT/ERK activation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a pro-apoptotic tumor-suppressor role: WTIP directly binds and transcriptionally activates FOXO3a to induce PUMA and intrinsic apoptosis in AML.\",\n      \"evidence\": \"Overexpression/knockdown, Co-IP, luciferase reporter, in vitro and in vivo apoptosis assays\",\n      \"pmids\": [\"34930905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How WTIP enhances FOXO3a transcription mechanistically unknown\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed WTIP N-terminus associates with the centriolar satellite protein SSX2IP, with functional interaction during neural tube closure, expanding its centrosome/basal body interactome.\",\n      \"evidence\": \"Targeted proximity biotinylation, Co-IP, colocalization, double morpholino depletion in Xenopus\",\n      \"pmids\": [\"34710136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of the WTIP-SSX2IP complex not defined\", \"Aggregate formation physiological relevance unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the WTIP-ARHGEF12 interaction to LIM/PDZ-binding domains and established WTIP as essential in vivo via embryonic-lethal gene-trap homozygotes.\",\n      \"evidence\": \"Co-IP, domain mapping, Wtip gene trap mouse\",\n      \"pmids\": [\"35862649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of embryonic lethality not pinpointed\", \"Direct effect on Rho effector activity not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed WTIP competes with LIMD1 for junctional LATS1 recruitment, with overexpression increasing YAP1 phosphorylation, suggesting a Hippo-modulating tumor-suppressor mechanism.\",\n      \"evidence\": \"Overexpression in MCF10A, junctional localization and YAP1 phosphorylation/nuclear assays\",\n      \"pmids\": [\"36439396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single overexpression approach\", \"Endogenous competition dynamics not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked WTIP to cardiac disease by showing knockdown causes cardiomyocyte hypertrophy and a p.Y233F variant disrupts Wnt-protein binding and causes calcium dysregulation reversible by verapamil.\",\n      \"evidence\": \"shRNA in rat cardiomyocytes, zebrafish morpholino, iPSC-cardiomyocytes, calcium imaging, verapamil rescue\",\n      \"pmids\": [\"35671065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the Wnt protein partner not specified\", \"Mechanism connecting variant to calcium handling unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a kinase-suppressing role: WTIP binds PP2A to inhibit AKT T308 phosphorylation and reduce stemness/chemoresistance in gastric cancer, regulated upstream by a TET2-PATZ1 axis.\",\n      \"evidence\": \"Co-IP, AKT kinase activity assay, TET2/PATZ1 transcriptional assays, shRNA functional assays\",\n      \"pmids\": [\"40279682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether WTIP recruits PP2A directly to AKT not shown\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WTIP's distinct activities — junctional RhoA/Hippo scaffolding, basal-body/PCP function, cytoplasmic miRISC bridging, and nuclear transcriptional regulation — are coordinated within one protein, and how its domains partition among these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating LIM and PDZ-binding domain functions\", \"Mechanism switching WTIP between junctional, ciliary, and nuclear pools not defined\", \"Tissue-specific partner selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4, 6, 11, 19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 16, 18]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\"miRISC\", \"P-body\"],\n    \"partners\": [\"ARHGEF12\", \"LATS1\", \"Ror2\", \"Shroom3\", \"Prickle3\", \"FOXO3a\", \"PP2A\", \"SSX2IP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}