{"gene":"PHIP","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2000,"finding":"PHIP (PH-interacting protein) selectively binds to the pleckstrin homology (PH) domain of IRS-1 in vitro and stably associates with IRS-1 in vivo. Mutants of the IRS-1 PH domain that disrupt the PH fold fail to bind PHIP. Overexpression of the PH-binding region of PHIP (dominant-negative) inhibits insulin-induced IRS-1 tyrosine phosphorylation and attenuates insulin-stimulated MAP kinase activity.","method":"In vitro binding assay, co-immunoprecipitation, dominant-negative overexpression with phosphotyrosine immunoblotting and MAPK activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro and in vivo binding with functional readout (MAPK, IRS-1 phosphorylation), single lab, two orthogonal methods","pmids":["11018022"],"is_preprint":false},{"year":2007,"finding":"A larger 1,821-aa WD40 repeat-containing isoform of PHIP (PHIP1) is expressed prominently in the nucleus of pancreatic beta-cells. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation via transcriptional upregulation of the cyclin D2 promoter. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression blocks free fatty acid-induced apoptosis through activation of PKB/AKT and inhibition of caspase-9 and caspase-3; this cytoprotective effect is attenuated by dominant-negative PKB.","method":"Cloning and expression of novel isoform, immunoblotting, immunohistochemistry, RNA interference, cyclin D2 promoter reporter assay, dominant-negative PKB overexpression, caspase cleavage assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, RNAi, dominant-negative, caspase assays), single lab","pmids":["17636024"],"is_preprint":false},{"year":2017,"finding":"BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse ESCs, and Drosophila. PHIP binds directly to H3K4 methylation through a novel chromatin-binding module related to Royal Family Tudor domains (named CryptoTudor domain). PHIP associates biochemically with the CUL4-RING ubiquitin E3 ligase (CRL4) complex, nucleosomes, and chromatin remodelers. CRISPR-Cas9 knockout of COMPASS H3K4 methyltransferase family members differentially regulates BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation patterns at enhancers and promoters.","method":"Genome-wide ChIP-seq, biochemical pulldown/Co-IP of CRL4 complex, CRISPR-Cas9 knockout, direct histone binding assay, Drosophila genetic depletion with RNA-seq and ChIP-seq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay identifying new domain, genome-wide occupancy data, orthogonal genetic and biochemical methods, functional validation in multiple species","pmids":["29089422"],"is_preprint":false},{"year":2018,"finding":"RepID/DCAF14/PHIP (a WD-40 protein) recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing an architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative SKP2-containing SCF ubiquitin ligase to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, triggering massive genome re-replication. RepID and SKP2 interact with distinct, non-overlapping groups of replication origins.","method":"RepID depletion (knockdown/knockout), chromatin fractionation, origin firing analysis, SKP2 inhibitor sensitivity assays, genome re-replication assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined molecular and cellular phenotype, epistasis with SCF/SKP2, multiple orthogonal readouts, single lab with rigorous controls","pmids":["30018425"],"is_preprint":false},{"year":2020,"finding":"The RepID/DCAF14/PHIP-CRL4 ubiquitin ligase complex regulates the metaphase-to-anaphase transition. During mitosis, CRL4 dissociates from RepID and associates with RBBP7, which ubiquitinates the SAC mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by association with PML nuclear bodies. Deficiencies in RepID, CRL4, or RBBP7 delay mitotic exit, increase genomic instability, and enhance sensitivity to paclitaxel.","method":"Co-immunoprecipitation, ubiquitination assay, live-cell imaging, RepID/RBBP7 knockdown/knockout with mitotic exit timing, genomic instability assays, PML body fractionation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted ubiquitination of BUB3 by CRL4-RBBP7, multiple orthogonal methods, clear mechanistic pathway from RepID to BUB3 degradation and mitotic exit","pmids":["31911655"],"is_preprint":false},{"year":2020,"finding":"Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repress POMC transcription in cell-based assays.","method":"Cell-based transcription assays with wild-type and mutant PHIP variants, nuclear localization of PHIP confirmed","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional regulation demonstrated in cells with disease-associated variants, single lab, limited methodological detail in abstract","pmids":["32492392"],"is_preprint":false},{"year":2020,"finding":"PHIP localizes to the leading edge of glioblastoma cells and to the force transduction layer of the focal adhesion complex together with vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), phospho-paxillin, and phospho-FAK. Immunoprecipitation revealed a direct physical interaction between PHIP and VCL. Suppression of PHIP downregulates focal adhesion proteins and disorganizes stress fibers. PHIP silencing significantly suppresses glioblastoma migration and invasion, partially restored by TLN1 or ZYX cDNA overexpression.","method":"Immunofluorescence, confocal microscopy, co-immunoprecipitation, shRNA knockdown, live-cell imaging with ZYX-GFP, cDNA rescue, intracranial implantation tumor model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP confirming physical interaction, localization by confocal to specific focal adhesion layer, loss-of-function with rescue experiment defining pathway, multiple orthogonal methods","pmids":["32273388"],"is_preprint":false},{"year":2021,"finding":"PHIP/BRWD2 is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader module: a CryptoTudor domain that reads H3K4 methylation, bromodomain 1 (BD1) that reads H3K14ac, and bromodomain 2 (BD2) that reads H4K12ac, characterized using semisynthetic nucleosomes with defined histone PTMs. Human disease-associated mutations in BD1, BD2, and the linker region disrupt chromatin binding.","method":"Semisynthetic nucleosome binding assays with defined histone PTMs, mutagenesis of BD1/BD2/linker, CRL4 chromatin recruitment assay, structural/domain analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted binding with semisynthetic nucleosomes, mutagenesis of reader domains, multiple PTM readouts defined, disease mutations validated functionally","pmids":["34819353"],"is_preprint":false},{"year":2021,"finding":"DCAF14/PHIP localizes rapidly to stalled replication forks and promotes genome integrity by preventing fork collapse into double-strand breaks. CRL4-DCAF14 mediates stalled fork protection in a RAD51-dependent manner, protecting nascent DNA from MRE11 and DNA2 nucleases.","method":"iPOND (isolation of proteins on nascent DNA) or proximity ligation assay for fork localization, DNA fiber assay for fork protection, DSB measurement, RAD51 epistasis, nuclease inhibition experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization to stalled forks, epistasis with RAD51 and nucleases MRE11/DNA2, multiple orthogonal assays (fiber assay, DSB quantification), mechanistic pathway defined","pmids":["33503431"],"is_preprint":false},{"year":2018,"finding":"PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP inhibits tumor cell proliferation and invasion, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1 in melanoma, breast, and lung cancer cell lines.","method":"Bromodomain binding assay (H4K91ac specificity), shRNA knockdown with proliferation and invasion assays, immunoblotting for pAKT, cyclin D1, talin1","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct bromodomain-histone binding assay plus loss-of-function phenotype, single lab, limited structural detail in abstract","pmids":["29866840"],"is_preprint":false},{"year":2012,"finding":"Systemic shRNA-mediated suppression of Phip inhibited metastatic progression of melanoma in vivo. Stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice.","method":"Plasmid-based shRNA in vivo, stable shRNA knockdown in melanoma cell lines, metastasis assays, survival analysis in tumor-bearing mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined metastatic phenotype, single lab, functional readout but limited mechanistic resolution in abstract","pmids":["22511720"],"is_preprint":false},{"year":2023,"finding":"PHIP promotes ubiquitination and degradation of CDK2, leading to G0/G1 growth arrest in colorectal cancer cells. PHIP transcription is regulated by DNMT3B-mediated promoter methylation downstream of the TRIM25/Sp1/DNMT3B axis.","method":"Western blotting, protein degradation assay, luciferase reporter, RNA-IP, RNA pulldown, EdU and soft agar assays, xenograft model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CDK2 ubiquitination and degradation by PHIP established by protein degradation assay and western blot, multiple methods, single lab","pmids":["37742010"],"is_preprint":false},{"year":2016,"finding":"Genotype-phenotype analysis of individuals with PHIP haploinsufficiency points toward PHIP/DCAF14 isoform (not NDRP) as the cause of the intellectual disability-overweight syndrome, implicating the CUL4-DDB1 ubiquitin ligase pathway (PHIP1/DCAF14 is a substrate receptor of this complex) in the neurodevelopmental phenotype.","method":"MIP-based targeted sequencing, phenotypic correlation of 23 individuals with PHIP mutations, isoform-specific genotype-phenotype analysis","journal":"European journal of human genetics : EJHG","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genotype-phenotype inference without direct functional experiment on the specific isoform; pathway placement is inferred, not experimentally reconstituted","pmids":["29209020"],"is_preprint":false}],"current_model":"PHIP (also known as DCAF14/RepID/BRWD2) is a chromatin-associated scaffold protein that acts as a substrate receptor for the CRL4 (CUL4-RING) ubiquitin E3 ligase complex; it recruits CRL4 to replication origins to license DNA replication, protects stalled replication forks from nuclease degradation in a RAD51-dependent manner, and triggers mitotic exit by enabling CRL4-RBBP7-mediated ubiquitination and degradation of the spindle assembly checkpoint mediator BUB3. PHIP reads multiple histone modifications through a trivalent chromatin reader module comprising a CryptoTudor domain (H3K4me), bromodomain 1 (H3K14ac), and bromodomain 2 (H4K12ac), and its chromatin occupancy is regulated by COMPASS-family H3K4 methyltransferases. Through its WD40/IRS-1 PH-domain-interacting region, PHIP also modulates insulin/IGF-1 signaling (promoting beta-cell growth and survival via AKT/cyclin D2), regulates focal adhesion dynamics and actin cytoskeleton organization (interacting physically with vinculin) to drive cell motility and invasion, directly enhances POMC transcription to regulate energy homeostasis, and promotes CDK2 degradation to control cell cycle progression; loss-of-function mutations cause Chung-Jansen syndrome characterized by intellectual disability, obesity, and behavioral abnormalities."},"narrative":{"mechanistic_narrative":"PHIP (DCAF14/RepID/BRWD2) is a chromatin-associated WD40 scaffold that functions as a substrate receptor for the CRL4 (CUL4-RING) ubiquitin E3 ligase, coupling histone-mark recognition to ubiquitin-dependent control of genome replication and cell division [PMID:29089422, PMID:30018425, PMID:34819353]. It engages chromatin through a trivalent reader module — a CryptoTudor domain reading H3K4 methylation together with two bromodomains reading H3K14ac (BD1) and H4K12ac (BD2) — and this reader activity, modulated by COMPASS-family H3K4 methyltransferases, positions PHIP genome-wide and is required for CRL4 recruitment to chromatin; disease-associated mutations in BD1, BD2, and the linker disrupt chromatin binding [PMID:29089422, PMID:34819353]. Through CRL4 recruitment, PHIP licenses replication origins prior to S phase, and its loss forces dependence on the alternative SKP2/SCF pathway and triggers genome re-replication [PMID:30018425]. PHIP also localizes rapidly to stalled replication forks, where CRL4-DCAF14 protects nascent DNA from MRE11 and DNA2 nucleases in a RAD51-dependent manner to prevent fork collapse [PMID:33503431], and it drives the metaphase-to-anaphase transition by enabling CRL4-RBBP7-mediated ubiquitination and degradation of the spindle-assembly-checkpoint mediator BUB3 [PMID:31911655]. Independently of its replication roles, nuclear PHIP directly enhances POMC transcription to regulate energy homeostasis [PMID:32492392], and it modulates focal adhesion dynamics and actin organization through a direct interaction with vinculin to promote cancer cell migration and invasion [PMID:32273388]. An earlier-characterized activity links PHIP to insulin/IGF-1 signaling via the IRS-1 PH domain, promoting beta-cell proliferation and survival through AKT and cyclin D2 [PMID:11018022, PMID:17636024]. Haploinsufficiency of PHIP causes an intellectual disability-overweight (Chung-Jansen) syndrome [PMID:29209020].","teleology":[{"year":2000,"claim":"Established PHIP's founding biochemical identity as a PH-domain-interacting partner that couples to insulin signaling, answering what protein selectively binds the IRS-1 PH domain.","evidence":"In vitro binding, co-IP, and dominant-negative overexpression with IRS-1 phosphorylation and MAPK readouts","pmids":["11018022"],"confidence":"Medium","gaps":["Does not define a catalytic activity for PHIP","Connection to chromatin/CRL4 functions not yet known","Single lab, in vitro binding"]},{"year":2007,"claim":"Identified a nuclear WD40 isoform and linked PHIP to beta-cell proliferation and survival, extending its signaling role into transcriptional and cytoprotective outputs.","evidence":"Isoform cloning, RNAi, cyclin D2 promoter reporter, dominant-negative PKB, and caspase cleavage assays in beta-cells","pmids":["17636024"],"confidence":"Medium","gaps":["Mechanism linking PHIP to cyclin D2 promoter not resolved","Whether nuclear function depends on CRL4 not addressed","Single cell-type focus"]},{"year":2012,"claim":"Demonstrated that PHIP is functionally required for cancer metastasis, motivating later mechanistic dissection of how it drives invasion.","evidence":"Systemic and stable shRNA suppression in melanoma cell lines with metastasis and survival assays in mice","pmids":["22511720"],"confidence":"Medium","gaps":["No molecular mechanism for the metastatic phenotype defined","Effector pathway unidentified at this stage"]},{"year":2016,"claim":"Genotype-phenotype analysis pinned the PHIP/DCAF14 isoform as the cause of an intellectual disability-overweight syndrome and implicated the CRL4 pathway in the neurodevelopmental phenotype.","evidence":"MIP-based targeted sequencing and isoform-specific phenotypic correlation across 23 individuals","pmids":["29209020"],"confidence":"Low","gaps":["Pathway placement inferred, not experimentally reconstituted","No functional assay on the specific isoform","Causality at the molecular level not established"]},{"year":2017,"claim":"Defined PHIP as a chromatin reader that binds H3K4 methylation through a novel CryptoTudor domain and associates with CRL4, reframing PHIP as a chromatin-coupled E3 ligase adaptor.","evidence":"Genome-wide ChIP-seq, direct histone binding assay, CRL4 Co-IP, CRISPR knockout of COMPASS members, and cross-species genetic depletion","pmids":["29089422"],"confidence":"High","gaps":["CRL4 substrates downstream of chromatin recruitment not yet identified","Full PTM combinatorics of the reader module not resolved here"]},{"year":2018,"claim":"Showed PHIP recruits CRL4 to replication origins to license DNA replication, establishing its architectural role in origin function and an epistatic relationship with the SKP2/SCF pathway.","evidence":"RepID depletion, chromatin fractionation, origin firing and re-replication assays, SKP2 inhibitor sensitivity","pmids":["30018425"],"confidence":"High","gaps":["The relevant CRL4 substrate at origins not defined","How RepID and SKP2 partition distinct origins mechanistically unclear"]},{"year":2018,"claim":"Confirmed PHIP's bromodomain reads an acetyl mark (H4K91ac) and linked PHIP loss to coordinate suppression of pAKT, cyclin D1, and talin1, connecting chromatin reading to proliferation and invasion.","evidence":"Bromodomain binding assay and shRNA knockdown with proliferation/invasion and immunoblot readouts across multiple cancer lines","pmids":["29866840"],"confidence":"Medium","gaps":["Direct causal chain from bromodomain binding to pAKT/cyclin D1/talin1 not reconstituted","Limited structural detail"]},{"year":2020,"claim":"Revealed a mitotic role: CRL4 switches partner from RepID to RBBP7 to ubiquitinate and degrade BUB3, driving the metaphase-to-anaphase transition.","evidence":"Co-IP, reconstituted BUB3 ubiquitination, live-cell mitotic timing, RepID/RBBP7 perturbation, PML body fractionation","pmids":["31911655"],"confidence":"High","gaps":["Signal controlling the RepID-to-RBBP7 handoff unknown","How PML bodies sequester BUB3 in interphase mechanistically unclear"]},{"year":2020,"claim":"Established a direct transcriptional role for nuclear PHIP at the POMC locus, providing a molecular route from PHIP to energy homeostasis and the obesity phenotype.","evidence":"Cell-based transcription assays comparing wild-type and obesity-associated PHIP variants","pmids":["32492392"],"confidence":"Medium","gaps":["Direct vs chromatin-mediated mechanism at POMC not dissected","Limited methodological detail","In vivo relevance not shown here"]},{"year":2020,"claim":"Placed PHIP at focal adhesions in direct contact with vinculin, defining a cytoskeletal mechanism for PHIP-driven cancer cell migration and invasion.","evidence":"Confocal localization, Co-IP with vinculin, shRNA knockdown with TLN1/ZYX rescue, and intracranial tumor model","pmids":["32273388"],"confidence":"High","gaps":["How a chromatin reader also operates at focal adhesions structurally unresolved","Whether CRL4 participates at adhesions unknown"]},{"year":2021,"claim":"Resolved the full trivalent reader module (CryptoTudor + BD1 + BD2 reading H3K4me/H3K14ac/H4K12ac) and showed it is required for CRL4 chromatin recruitment, with disease mutations disrupting binding.","evidence":"Semisynthetic nucleosome binding with defined PTMs, mutagenesis of BD1/BD2/linker, and CRL4 recruitment assay","pmids":["34819353"],"confidence":"High","gaps":["High-resolution structure of the assembled module not reported","Combinatorial PTM dependence in vivo not fully mapped"]},{"year":2021,"claim":"Defined PHIP's role in fork protection: CRL4-DCAF14 localizes to stalled forks and shields nascent DNA from MRE11/DNA2 nucleases in a RAD51-dependent manner.","evidence":"Fork localization assay, DNA fiber and DSB measurements, RAD51 epistasis, and nuclease inhibition","pmids":["33503431"],"confidence":"High","gaps":["Relevant CRL4-DCAF14 ubiquitination substrate at forks not identified","How RAD51 and PHIP cooperate mechanistically unresolved"]},{"year":2023,"claim":"Linked PHIP to CDK2 turnover, showing PHIP promotes CDK2 ubiquitination/degradation and G0/G1 arrest, and is itself controlled by a TRIM25/Sp1/DNMT3B promoter-methylation axis.","evidence":"Protein degradation assay, western blot, luciferase reporter, RNA-IP/pulldown, EdU/soft agar, and xenograft in colorectal cancer cells","pmids":["37742010"],"confidence":"Medium","gaps":["Whether CDK2 degradation is CRL4-dependent not established","Direct vs indirect role of PHIP in CDK2 ubiquitination unresolved"]},{"year":null,"claim":"How a single chromatin reader/CRL4 adaptor coordinates its distinct nuclear (replication, mitosis, transcription) and cytoplasmic (focal adhesion, IRS-1 signaling) activities, and which CRL4 substrates execute the replication and fork-protection roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["CRL4-DCAF14 substrates at origins and stalled forks unidentified","Mechanistic basis for cytoplasmic vs nuclear partitioning unknown","Whether disease phenotypes arise from chromatin-reading or signaling defects undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,7,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,8,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,3,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[3]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]}],"complexes":["CRL4 (CUL4-RING) ubiquitin ligase","focal adhesion complex"],"partners":["CUL4","DDB1","RBBP7","IRS-1","VCL","TLN1","ITGB1","BUB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WWQ0","full_name":"PH-interacting protein","aliases":["DDB1- and CUL4-associated factor 14","IRS-1 PH domain-binding protein","WD repeat-containing protein 11"],"length_aa":1821,"mass_kda":206.7,"function":"Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8WWQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHIP","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"NUMA1","stoichiometry":4.0},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"NCK1","stoichiometry":0.2},{"gene":"NECAP1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHIP","total_profiled":1310},"omim":[{"mim_id":"617991","title":"CHUNG-JANSEN SYNDROME; CHUJANS","url":"https://www.omim.org/entry/617991"},{"mim_id":"617824","title":"BROMODOMAIN AND WD REPEAT DOMAIN-CONTAINING PROTEIN 1; BRWD1","url":"https://www.omim.org/entry/617824"},{"mim_id":"612870","title":"PLECKSTRIN HOMOLOGY DOMAIN-INTERACTING PROTEIN; PHIP","url":"https://www.omim.org/entry/612870"},{"mim_id":"603756","title":"ATP-BINDING CASSETTE, SUBFAMILY G, MEMBER 2; ABCG2","url":"https://www.omim.org/entry/603756"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli rim","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHIP"},"hgnc":{"alias_symbol":["ndrp","BRWD2","RepID","DCAF14","FLJ20705"],"prev_symbol":["WDR11"]},"alphafold":{"accession":"Q8WWQ0","domains":[{"cath_id":"-","chopping":"2-121","consensus_level":"medium","plddt":81.6739,"start":2,"end":121},{"cath_id":"2.130.10.10","chopping":"165-410_423-604_724-732","consensus_level":"medium","plddt":92.6936,"start":165,"end":732},{"cath_id":"-","chopping":"953-1062","consensus_level":"medium","plddt":86.2257,"start":953,"end":1062},{"cath_id":"2.30.30.1040","chopping":"1066-1148","consensus_level":"medium","plddt":87.0736,"start":1066,"end":1148},{"cath_id":"1.20.920.10","chopping":"1158-1280","consensus_level":"medium","plddt":90.1076,"start":1158,"end":1280},{"cath_id":"1.20.920.10","chopping":"1320-1433","consensus_level":"medium","plddt":89.1552,"start":1320,"end":1433}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWQ0-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHIP","jax_strain_url":"https://www.jax.org/strain/search?query=PHIP"},"sequence":{"accession":"Q8WWQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WWQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WWQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWQ0"}},"corpus_meta":[{"pmid":"30190553","id":"PMC_30190553","title":"PhIP-Seq characterization of serum antibodies using oligonucleotide-encoded peptidomes.","date":"2018","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/30190553","citation_count":154,"is_preprint":false},{"pmid":"8055652","id":"PMC_8055652","title":"Metabolic activation pathway for the formation of DNA adducts of the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat extrahepatic tissues.","date":"1994","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8055652","citation_count":147,"is_preprint":false},{"pmid":"1576716","id":"PMC_1576716","title":"Reaction of the N2-acetoxy derivative of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with 2'-deoxyguanosine and DNA. Synthesis and identification of N2-(2'-deoxyguanosin-8-yl)-PhIP.","date":"1992","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/1576716","citation_count":128,"is_preprint":false},{"pmid":"12949046","id":"PMC_12949046","title":"Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes.","date":"2003","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/12949046","citation_count":94,"is_preprint":false},{"pmid":"8330355","id":"PMC_8330355","title":"32P-postlabeling analysis of IQ, MeIQx and PhIP adducts formed in vitro in DNA and polynucleotides and found in vivo in hepatic DNA from IQ-, MeIQx- and PhIP-treated monkeys.","date":"1993","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8330355","citation_count":93,"is_preprint":false},{"pmid":"8222059","id":"PMC_8222059","title":"Enzymatic phase II activation of the N-hydroxylamines of IQ, MeIQx and PhIP by various organs of monkeys and 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symposia","url":"https://pubmed.ncbi.nlm.nih.gov/8844812","citation_count":18,"is_preprint":false},{"pmid":"10050262","id":"PMC_10050262","title":"Inhibition of DNA adduct formation of PhIP in female F344 rats by dietary conjugated linoleic acid.","date":"1998","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10050262","citation_count":18,"is_preprint":false},{"pmid":"36857108","id":"PMC_36857108","title":"Real-Time Pyruvate Chemical Conversion Monitoring Enabled by PHIP.","date":"2023","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/36857108","citation_count":17,"is_preprint":false},{"pmid":"23400709","id":"PMC_23400709","title":"2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in benign prostate and subsequent risk for prostate cancer.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23400709","citation_count":17,"is_preprint":false},{"pmid":"36101433","id":"PMC_36101433","title":"PhIP-Seq Reveals Autoantibodies for Ubiquitously Expressed Antigens in Viral Myocarditis.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36101433","citation_count":17,"is_preprint":false},{"pmid":"11593414","id":"PMC_11593414","title":"Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11593414","citation_count":17,"is_preprint":false},{"pmid":"10050263","id":"PMC_10050263","title":"Effects of dietary conjugated linoleic acid on DNA adduct formation of PhIP and IQ after bolus administration to female F344 rats.","date":"1998","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10050263","citation_count":17,"is_preprint":false},{"pmid":"9288881","id":"PMC_9288881","title":"Pancreatic DNA adducts formed in vitro and in vivo by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alphaC).","date":"1997","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/9288881","citation_count":16,"is_preprint":false},{"pmid":"17081492","id":"PMC_17081492","title":"Hydroxyl-specific fluorescence labeling of ABP-deoxyguanosine, PhIP-deoxyguanosine, and AFB1-formamidopyrimidine with BODIPY-FL.","date":"2006","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17081492","citation_count":16,"is_preprint":false},{"pmid":"33503431","id":"PMC_33503431","title":"DCAF14 promotes stalled fork stability to maintain genome integrity.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33503431","citation_count":15,"is_preprint":false},{"pmid":"37742010","id":"PMC_37742010","title":"LINC00955 suppresses colorectal cancer growth by acting as a molecular scaffold of TRIM25 and Sp1 to Inhibit DNMT3B-mediated methylation of the PHIP promoter.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37742010","citation_count":15,"is_preprint":false},{"pmid":"18375078","id":"PMC_18375078","title":"The microbial PhIP metabolite 7-hydroxy-5-methyl-3-phenyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidin-5-ium chloride (PhIP-M1) induces DNA damage, apoptosis and cell cycle arrest towards Caco-2 cells.","date":"2008","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/18375078","citation_count":15,"is_preprint":false},{"pmid":"29953158","id":"PMC_29953158","title":"A comparison of mutagenic PhIP and beneficial 8-C-(E-phenylethenyl)quercetin and 6-C-(E-phenylethenyl)quercetin formation under microwave and conventional heating.","date":"2018","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/29953158","citation_count":15,"is_preprint":false},{"pmid":"10418945","id":"PMC_10418945","title":"Dietary omega-3 fatty acids as potential inhibitors of carcinogenesis: effect on DNA adduct formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice and rats.","date":"1999","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/10418945","citation_count":15,"is_preprint":false},{"pmid":"12628517","id":"PMC_12628517","title":"Direct reduction of N-acetoxy-PhIP by tea polyphenols: a possible mechanism for chemoprevention against PhIP-DNA adduct formation.","date":"2003","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12628517","citation_count":14,"is_preprint":false},{"pmid":"31569368","id":"PMC_31569368","title":"6-Shogaol Suppresses 2-Amino-1-Methyl-6-Phenylimidazo [4,5-b] Pyridine (PhIP)-Induced Human 786-O Renal Cell Carcinoma Osteoclastogenic Activity and Metastatic Potential.","date":"2019","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/31569368","citation_count":14,"is_preprint":false},{"pmid":"23313794","id":"PMC_23313794","title":"Effects of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) on histopathology, oxidative stress, and expression of c-fos, c-jun and p16 in rat stomachs.","date":"2013","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/23313794","citation_count":14,"is_preprint":false},{"pmid":"10082914","id":"PMC_10082914","title":"Mutant yields and mutational spectra of the heterocyclic amines MeIQ and PhIP at the S1 locus of human-hamster AL cells with activation by chick embryo liver (CELC) co-cultures.","date":"1999","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/10082914","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":60554,"output_tokens":4060,"usd":0.121281,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11927,"output_tokens":4888,"usd":0.090917,"stage2_stop_reason":"end_turn"},"total_usd":0.212198,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"PHIP (PH-interacting protein) selectively binds to the pleckstrin homology (PH) domain of IRS-1 in vitro and stably associates with IRS-1 in vivo. Mutants of the IRS-1 PH domain that disrupt the PH fold fail to bind PHIP. Overexpression of the PH-binding region of PHIP (dominant-negative) inhibits insulin-induced IRS-1 tyrosine phosphorylation and attenuates insulin-stimulated MAP kinase activity.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, dominant-negative overexpression with phosphotyrosine immunoblotting and MAPK activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro and in vivo binding with functional readout (MAPK, IRS-1 phosphorylation), single lab, two orthogonal methods\",\n      \"pmids\": [\"11018022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A larger 1,821-aa WD40 repeat-containing isoform of PHIP (PHIP1) is expressed prominently in the nucleus of pancreatic beta-cells. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation via transcriptional upregulation of the cyclin D2 promoter. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression blocks free fatty acid-induced apoptosis through activation of PKB/AKT and inhibition of caspase-9 and caspase-3; this cytoprotective effect is attenuated by dominant-negative PKB.\",\n      \"method\": \"Cloning and expression of novel isoform, immunoblotting, immunohistochemistry, RNA interference, cyclin D2 promoter reporter assay, dominant-negative PKB overexpression, caspase cleavage assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, RNAi, dominant-negative, caspase assays), single lab\",\n      \"pmids\": [\"17636024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse ESCs, and Drosophila. PHIP binds directly to H3K4 methylation through a novel chromatin-binding module related to Royal Family Tudor domains (named CryptoTudor domain). PHIP associates biochemically with the CUL4-RING ubiquitin E3 ligase (CRL4) complex, nucleosomes, and chromatin remodelers. CRISPR-Cas9 knockout of COMPASS H3K4 methyltransferase family members differentially regulates BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation patterns at enhancers and promoters.\",\n      \"method\": \"Genome-wide ChIP-seq, biochemical pulldown/Co-IP of CRL4 complex, CRISPR-Cas9 knockout, direct histone binding assay, Drosophila genetic depletion with RNA-seq and ChIP-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay identifying new domain, genome-wide occupancy data, orthogonal genetic and biochemical methods, functional validation in multiple species\",\n      \"pmids\": [\"29089422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RepID/DCAF14/PHIP (a WD-40 protein) recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing an architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative SKP2-containing SCF ubiquitin ligase to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, triggering massive genome re-replication. RepID and SKP2 interact with distinct, non-overlapping groups of replication origins.\",\n      \"method\": \"RepID depletion (knockdown/knockout), chromatin fractionation, origin firing analysis, SKP2 inhibitor sensitivity assays, genome re-replication assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined molecular and cellular phenotype, epistasis with SCF/SKP2, multiple orthogonal readouts, single lab with rigorous controls\",\n      \"pmids\": [\"30018425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The RepID/DCAF14/PHIP-CRL4 ubiquitin ligase complex regulates the metaphase-to-anaphase transition. During mitosis, CRL4 dissociates from RepID and associates with RBBP7, which ubiquitinates the SAC mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by association with PML nuclear bodies. Deficiencies in RepID, CRL4, or RBBP7 delay mitotic exit, increase genomic instability, and enhance sensitivity to paclitaxel.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, live-cell imaging, RepID/RBBP7 knockdown/knockout with mitotic exit timing, genomic instability assays, PML body fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted ubiquitination of BUB3 by CRL4-RBBP7, multiple orthogonal methods, clear mechanistic pathway from RepID to BUB3 degradation and mitotic exit\",\n      \"pmids\": [\"31911655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repress POMC transcription in cell-based assays.\",\n      \"method\": \"Cell-based transcription assays with wild-type and mutant PHIP variants, nuclear localization of PHIP confirmed\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional regulation demonstrated in cells with disease-associated variants, single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"32492392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHIP localizes to the leading edge of glioblastoma cells and to the force transduction layer of the focal adhesion complex together with vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), phospho-paxillin, and phospho-FAK. Immunoprecipitation revealed a direct physical interaction between PHIP and VCL. Suppression of PHIP downregulates focal adhesion proteins and disorganizes stress fibers. PHIP silencing significantly suppresses glioblastoma migration and invasion, partially restored by TLN1 or ZYX cDNA overexpression.\",\n      \"method\": \"Immunofluorescence, confocal microscopy, co-immunoprecipitation, shRNA knockdown, live-cell imaging with ZYX-GFP, cDNA rescue, intracranial implantation tumor model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP confirming physical interaction, localization by confocal to specific focal adhesion layer, loss-of-function with rescue experiment defining pathway, multiple orthogonal methods\",\n      \"pmids\": [\"32273388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHIP/BRWD2 is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader module: a CryptoTudor domain that reads H3K4 methylation, bromodomain 1 (BD1) that reads H3K14ac, and bromodomain 2 (BD2) that reads H4K12ac, characterized using semisynthetic nucleosomes with defined histone PTMs. Human disease-associated mutations in BD1, BD2, and the linker region disrupt chromatin binding.\",\n      \"method\": \"Semisynthetic nucleosome binding assays with defined histone PTMs, mutagenesis of BD1/BD2/linker, CRL4 chromatin recruitment assay, structural/domain analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted binding with semisynthetic nucleosomes, mutagenesis of reader domains, multiple PTM readouts defined, disease mutations validated functionally\",\n      \"pmids\": [\"34819353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DCAF14/PHIP localizes rapidly to stalled replication forks and promotes genome integrity by preventing fork collapse into double-strand breaks. CRL4-DCAF14 mediates stalled fork protection in a RAD51-dependent manner, protecting nascent DNA from MRE11 and DNA2 nucleases.\",\n      \"method\": \"iPOND (isolation of proteins on nascent DNA) or proximity ligation assay for fork localization, DNA fiber assay for fork protection, DSB measurement, RAD51 epistasis, nuclease inhibition experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization to stalled forks, epistasis with RAD51 and nucleases MRE11/DNA2, multiple orthogonal assays (fiber assay, DSB quantification), mechanistic pathway defined\",\n      \"pmids\": [\"33503431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP inhibits tumor cell proliferation and invasion, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1 in melanoma, breast, and lung cancer cell lines.\",\n      \"method\": \"Bromodomain binding assay (H4K91ac specificity), shRNA knockdown with proliferation and invasion assays, immunoblotting for pAKT, cyclin D1, talin1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct bromodomain-histone binding assay plus loss-of-function phenotype, single lab, limited structural detail in abstract\",\n      \"pmids\": [\"29866840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Systemic shRNA-mediated suppression of Phip inhibited metastatic progression of melanoma in vivo. Stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice.\",\n      \"method\": \"Plasmid-based shRNA in vivo, stable shRNA knockdown in melanoma cell lines, metastasis assays, survival analysis in tumor-bearing mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined metastatic phenotype, single lab, functional readout but limited mechanistic resolution in abstract\",\n      \"pmids\": [\"22511720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHIP promotes ubiquitination and degradation of CDK2, leading to G0/G1 growth arrest in colorectal cancer cells. PHIP transcription is regulated by DNMT3B-mediated promoter methylation downstream of the TRIM25/Sp1/DNMT3B axis.\",\n      \"method\": \"Western blotting, protein degradation assay, luciferase reporter, RNA-IP, RNA pulldown, EdU and soft agar assays, xenograft model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CDK2 ubiquitination and degradation by PHIP established by protein degradation assay and western blot, multiple methods, single lab\",\n      \"pmids\": [\"37742010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genotype-phenotype analysis of individuals with PHIP haploinsufficiency points toward PHIP/DCAF14 isoform (not NDRP) as the cause of the intellectual disability-overweight syndrome, implicating the CUL4-DDB1 ubiquitin ligase pathway (PHIP1/DCAF14 is a substrate receptor of this complex) in the neurodevelopmental phenotype.\",\n      \"method\": \"MIP-based targeted sequencing, phenotypic correlation of 23 individuals with PHIP mutations, isoform-specific genotype-phenotype analysis\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genotype-phenotype inference without direct functional experiment on the specific isoform; pathway placement is inferred, not experimentally reconstituted\",\n      \"pmids\": [\"29209020\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHIP (also known as DCAF14/RepID/BRWD2) is a chromatin-associated scaffold protein that acts as a substrate receptor for the CRL4 (CUL4-RING) ubiquitin E3 ligase complex; it recruits CRL4 to replication origins to license DNA replication, protects stalled replication forks from nuclease degradation in a RAD51-dependent manner, and triggers mitotic exit by enabling CRL4-RBBP7-mediated ubiquitination and degradation of the spindle assembly checkpoint mediator BUB3. PHIP reads multiple histone modifications through a trivalent chromatin reader module comprising a CryptoTudor domain (H3K4me), bromodomain 1 (H3K14ac), and bromodomain 2 (H4K12ac), and its chromatin occupancy is regulated by COMPASS-family H3K4 methyltransferases. Through its WD40/IRS-1 PH-domain-interacting region, PHIP also modulates insulin/IGF-1 signaling (promoting beta-cell growth and survival via AKT/cyclin D2), regulates focal adhesion dynamics and actin cytoskeleton organization (interacting physically with vinculin) to drive cell motility and invasion, directly enhances POMC transcription to regulate energy homeostasis, and promotes CDK2 degradation to control cell cycle progression; loss-of-function mutations cause Chung-Jansen syndrome characterized by intellectual disability, obesity, and behavioral abnormalities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHIP (DCAF14/RepID/BRWD2) is a chromatin-associated WD40 scaffold that functions as a substrate receptor for the CRL4 (CUL4-RING) ubiquitin E3 ligase, coupling histone-mark recognition to ubiquitin-dependent control of genome replication and cell division [#2, #3, #7]. It engages chromatin through a trivalent reader module — a CryptoTudor domain reading H3K4 methylation together with two bromodomains reading H3K14ac (BD1) and H4K12ac (BD2) — and this reader activity, modulated by COMPASS-family H3K4 methyltransferases, positions PHIP genome-wide and is required for CRL4 recruitment to chromatin; disease-associated mutations in BD1, BD2, and the linker disrupt chromatin binding [#2, #7]. Through CRL4 recruitment, PHIP licenses replication origins prior to S phase, and its loss forces dependence on the alternative SKP2/SCF pathway and triggers genome re-replication [#3]. PHIP also localizes rapidly to stalled replication forks, where CRL4-DCAF14 protects nascent DNA from MRE11 and DNA2 nucleases in a RAD51-dependent manner to prevent fork collapse [#8], and it drives the metaphase-to-anaphase transition by enabling CRL4-RBBP7-mediated ubiquitination and degradation of the spindle-assembly-checkpoint mediator BUB3 [#4]. Independently of its replication roles, nuclear PHIP directly enhances POMC transcription to regulate energy homeostasis [#5], and it modulates focal adhesion dynamics and actin organization through a direct interaction with vinculin to promote cancer cell migration and invasion [#6]. An earlier-characterized activity links PHIP to insulin/IGF-1 signaling via the IRS-1 PH domain, promoting beta-cell proliferation and survival through AKT and cyclin D2 [#0, #1]. Haploinsufficiency of PHIP causes an intellectual disability-overweight (Chung-Jansen) syndrome [#12].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established PHIP's founding biochemical identity as a PH-domain-interacting partner that couples to insulin signaling, answering what protein selectively binds the IRS-1 PH domain.\",\n      \"evidence\": \"In vitro binding, co-IP, and dominant-negative overexpression with IRS-1 phosphorylation and MAPK readouts\",\n      \"pmids\": [\"11018022\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not define a catalytic activity for PHIP\", \"Connection to chromatin/CRL4 functions not yet known\", \"Single lab, in vitro binding\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified a nuclear WD40 isoform and linked PHIP to beta-cell proliferation and survival, extending its signaling role into transcriptional and cytoprotective outputs.\",\n      \"evidence\": \"Isoform cloning, RNAi, cyclin D2 promoter reporter, dominant-negative PKB, and caspase cleavage assays in beta-cells\",\n      \"pmids\": [\"17636024\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking PHIP to cyclin D2 promoter not resolved\", \"Whether nuclear function depends on CRL4 not addressed\", \"Single cell-type focus\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that PHIP is functionally required for cancer metastasis, motivating later mechanistic dissection of how it drives invasion.\",\n      \"evidence\": \"Systemic and stable shRNA suppression in melanoma cell lines with metastasis and survival assays in mice\",\n      \"pmids\": [\"22511720\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular mechanism for the metastatic phenotype defined\", \"Effector pathway unidentified at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genotype-phenotype analysis pinned the PHIP/DCAF14 isoform as the cause of an intellectual disability-overweight syndrome and implicated the CRL4 pathway in the neurodevelopmental phenotype.\",\n      \"evidence\": \"MIP-based targeted sequencing and isoform-specific phenotypic correlation across 23 individuals\",\n      \"pmids\": [\"29209020\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Pathway placement inferred, not experimentally reconstituted\", \"No functional assay on the specific isoform\", \"Causality at the molecular level not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PHIP as a chromatin reader that binds H3K4 methylation through a novel CryptoTudor domain and associates with CRL4, reframing PHIP as a chromatin-coupled E3 ligase adaptor.\",\n      \"evidence\": \"Genome-wide ChIP-seq, direct histone binding assay, CRL4 Co-IP, CRISPR knockout of COMPASS members, and cross-species genetic depletion\",\n      \"pmids\": [\"29089422\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"CRL4 substrates downstream of chromatin recruitment not yet identified\", \"Full PTM combinatorics of the reader module not resolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PHIP recruits CRL4 to replication origins to license DNA replication, establishing its architectural role in origin function and an epistatic relationship with the SKP2/SCF pathway.\",\n      \"evidence\": \"RepID depletion, chromatin fractionation, origin firing and re-replication assays, SKP2 inhibitor sensitivity\",\n      \"pmids\": [\"30018425\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"The relevant CRL4 substrate at origins not defined\", \"How RepID and SKP2 partition distinct origins mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed PHIP's bromodomain reads an acetyl mark (H4K91ac) and linked PHIP loss to coordinate suppression of pAKT, cyclin D1, and talin1, connecting chromatin reading to proliferation and invasion.\",\n      \"evidence\": \"Bromodomain binding assay and shRNA knockdown with proliferation/invasion and immunoblot readouts across multiple cancer lines\",\n      \"pmids\": [\"29866840\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct causal chain from bromodomain binding to pAKT/cyclin D1/talin1 not reconstituted\", \"Limited structural detail\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a mitotic role: CRL4 switches partner from RepID to RBBP7 to ubiquitinate and degrade BUB3, driving the metaphase-to-anaphase transition.\",\n      \"evidence\": \"Co-IP, reconstituted BUB3 ubiquitination, live-cell mitotic timing, RepID/RBBP7 perturbation, PML body fractionation\",\n      \"pmids\": [\"31911655\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signal controlling the RepID-to-RBBP7 handoff unknown\", \"How PML bodies sequester BUB3 in interphase mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a direct transcriptional role for nuclear PHIP at the POMC locus, providing a molecular route from PHIP to energy homeostasis and the obesity phenotype.\",\n      \"evidence\": \"Cell-based transcription assays comparing wild-type and obesity-associated PHIP variants\",\n      \"pmids\": [\"32492392\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs chromatin-mediated mechanism at POMC not dissected\", \"Limited methodological detail\", \"In vivo relevance not shown here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed PHIP at focal adhesions in direct contact with vinculin, defining a cytoskeletal mechanism for PHIP-driven cancer cell migration and invasion.\",\n      \"evidence\": \"Confocal localization, Co-IP with vinculin, shRNA knockdown with TLN1/ZYX rescue, and intracranial tumor model\",\n      \"pmids\": [\"32273388\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How a chromatin reader also operates at focal adhesions structurally unresolved\", \"Whether CRL4 participates at adhesions unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the full trivalent reader module (CryptoTudor + BD1 + BD2 reading H3K4me/H3K14ac/H4K12ac) and showed it is required for CRL4 chromatin recruitment, with disease mutations disrupting binding.\",\n      \"evidence\": \"Semisynthetic nucleosome binding with defined PTMs, mutagenesis of BD1/BD2/linker, and CRL4 recruitment assay\",\n      \"pmids\": [\"34819353\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"High-resolution structure of the assembled module not reported\", \"Combinatorial PTM dependence in vivo not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined PHIP's role in fork protection: CRL4-DCAF14 localizes to stalled forks and shields nascent DNA from MRE11/DNA2 nucleases in a RAD51-dependent manner.\",\n      \"evidence\": \"Fork localization assay, DNA fiber and DSB measurements, RAD51 epistasis, and nuclease inhibition\",\n      \"pmids\": [\"33503431\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Relevant CRL4-DCAF14 ubiquitination substrate at forks not identified\", \"How RAD51 and PHIP cooperate mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked PHIP to CDK2 turnover, showing PHIP promotes CDK2 ubiquitination/degradation and G0/G1 arrest, and is itself controlled by a TRIM25/Sp1/DNMT3B promoter-methylation axis.\",\n      \"evidence\": \"Protein degradation assay, western blot, luciferase reporter, RNA-IP/pulldown, EdU/soft agar, and xenograft in colorectal cancer cells\",\n      \"pmids\": [\"37742010\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether CDK2 degradation is CRL4-dependent not established\", \"Direct vs indirect role of PHIP in CDK2 ubiquitination unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single chromatin reader/CRL4 adaptor coordinates its distinct nuclear (replication, mitosis, transcription) and cytoplasmic (focal adhesion, IRS-1 signaling) activities, and which CRL4 substrates execute the replication and fork-protection roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"CRL4-DCAF14 substrates at origins and stalled forks unidentified\", \"Mechanistic basis for cytoplasmic vs nuclear partitioning unknown\", \"Whether disease phenotypes arise from chromatin-reading or signaling defects undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 7, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 8, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"CRL4 (CUL4-RING) ubiquitin ligase\", \"focal adhesion complex\"],\n    \"partners\": [\"CUL4\", \"DDB1\", \"RBBP7\", \"IRS-1\", \"VCL\", \"TLN1\", \"ITGB1\", \"BUB3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}